may 2009 vol. 2 no. 3

© 2009 Green Hill Healthcare Communications, LLC

Review articlesemphasizing advances in

management based on the

most up-to-date studies.

Commentaries on implications

for oncology nurses.

SOLID TUMORS

• Renal Cell Carcinoma: Review and RecentAdvances

• Prostate Cancer 2008• Recent Advances in Diagnosis and Treatment

of Breast Cancer

HEMATOLOGIC CANCERS

• Beyond Chemotherapy: Non-Hodgkin’sLymphoma Update

• Evaluating and Treating Patients with MultipleMyeloma

• Scientific Developments in the Management of Myelodysplastic Syndromes

SUPPORTIVE CARE

• Venous Thromboembolism in Patients withCancer: Current Approaches to Management

• Chemotherapy-induced Nausea and Vomiting• Oral Mucositis: The Challenging Issues Facing

Oncology Clinicians• Extravasation: Assessment and Treatment

New treatment for extravasationpage 49

Targeted therapies for renal cell carcinomapage 5

MAY 2009 • VOL. 2, NO. 3 www.theoncologynurse.com

RENAL CELL CANCER

PROSTATE CANCER

BREAST CANCER

LYMPHOMA

MYELOMA

MDS

VTE

CINV

MUCOSITIS

©iStockphoto.com

Sarah L. Scarpace, PharmD, BCOP Marianne Bunce-Houston, RN, MS, AOCNS, CRNI

First Annual Review

http://www.theoncologynurse.com

http://iStockphoto.com

* High-risk features for patients with ER/PR+ breast cancer include: tumor size >2 cm, age <35 years, and histologic and/or nuclear grade 2/3.

When treating patients with HER2+ breast cancer

HER2-positive status is associated with more aggressive disease and poorer outcomes

than HER2-negative breast cancer. Women who received 1 year of Herceptin had a

lower risk of HER2+ breast cancer returning.

We applaud you for playing such a critical role in helping patients with HER2+ breast cancer

complete the full course of treatment with Herceptin.

No one touches their

©2009 Genentech USA So. San Francisco, CA All rights reserved.

Adjuvant indications

Herceptin is indicated for adjuvant treatment of HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature*) breast cancer:s As part of a treatment regimen containing doxorubicin,

cyclophosphamide, and either paclitaxel or docetaxel

s With docetaxel and carboplatin

s As a single agent following multi-modality anthracycline-based therapy

Metastatic indications

Herceptin is indicated:s In combination with paclitaxel for first-line treatment of

HER2-overexpressing metastatic breast cancer

s As a single agent for treatment of HER2-overexpressingbreast cancer in patients who have received one or morechemotherapy regimens for metastatic disease

Boxed WARNINGS and Additional Important Safety Information

Herceptin administration can result in sub-clinical and clinical cardiac failure manifesting as congestive heart failure (CHF) and decreased left ventricular ejection fraction (LVEF). The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.

Patients should undergo monitoring for decreased left ventricular function before Herceptin treatment, and frequently during and after Herceptin treatment. More frequent monitoring should be employed if Herceptin is

lives like you

9568900 01/09

www.herceptin.com

Please see brief summary of full Prescribing Information, including Boxed WARNINGS and additional important safety information, on the following pages.

withheld in patients who develop significant left ventricular cardiac dysfunction. In one adjuvant clinical trial, cardiac ischemia or infarction occurred in the Herceptin-containing regimens.

Serious infusion reactions and pulmonary toxicity have occurred; fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Exacerbation of chemotherapy-induced neutropenia has also occurred. Herceptin can cause oligohydramnios and fetal harm

when administered to a pregnant woman. The most common adverse reactions associated with Herceptin use were fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

http://www.herceptin.com

HERCEPTIN® (trastuzumab)Brief Summary For full Prescribing Information, see package insert.

WARNING: CARDIOMYOPATHY, INFUSION REACTIONS, and PULMONARY TOXICITY Cardiomyopathy Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function. [see Warnings and Precautions and Dosage and Administration]Infusion Reactions; Pulmonary Toxicity Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. [see Warnings and Precautions]

INDICATIONS AND USAGE Adjuvant Breast Cancer Herceptin is indicated for adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature [see Clinical Studies/��1A40BC�20=24A�K��B�?0AC�>5�0�CA40C<4=C�A468<4=�consisting of doxorubicin, Cyclophosphamide, and either ?02;8C0G4;�>A�3>24C0G4;�K�,8C7�3>24C0G4;�0=3�20A1>?;0C8=�K��B�0�B8=6;4�064=C�5>;;>F8=6�<D;C8�<>30;8CH�0=C7A02H2;8=4�based therapy. Metastatic Breast Cancer Herceptin 8B� 8=3820C43�� K� =� 2><18=0C8>=� F8C7� ?02;8C0G4;� 5>A� 58ABC�;8=4� CA40C<4=C� >5� ��'��>E4A4G?A4BB8=6� <4C0BC0C82�1A40BC� 20=24A� K� �B� 0� B8=6;4� 064=C� 5>A� CA40C<4=C� >5��'��>E4A4G?A4BB8=6� 1A40BC� 20=24A� 8=� ?0C84=CB� F7>�have received one or more chemotherapy regimens for metastatic disease. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Cardiomyopathy Herceptin can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death [see Boxed Warning: Cardiomyopathy] . Herceptin can also cause asymptomatic decline in left ventricular ejection fraction (LVEF). There is a 4–6 fold increase in the incidence of symptomatic myocardial dysfunction among patients receiving Herceptin as a single agent or in combination therapy compared with those not receiving Herceptin. The highest absolute incidence occurs when Herceptin is 03<8=8BC4A43�F8C7�0=�0=C7A02H2;8=4��,8C77>;3��4A24?C8=�for ��01B>;DC4�342A40B4� 8=�"+��5A><�?A4�CA40C<4=C�values or an LVEF value below institutional limits of normal and �� 01B>;DC4� 342A40B4� 8=� "+�� 5A><� ?A4�treatment values. [see Dosage and Administration] The safety of continuation or resumption of Herceptin in ?0C84=CB�F8C7��4A24?C8=�8=3D243�;45C�E4=CA82D;0A�20A3802�dysfunction has not been studied. Cardiac Monitoring Conduct thorough cardiac assessment, including history, physical examination, and determination >5� "+�� 1H� 427>20A38>6A0<� >A� #*�� B20=�� )74�5>;;>F8=6� B2743D;4� 8B� A42><<4=343�� K� �0B4;8=4� "+��measurement immediately prior to initiation of Herceptin K� "+�� <40BDA4<4=CB� 4E4AH� � <>=C7B� 3DA8=6� 0=3� D?>=�2><?;4C8>=�>5��4A24?C8=�K�'4?40C�"+��<40BDA4<4=C�0C�4 week intervals if Herceptin is withheld for significant left ventricular cardiac dysfunction [see Dosage and Administration/� K� "+�� <40BDA4<4=CB� 4E4AH� �� <>=C7B�for at least 2 years following completion of Herceptin as a component of adjuvant therapy. In Study 1, 16% �� >5� ?0C84=CB� 38B2>=C8=D43� �4A24?C8=� 3D4� C>�clinical evidence of myocardial dysfunction or significant 342;8=4� 8=�"+�� =�(CD3H� �� C74�=D<14A�>5�?0C84=CB�F7>�discontinued Herceptin due to cardiac toxicity was �� =� (CD3H� �� 0� C>C0;� >5� �� ?0C84=CB� 8=�C74�)��0A<��3DA8=6�C74�274<>C74A0?H�?70B4�0=3��3DA8=6�C74�<>=>C74A0?H�?70B4��0=3�� ?0C84=CB� 8=� C74� ��)�� 0A<� �� 3DA8=6� C74�chemotherapy phase and 4.2% during the monotherapy phase) discontinued Herceptin due to cardiac toxicity. �<>=6� �� ?0C84=CB� A4248E8=6� 039DE0=C� 274<>C74A0?H�(Studies 1 and 2) who developed congestive heart failure, one patient died of cardiomyopathy and all other patients F4A4� A4248E8=6� 20A3802� <43820C8>=� 0C� ;0BC� 5>;;>F�D?��??A>G8<0C4;H�70;5�>5�C74�BDAE8E8=6�?0C84=CB�703�A42>E4AH�to a normal LVEF (defined as ��>=�2>=C8=D8=6�<43820;�<0=064<4=C� 0C� C74� C8<4� >5� ;0BC� 5>;;>F�D?�� =2834=24�of congestive heart failure is presented in Table 1. The safety of continuation or resumption of Herceptin in ?0C84=CB�F8C7��4A24?C8=�8=3D243�;45C�E4=CA82D;0A�20A3802�dysfunction has not been studied.

Table 1 =2834=24�>5��>=64BC8E4��40AC��08;DA4�8=��39DE0=C��A40BC��0=24A�(CD384B

Incidence of CHF

Study Regimen Herceptin Control

1 & 2a ACbJPaclitaxel+

Herceptin 2% (32/1677) 0.4% (7/1600)

3 ChemoJHerceptin monotherapy 2% (30/1678) 0.3% (5/1708)

4 ACbJDocetaxel+

Herceptin 2% (20/1068) 0.3% (3/1050)

4 Docetaxel+Carbo+ Herceptin 0.4% (4/1056) 0.3% (3/1050))

a Includes 1 patient with fatal cardiomyopathy.b��=C7A02H2;8=4��3>G>AD1828=��0=3�2H2;>?7>B?70<834�

Table 2 Incidence of Cardiac Dysfunctiona in Metastatic �A40BC��0=24A�(CD384B

Incidence

NYHA I-IV NYHA III-IV

Study Event Herceptin Control Herceptin Control

5 Cardiac (AC)b Dysfunction 28% 7% 19% 3%

5 Cardiac (paclitaxel) Dysfunction 11% 1% 4% 1%

6 Cardiac Dysfunctionc 7% N/A 5% N/A

aCongestive heart failure or significant asymptomatic decrease in LVEF. b�=C7A02H2;8=4��3>G>AD1828=�>A�4?8AD1828=��and cyclophosphamide. cIncludes 1 patient with fatal cardiomyopathy.

Infusion Reactions Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion included nausea, vomiting, pain (in some cases at tumor sites) , headache, dizziness, dyspnea, hypotension, rash, and asthenia. [see Adverse Reactions ] . In postmarketing reports, serious and fatal infusion reactions have been reported. Severe reactions which include bronchospasm, anaphylaxis, angioedema, hypoxia, and severe hypotension, were usually reported during or immediately following the initial infusion. However, the onset and clinical course were variable including progressive worsening, initial improvement 5>;;>F43� 1H� 2;8=820;� 34C4A8>A0C8>=�� >A� 34;0H43� ?>BC�infusion events with rapid clinical deterioration. For fatal events, death occurred within hours to days following a serious infusion reaction. Interrupt Herceptin infusion in all patients experiencing dyspnea, clinically significant hypotension, and intervention of medical therapy administered, which may include: epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered in all patients with severe infusion reactions. There are no data regarding the most appropriate method of identification of patients who may safely be retreated with Herceptin after experiencing a severe infusion reaction. Prior to resumption of Herceptin infusion, the majority of patients who experienced a severe infusion A402C8>=�F4A4�?A4�<43820C43�F8C7�0=C878BC0<8=4B�0=3>A�2>AC82>BC4A>83B��,78;4�B><4�?0C84=CB�C>;4A0C43��4A24?C8=�infusions, others had recurrent severe infusion reactions 34B?8C4�?A4�<43820C8>=B��Exacerbation of Chemotherapy-Induced Neutropenia In randomized, controlled clinical CA80;B� 8=�F><4=�F8C7�<4C0BC0C82�1A40BC�20=24A�� C74�?4A�?0C84=C�8=2834=24B�>5�$� ��)��A034� ��=4DCA>?4=80�0=3�of febrile neutropenia were higher in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was not significantly increased. [see Adverse Reactions ] . Pulmonary Toxicity Herceptin use can result in serious and fatal pulmonary toxicity. Pulmonary toxicity includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, ?;4DA0;� 455DB8>=B�� =>=�20A38>64=82� ?D;<>=0AH� 434<0��pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions [see Warnings and Precautions ] . Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity. HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for Herceptin therapy because these are the only patients studied and for whom benefit has been B7>F=��BB4BB<4=C�5>A��'��>E4A4G?A4BB8>=�0=3�>5��'��gene amplification should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, 20=� ;403� C>� D=A4;801;4� A4BD;CB�� (4E4A0;� ��0??A>E43�commercial assays are available to aid in the selection of patients for Herceptin therapy. These include HercepTestTM and Pathway®��'��=4D� � ��0BB0HB��0=3�&0C7+HB8>=® and HER2 FISH pharmDxTM (FISH assays). Users should refer to the package inserts of specific assay kits for information on the validation and performance of each assay. Limitations in assay precision (particularly for the IHC method) and in the direct linkage between assay result and overexpression of the Herceptin target (for the FISH method) make it inadvisable to rely on a single <4C7>3�C>�AD;4�>DC�?>C4=C80;��4A24?C8=�14=458C��=460C8E4�FISH result does not rule out HER2 overexpression and potential benefit from Herceptin. Treatment outcomes 5>A� <4C0BC0C82� 1A40BC� 20=24A� �(CD3H� �� 0B� 0� 5D=2C8>=� >5� �� 0=3� � (�� C4BC8=6� 0A4� ?A>E8343� 8=� )01;4� �� )A40C<4=C�>DC2><4B�5>A�039DE0=C�1A40BC�20=24A��(CD384B��0=3� ��0B�a function of IHC and FISH testing are provided in Table 7. HER2 Protein Overexpression Detection Methods HER2 protein overexpression can be established by measuring HER2 protein using an IHC method. HercepTest®, one test approved for this use, was assessed for concordance with C74� �;8=820;� )A80;� �BB0H� ��)�� DB8=6� CD<>A� B?428<4=B�collected and stored independently from those obtained in Herceptin clinical studies in women with metastatic breast cancer. Data are provided in the package insert for HercepTest®. HER2 Gene Amplification Detection Method The presence of HER2 protein overexpression and gene amplification are highly correlated, therefore the use of FISH to detect gene amplification may be employed for selection of patients appropriate for Herceptin therapy. PathVysion®, one test approved for this use, was evaluated in an exploratory, retrospective assessment >5� 0E08;01;4��)�� >A� �� CD<>A� B?428<4=B� 2>;;42C43� 0B�part of patient screening for clinical studies in metastatic 1A40BC�20=24A��(CD384B��0=3��0C0�0A4�?A>E8343�8=�C74�package insert for PathVysion®. Embryo-Fetal Toxicity (Pregnancy Category D) Herceptin can cause fetal harm F74=�03<8=8BC4A43�C>�0�?A46=0=C�F><0=��&>BC�<0A:4C8=6�case reports suggest that Herceptin use during pregnancy increases the risk of oligohydramnios during the second and third trimesters. If Herceptin is used during pregnancy

or if a woman becomes pregnant while taking Herceptin, she should be apprised of the potential hazard to a fetus. [see Use in Specific Populations ] . ADVERSE REACTIONS The following adverse reactions are discussed in greater 34C08;� 8=� >C74A� B42C8>=B� >5� C74� ;014;�� K� �0A38><H>?0C7H�[see Warnings and Precautions /� K� =5DB8>=� A402C8>=B�[see Warnings and Precautions /� K� �G024A10C8>=� >5�274<>C74A0?H�8=3D243� =4DCA>?4=80� .see Warnings and Precautions /� K� &D;<>=0AH� C>G828CH� .see Warnings and Precautions ] The most common adverse reactions in patients receiving Herceptin are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, 0=3� <H0;680�� 3E4AB4� A402C8>=B� A4@D8A8=6� 8=C4AAD?C8>=�or discontinuation of Herceptin treatment include CHF, significant decline in left ventricular cardiac function, severe infusion reactions, and pulmonary toxicity [see Dosage and Administration ] . Clinical Trials Experience �420DB4� 2;8=820;� CA80;B� 0A4� 2>=3D2C43� D=34A� F834;H�varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adjuvant Breast Cancer Studies The data below reflect exposure to �4A24?C8=�02A>BB� C7A44�A0=3><8I43��>?4=�;014;�BCD384B��(CD384B��0=3� ��F8C7� �=�� >A�F8C7>DC� �=�� trastuzumab in the adjuvant treatment of breast cancer. )74� 30C0� BD<<0A8I43� 8=� )01;4� � 14;>F�� 5A><� (CD3H� ��A45;42C� 4G?>BDA4� C>� �4A24?C8=� 8=� �� ?0C84=CB�� C74�<4380=� CA40C<4=C� 3DA0C8>=� F0B� �� F44:B� 0=3� <4380=�=D<14A� >5� 8=5DB8>=B� F0B� �� <>=6� C74� �� ?0C84=CB�4=A>;;43�8=�(CD3H� ��C74�<4380=�064�F0B��H40AB��A0=64�� C>� �� H40AB�� >5� ?0C84=CB� F4A4� �0D20B80=�� 0=3�� F4A4��B80=�

Table 3 �3E4AB4�'402C8>=B�5>A�(CD3H� ��;;��A034Ba:

MedDRA (v. 7.1) 1 Year Herceptin Observation Adverse Event Preferred Term (n= 1678) (n= 1708)

Cardiac

Hypertension 64 (4%) 35 (2%)

Dizziness 60 (4%) 29 (2%)

Ejection Fraction Decreased 58 (3.5%) 11 (0.6%)

Palpitations 48 (3%) 12 (0.7%)

Cardiac Arrhythmiasb 40 (3%) 17 (1%)

Cardiac Failure Congestive 30 (2%) 5 (0.3%)

Cardiac Failure 9 (0.5%) 4 (0.2%)

Cardiac Disorder 5 (0.3%) 0 (0%)

Ventricular Dysfunction 4 (0.2%) 0 (0%)

Respiratory Thoracic Mediastinal Disorders

Nasopharyngitis 135 (8%) 43 (3%)

Cough 81 (5%) 34 (2%)

Influenza 70 (4%) 9 (0.5%)

Dyspnea 57 (3%) 26 (2%)

URI 46 (3%) 20 (1%)

Rhinitis 36 (2%) 6 (0.4%)

Pharyngolaryngeal Pain 32 (2%) 8 (0.5%)

Sinusitis 26 (2%) 5 (0.3%)

Epistaxis 25 (2%) 1 (0.06%)

Pulmonary Hypertension 4 (0.2%) 0 (0%)

Interstitial Pneumonitis 4 (0.2%) 0 (0%)

Gastrointestinal Disorders

Diarrhea 123 (7%) 16 (1%)

Nausea 108 (6%) 19 (1%)

Vomiting 58 (3.5%) 10 (0.6%)

Constipation 33 (2%) 17 (1%)

Dyspepsia 30 (2%) 9 (0.5%)

Upper Abdominal Pain 29 (2%) 15 (1%)

Musculoskeletal & Connective Tissue Disorders

Arthralgia 137 (8%) 98 (6%)

Back Pain 91 (5%) 58 (3%)

Myalgia 63 (4%) 17 (1%)

Bone Pain 49 (3%) 26 (2%)

Muscle Spasm 46 (3%) 3 (0.2%)

Nervous System Disorders

Headache 162 (10%) 49 (3%)

Paraesthesia 29 (2%) 11 (0.6%)

Skin & Subcutaneous Tissue Disorders

Rash 70 (4%) 10 (0.6%)

Nail Disorders 43 (2%) 0 (0%)

Pruritus 40 (2%) 10 (0.6%)

General Disorders

Pyrexia 100 (6%) 6 (0.4%)

Edema Peripheral 79 (5%) 37 (2%)

Chills 85 (5%) 0 (0%)

Asthenia 75 (4.5%) 30 (2%)

Influenza-like Illness 40 (2%) 3 (0.2%)

Sudden Death 1 (0.06%) 0 (0%)

Infections

Nasopharyngitis 135 (8%) 43 (3%)

UTI 39 (3%) 13 (0.8%)

Immune System Disorders

Hypersensitivity 10 (0.6%) 1 (0.06%)

Autoimmune Thyroiditis 4 (0.3%) 0 (0%)

a�)74�8=2834=24�>5��A034� ��03E4AB4�A402C8>=B�F0B��8=�both arms for each listed term. b Higher level grouping term.

The data from Studies 1 and 2 were obtained from ��?0C84=CB�4=A>;;43��>5�F7827�� ?0C84=CB� A4248E43��4A24?C8=��C74�<4380=�CA40C<4=C�3DA0C8>=�F0B��F44:B��)74� <4380=� 064� F0B� �� H40AB� �A0=64�� >5� ?0C84=CB� F4A4� ,78C4�� 0=3� �� F4A4� �;02:�� F4A4��8B?0=82��0=3��F4A4��B80=�� =�(CD3H��>=;H��A034� J��03E4AB4� 4E4=CB�� CA40C<4=C�A4;0C43� �A034� �� 4E4=CB�� 0=3��A034��J��3HB?=40�F4A4�2>;;42C43�3DA8=6�0=3� 5>A�D?� C>� � <>=C7B� 5>;;>F8=6� ?A>C>2>;�B?4285843� CA40C<4=C�� )74�5>;;>F8=6� =>=�20A3802� 03E4AB4� A402C8>=B� >5� �A034� ��occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as 2><?0A43� C>� 274<>C74A0?H� 0;>=4�� 0AC7A0;680� � �� EB��50C86D4��EB��8=542C8>=��EB��7>C�5;0B74B��EB��0=4<80�� EB��3HB?=40��vs. 4%), rash/desquamation (11% vs. 7%), neutropenia ��EB��74030274��EB��0=3�8=B><=80�� EB�� )74� <09>A8CH� >5� C74B4� 4E4=CB� F4A4� �A034� ��in severity. In Study 2, data collection was limited to

C74� 5>;;>F8=6� 8=E4BC860C>A�0CCA81DC43� CA40C<4=C�A4;0C43�03E4AB4�A402C8>=B��$� ��)��A034��0=3��74<0C>;>682�C>G828C84B��A034� J��=>=�74<0C>;>682�C>G828C84B��B4;42C43��A034� �J�� C>G828C84B� 0BB>280C43� F8C7� C0G0=4B� �<H0;680��arthralgias, nail changes, motor neuropathy, sensory =4DA>?0C7H��0=3��A034��J��20A3802� C>G828C84B�>22DAA8=6�during chemotherapy and/or Herceptin treatment. The 5>;;>F8=6� =>=�20A3802� 03E4AB4� A402C8>=B� >5� �A034� �J��occurred at an incidence of at least 2% greater among patients randomized to Herceptin plus chemotherapy as compared to chemotherapy alone: arthralgia (11% vs. ��<H0;680� ��EB��=08;�270=64B� ��EB��0=3�3HB?=40��EB��)74�<09>A8CH�>5�C74B4�4E4=CB�were Grade 2 in severity. Safety data from Study 4 reflect exposure to Herceptin as part of an adjuvant treatment regimen from 2124 patients receiving at least one dose >5� BCD3H� CA40C<4=C� .��)�� =� �� )�� =� �� /��)74� >E4A0;;� <4380=� CA40C<4=C� 3DA0C8>=� F0B� �� F44:B�8=� 1>C7� C74� ��)�� 0=3� )�� 0A<B�� )74� <4380=� =D<14A�>5� 8=5DB8>=B�F0B��8=�C74��)��0A<�0=3� �8=�C74�)��arm, including weekly infusions during the chemotherapy phase and every three week dosing in the monotherapy ?4A8>3�� <>=6� C74B4� ?0C84=CB�� C74� <4380=� 064� F0B� ��years (range 22 to 74 years). In Study 4, the toxicity ?A>58;4�F0B�B8<8;0A�C>�C70C�A4?>AC43�8=�(CD384B��0=3� �with the exception of a low incidence of CHF in the TCH arm. Metastatic Breast Cancer Studies The data below A45;42C�4G?>BDA4� C>��4A24?C8=� 8=�>=4�A0=3><8I43��>?4=�;014;� BCD3H�� (CD3H� �� >5� 274<>C74A0?H� F8C7� �=�� >A�F8C7>DC��=�� CA0BCDID<01�8=�?0C84=CB�F8C7�<4C0BC0C82�1A40BC� 20=24A�� 0=3� >=4� B8=6;4�0A<� BCD3H� �(CD3H� ��=�� 8=� ?0C84=CB�F8C7�<4C0BC0C82� 1A40BC� 20=24A��0C0�8=�)01;4��0A4�10B43�>=�(CD384B��0=3��<>=6�C74��?0C84=CB�CA40C43�8=�(CD3H��C74�<4380=�064�F0B��H40AB��A0=64�� J�� H40AB�� 867CH�=8=4� ?4A24=C� F4A4� ,78C4��;02:��B80=�0=3��>C74A� A0280;4C7=82�6A>D?B��;;� ?0C84=CB� A4248E43� �� <6:6� 8=8C80;� 3>B4� >5� �4A24?C8=�followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for � 6 months and �� <>=C7B� F4A4� �� 0=3� �� A4B?42C8E4;H�� <>=6�C74� �� ?0C84=CB� CA40C43� 8=� B8=6;4� 064=C� BCD384B� �� ?0C84=CB� 5A><� (CD3H� �� C74� <4380=� 064� F0B� �� H40AB��A0=64� ��J�� H40AB�� 703� 1A40BC� 20=24A�� F4A4� ,78C4�� F4A4� �;02:�� F4A4� �B80=�� 0=3� ��in other racial/ethnic groups. Most of the patients received 4 mg/kg initial dose of Herceptin followed by 2 mg/kg weekly. The percentages of patients who received Herceptin treatment for � 6 months and ��<>=C7B�F4A4� ��0=3��A4B?42C8E4;H�

Table 4 &4A�&0C84=C� =2834=24� >5� �3E4AB4� '402C8>=B�Occurring in ��>5�&0C84=CB�8=�*=2>=CA>;;43�(CD384B�>A�0C� =2A40B43� =2834=24� 8=� C74��4A24?C8=��A<� �(CD384B��and 6) (Percent of Patients)

Herceptin Single + Paclitaxel Herceptin ACb

Agenta Paclitaxel Alone + ACb Alone n = 352 n = 91 n = 95 n = 143 n = 135

Body as a Whole Pain 47 61 62 57 42 Asthenia 42 62 57 54 55 Fever 36 49 23 56 34 Chills 32 41 4 35 11 Headache 26 36 28 44 31 Abdominal pain 22 34 22 23 18 Back pain 22 34 30 27 15 Infection 20 47 27 47 31 Flu syndrome 10 12 5 12 6 Accidental injury 6 13 3 9 4 Allergic reaction 3 8 2 4 2

Cardiovascular Tachycardia 5 12 4 10 5 Congestive heart failure 7 11 1 28 7

Digestive Nausea 33 51 9 76 77 Diarrhea 25 45 29 45 26 Vomiting 23 37 28 53 49 Nausea and 8 14 11 18 9 vomiting Anorexia 14 24 16 31 26

Heme & Lymphatic Anemia 4 14 9 36 26 Leukopenia 3 24 17 52 34

Metabolic Peripheral edema 10 22 20 20 17 Edema 8 10 8 11 5

Musculoskeletal Bone pain 7 24 18 7 7 Arthralgia 6 37 21 8 9

Nervous Insomnia 14 25 13 29 15 Dizziness 13 22 24 24 18 Paresthesia 9 48 39 17 11 Depression 6 12 13 20 12 Peripheral neuritis 2 23 16 2 2 Neuropathy 1 13 5 4 4

Respiratory Cough increased 26 41 22 43 29 Dyspnea 22 27 26 42 25 Rhinitis 14 22 5 22 16 Pharyngitis 12 22 14 30 18 Sinusitis 9 21 7 13 6

Skin Rash 18 38 18 27 17 Herpes simplex 2 12 3 7 9 Acne 2 11 3 3 < 1

Urogenital Urinary tract infection 5 18 14 13 7

aData for Herceptin single agent were from 4 studies, 8=2;D38=6� �� ?0C84=CB� 5A><� (CD3H� �� b�=C7A02H2;8=4�(doxorubicin or epirubicin) and cyclophosphamide.

The following subsections provide additional detail regarding adverse reactions observed in clinical

trials of adjuvant breast, metastatic breast cancer, or post-marketing experience. Cardiomyopathy Serial measurement of cardiac function (LVEF) was obtained in clinical trials in the adjuvant treatment of breast cancer. In Study 3, the median duration of follow-up was 12.6 months (12.4 months in the observation arm; 12.6 months in the 1-year Herceptin arm); and in Studies 1 and 2, 23 months in the AC-T arm, 24 months in the AC-TH arm. In Studies 1 and 2, 6% of patients were not permitted to initiate Herceptin following completion of AC chemotherapy due to cardiac dysfunction (LVEF < 50% or �15 point decline in LVEF from baseline to end of AC). Following initiation of Herceptin therapy, the incidence of new-onset dose-limiting myocardial dysfunction was higher among patients receiving Herceptin and paclitaxel as compared to those receiving paclitaxel alone in Studies 1 and 2, and in patients receiving Herceptin monotherapy compared to observation in Study 3 (see Table 5, Figures 1 and 2).

Table 5a Per-patient Incidence of New Onset Myocardial Dysfunction (by LVEF) Studies 1, 2, 3 and 4

LVEF <50% and Absolute Absolute LVEF Decrease from Baseline Decrease

LVEF � 10% � 16% <20% and <50% decrease decrease � 10% � 20%

Studies 1 & 2b ACJTH 22.8% 18.3% 11.7% 33.4% 9.2% (n=1606) (366) (294) (188) (536) (148)

ACJT 9.1% 5.4% 2.2% 18.3% 2.4% (n=1488) (136) (81) (33) (272) (36)

Study 3 Herceptin 8.6% 7.0% 3.8% 22.4% 3.5% (n=1678) (144) (118) (64) (376) (59)

Observation 2.7% 2.0% 1.2% 11.9% 1.2% (n=1708) (46) (35) (20) (204) (21)

Study 4c

TCH 8.5% 5.9% 3.3% 34.5% 6.3% (n=1056) (90) (62) (35) (364) (67)

ACJTH 17% 13.3% 9.8% 44.3% 13.2% (n=1068) (182) (142) (105) (473) (141)

ACJT 9.5% 6.6% 3.3% 34% 5.5% (n=1050) (100) (69) (35) (357) (58)

aFor Studies 1, 2 and 3, events are counted from the beginning of Herceptin treatment. For Study 4, events are counted from the date of randomization. bStudies 1 and 2 regimens: doxorubicin and cyclophosphamide followed by paclitaxel (ACJT) or paclitaxel plus Herceptin (ACJTH). cStudy 4 regimens: doxorubicin and cyclophosphamide followed by docetaxel (ACJT) or docetaxel plus Herceptin (ACJTH); docetaxel and carboplatin plus Herceptin (TCH).

Figure 1 Studies 1 and 2: Cumulative Incidence of Time to First LVEF Decline of � 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is initiation of paclitaxel or Herceptin + paclitaxel therapy.

Figure 2 Study 3: Cumulative Incidence of Time to First LVEF Decline of � 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

Figure 3 Study 4: Cumulative Incidence of Time to First LVEF Decline of � 10 Percentage Points from Baseline and to Below 50% with Death as a Competing Risk Event

Time 0 is the date of randomization.

The incidence of treatment emergent congestive heart failure among patients in the metastatic breast cancer trials was classified for severity using the New York Heart Association classification system (I–IV, where IV is the most severe level of cardiac failure) (see Table 2). In the metastatic breast cancer trials the probability of cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracyclines. Infusion Reactions During the first infusion with Herceptin, the symptoms most commonly reported were chills and fever, occurring in approximately 40% of patients in clinical trials. Symptoms were treated with acetaminophen, diphenhydramine, and meperidine (with or without reduction in the rate of Herceptin infusion); permanent discontinuation of Herceptin for infusional toxicity was required in <1% of patients. Other signs and/or symptoms may include nausea, vomiting, pain (in some cases at tumor sites), rigors, headache, dizziness, dyspnea, hypotension, elevated blood pressure, rash, and asthenia. Infusional toxicity occurred in 21% and 35% of patients, and was

severe in 1.4% and 9% of patients, on second or subsequent Herceptin infusions administered as monotherapy or in combination with chemotherapy, respectively. In the post-marketing setting, severe infusion reactions, including hypersensitivity, anaphylaxis, and angioedema have been reported. Anemia In randomized controlled clinical trials, the overall incidence of anemia (30% vs. 21% [Study 5]), of selected NCI-CTC Grade 2–5 anemia (12.5% vs. 6.6% [Study 1]), and of anemia requiring transfusions (0.1% vs. 0 patients [Study 2]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. Following the administration of Herceptin as a single agent (Study 6), the incidence of NCI-CTC Grade 3 anemia was <1%. Neutropenia In randomized controlled clinical trials in the adjuvant setting, the incidence of selected NCI-CTC Grade 4–5 neutropenia (2% vs. 0.7% [Study 2]) and of selected Grade 2–5 neutropenia (7.1% vs. 4.5 % [Study 1]) were increased in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. In a randomized, controlled trial in patients with metastatic breast cancer, the incidences of NCI-CTC Grade 3/4 neutropenia (32% vs. 22%) and of febrile neutropenia (23% vs. 17%) were also increased in patients randomized to Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Infection The overall incidences of infection (46% vs. 30% [Study 5]), of selected NCI-CTC Grade 2–5 infection/febrile neutropenia (22% vs. 14% [Study 1]) and of selected Grade 3–5 infection/febrile neutropenia (3.3% vs. 1.4%) [Study 2]), were higher in patients receiving Herceptin and chemotherapy compared with those receiving chemotherapy alone. The most common site of infections in the adjuvant setting involved the upper respiratory tract, skin, and urinary tract. In Study 4, the overall incidence of infection was higher with the addition of Herceptin to AC-T but not to TCH [44% (AC-TH), 37% (TCH), 38% (AC-T)] . The incidences of NCI-CTC grade 3-4 infection were similar [25% (AC-TH), 21% (TCH), 23% (AC-T)] across the three arms. In a randomized, controlled trial in treatment of metastatic breast cancer, the reported incidence of febrile neutropenia was higher (23% vs. 17%) in patients receiving Herceptin in combination with myelosuppressive chemotherapy as compared to chemotherapy alone. Pulmonary Toxicity Adjuvant Breast Cancer: Among women receiving adjuvant therapy for breast cancer, the incidence of selected NCI-CTC Grade 2–5 pulmonary toxicity (14% vs. 5% [Study 1]) and of selected NCI-CTC Grade 3–5 pulmonary toxicity and spontaneous reported Grade 2 dyspnea (3.4% vs. 1% [Study 2]) was higher in patients receiving Herceptin and chemotherapy compared with chemotherapy alone. The most common pulmonary toxicity was dyspnea (NCI CTC Grade 2–5: 12% vs. 4% [Study 1]; NCI-CTC Grade 2–5: 2.5% vs. 0.1% [Study 2]). Pneumonitis/pulmonary infiltrates occurred in 0.7% of patients receiving Herceptin compared with 0.3% of those receiving chemotherapy alone. Fatal respiratory failure occurred in 3 patients receiving Herceptin, one as a component of multi-organ system failure, as compared to 1 patient receiving chemotherapy alone. In Study 3, there were 4 cases of interstitial pneumonitis in Herceptin-treated patients compared to none in the control arm. Metastatic Breast Cancer: Among women receiving Herceptin for treatment of metastatic breast cancer, the incidence of pulmonary toxicity was also increased. Pulmonary adverse events have been reported in the post-marketing experience as part of the symptom complex of infusion reactions. Pulmonary events include bronchospasm, hypoxia, dyspnea, pulmonary infiltrates, pleural effusions, non-cardiogenic pulmonary edema, and acute respiratory distress syndrome. For a detailed description, see Warnings and Precautions. Thrombosis/Embolism In 4 randomized, controlled clinical trials, the incidence of thrombotic adverse events was higher in patients receiving Herceptin and chemotherapy compared to chemotherapy alone in three studies (3.0% vs. 1.3% [Study 1] , 2.5% and 3.7% vs. 2.2% [Study 4] and 2.1% vs. 0% [Study 5]). Diarrhea Among women receiving adjuvant therapy for breast cancer, the incidence of NCI-CTC Grade 2–5 diarrhea (6.2% vs. 4.8% [Study 1]) and of NCI-CTC Grade 3–5 diarrhea (1.6% vs. 0% [Study 2]), and of Grade 1–4 diarrhea (7% vs. 1% [Study 3]) were higher in patients receiving Herceptin as compared to controls. In Study 4, the incidence of Grade 3–4 diarrhea was higher [5.7% AC-TH, 5.5% TCH vs. 3.0% AC-T] and of Grade 1–4 was higher [51% AC-TH, 63% TCH vs. 43% AC-T] among women receiving Herceptin. Of patients receiving Herceptin as a single agent for the treatment of metastatic breast cancer, 25% experienced diarrhea. An increased incidence of diarrhea was observed in patients receiving Herceptin in combination with chemotherapy for treatment of metastatic breast cancer. Glomerulopathy In the post-marketing setting, rare cases of nephrotic syndrome with pathologic evidence of glomerulopathy have been reported. The time to onset ranged from 4 months to approximately 18 months from initiation of Herceptin therapy. Pathologic findings included membranous glomerulonephritis, focal glomerulosclerosis, and fibrillary glomerulonephritis. Complications included volume overload and congestive heart failure. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Among 903 women with metastatic breast cancer, human anti-human antibody (HAHA) to Herceptin was detected in one patient using an enzyme-linked immunosorbent assay (ELISA). This patient did not experience an allergic reaction. Samples for assessment of HAHA were not collected in studies of adjuvant breast cancer. The incidence of antibody formation is highly dependent on the sensitivity and the specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Herceptin with the incidence of antibodies to other products may be misleading. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category D [see Warnings and Precautions] Herceptin can cause fetal harm when administered to a pregnant woman. Post-marketing case reports suggest that Herceptin use during pregnancy increases the risk for oligohydramnios during the second and third trimester. If Herceptin is used during pregnancy or if a woman becomes pregnant while taking Herceptin,

she should be apprised of the potential hazard to a fetus. In the post-marketing setting, oligohydramnios was reported in women who received Herceptin during pregnancy, either alone or in combination with chemotherapy. In half of these women, amniotic fluid index increased after Herceptin was stopped. In one case, Herceptin was resumed after the amniotic fluid index improved, and oligohydramnios recurred. Women using Herceptin during pregnancy should be monitored for oligohydramnios. If oligohydramnios occurs, fetal testing should be done that is appropriate for gestational age and consistent with community standards of care. Additional intravenous (IV) hydration has been helpful when oligohydramnios has occurred following administration of other chemotherapy agents; however, the effects of additional IV hydration with Herceptin treatment are not known. Reproduction studies in cynomolgus monkeys at doses up to 25 times the recommended weekly human dose of 2 mg/kg trastuzumab have revealed no evidence of harm to the fetus. However, HER2 protein expression is high in many embryonic tissues including cardiac and neural tissues; in mutant mice lacking HER2, embryos died in early gestation. Placental transfer of trastuzumab during the early (Days 20-50 of gestation) and late (Days 120-150 of gestation) fetal development period was observed in monkeys. [See Nonclinical Toxicology ] Because animal reproduction studies are not always predictive of human response, Herceptin should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether Herceptin is excreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Trastuzumab was present in the breast milk of lactating cynomolgus monkeys given 12.5 times the recommended weekly human dose of 2 mg/kg of Herceptin. Infant monkeys with detectable serum levels of trastuzumab did not have any adverse effects on growth or development from birth to 3 months of age; however, trastuzumab levels in animal breast milk may not accurately reflect human breast milk levels. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from Herceptin, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of trastuzumab and the importance of the drug to the mother. Pediatric Use The safety and effectiveness of Herceptin in pediatric patients has not been established. Geriatric Use Herceptin has been administered to 386 patients who were 65 years of age or over (253 in the adjuvant treatment and 133 in metastatic breast cancer treatment settings). The risk of cardiac dysfunction was increased in geriatric patients as compared to younger patients in both those receiving treatment for metastatic disease in Studies 5 and 6, or adjuvant therapy in Studies 1 and 2. Limitations in data collection and differences in study design of the 4 studies of Herceptin in adjuvant treatment of breast cancer preclude a determination of whether the toxicity profile of Herceptin in older patients is different from younger patients. The reported clinical experience is not adequate to determine whether the efficacy improvements (ORR, TTP, OS, DFS) of Herceptin treatment in older patients is different from that observed in patients <65 years of age for metastatic disease and adjuvant treatment. OVERDOSAGE There is no experience with overdosage in human clinical trials. Single doses higher than 8 mg/kg have not been tested. PATIENT COUNSELING INFORMATION K��3E8B4�?0C84=CB�C>�2>=C02C�0�740;C7�20A4�professional immediately for any of the following: new onset or worsening shortness of breath, cough, swelling of the ankles/legs, swelling of the face, palpitations, weight gain of more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Boxed Warning: Cardiomyopathy ] . K� �3E8B4� F><4=� F8C7� A4?A>3D2C8E4� ?>C4=C80;� C>� DB4�effective contraceptive methods during treatment and for a minimum of six months following Herceptin [see Pregnancy / �� K� �=2>DA064�?A46=0=C�F><4=�F7>�0A4�DB8=6�Herceptin to enroll in the Cancer and Childbirth Registry [see Pregnancy ] .

HERCEPTIN® [trastuzumab]Manufactured by: 4839802Genentech, Inc. Initial US Approval: Sept. 19981 DNA Way Revision Date: May 2008South San Francisco, CA LK0726 717291094080-4990 9317800

©2008 Genentech USA

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OncologyNurse

TheOncologyNurse

The

The Official Newspaperof Record for

the Hem/Onc Nurse

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PublisherPhilip [email protected]

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Vol. 2, No. 3 May 2009

Green Hill Healthcare Communications LLCGreen Hill Healthcare Communications, LLCHGYour Innovative Partners in Medical Media™

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OncologyNurse

TheOncologyNurse

The

The Official Newspaperof Record for

the Hem/Onc Nurse

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EDITORIAL BOARD

EDITOR-IN-CHIEF

Beth Faiman, RN, MSN, APRN, BC,

AOCN

Cleveland Clinic Taussig

Cancer Institute

Cleveland, OH

Feature Articles5 Renal Cell Carcinoma

Renal cell carcinoma: review and recent advances

10 Prostate CancerProstate cancer 2008

14 Supportive CareVenous thromboembolism in patients with cancer: currentapproaches to management

18 Supportive CareChemotherapy-induced nausea and vomiting

23 Non-Hodgkin’s LymphomaBeyond chemotherapy: non-Hodgkin’s lymphoma update

30 Multiple MyelomaEvaluating and treating patients with multiple myeloma

Isabell Castellano, RN

Bristol-Myers Squibb Children’s Hospital

Robert Wood Johnson University Hospital

New Brunswick, NJ

Deena Damsky Dell, RN, MSN, AOCN, BC

Fox Chase Cancer Center

Philadelphia, PA

Wendy DiSalvo, BSN, MSN, FNP, AOCN

Dartmouth Hitchcock Medical Center

Norris Cotton Cancer Center

Lebanon, NH

Denice Economou, RN, MN, AOCN

City of Hope National Medical Center

Duarte, CA

Constance Engelking, RN, MS, OCN

The CHE Consulting Group, Inc.

Mt. Kisco, NY

Amy Ford, RN, BSN, OCN

Creative Cancer Concepts, Inc.

Rockwall, TX

Lyssa Friedman, RN, MPA, OCN

Veracyte, Inc

South San Francisco, CA

Sharon S. Gentry, RN, MSN, AOCN

Derrick L. Davis Forsyth Regional Cancer Center

Winston-Salem, NC

Marilyn L. Haas, PhD, RN, CNS, ANP-C

Mountain Radiation Oncology

Asheville, NC

Cassandra J. Hammond, RN, MSN, CRNP

Avid Education Partners, LLC

Sharpsburg, MD

Taline Khoukaz, NP, MSN, ACNP-C

University of Southern California

Norris Cancer Center & Hospital

Los Angeles, CA

Sandra E. Kurtin, RN, MS, AOCN, ANP-C

Arizona Cancer Center

Tucson, AZ

Ann McNeill, MSN, RN, NP-C, OCN

The Cancer Center at Hackensack University

Medical Center

Hackensack, NJ

Kena C. Miller, RN, MSN, FNP

Roswell Park Cancer Institute

Buffalo, NY

Dolores “Jeff” Nordquist, RN, MS, CS, FNP

Mayo Clinic

Rochester, MN

Melinda Oberleitner, RN, DNS, APRN, CNS

College of Nursing and Allied Health Professions

University of Louisiana

Lafayette, LA

Gary Shelton, MSN, ARNP, AOCNNYU Cancer InstituteNew York, NY

Lori Stover, RN, BSNWestern Pennsylvania Cancer Institute Pittsburgh, PA

Joseph D. Tariman, RN, MN, ARNP-BC, OCNUniversity of Washington School of Nursing Seattle, WA

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNSaratoga, CA

Connie Visovsky, RN, PhD, APRNUniversity of Nebraska, College of NursingOmaha, NE

Jeanne Westphal, RNMeeker County Memorial HospitalLitchfield, MN

Rita Wickham, OCN, PhD, RNRush University College of NursingRush-Presbyterian-St. Luke’s Medical CenterChicago, IL

Karla Wilson, RN, MSN, FNP-C, CPONCity of Hope National Medical CenterDuarte, CA

OTHER SPECIALTIES

John F. Aforismo, BSc Pharm, RPh, FASCP

R. J. Health Systems, LLC

Wethersfield, CT

Susan Goodin, PharmD, FCCP, BCOPCancer Institute of New JerseyNew Brunswick, NJ

Amanda Saldivar, MS, RD, LD Cleveland Clinic Taussig Cancer InstituteCleveland, OH

Barbara Savage, LISWCleveland Clinic Taussig Cancer InstituteCleveland, OH

37 Hematologic CancersScientific developments in the management ofmyelodysplastic syndromes

43 Supportive CareOral mucositis: the challenging issues facingoncology clinicians

49 Supportive CareExtravasation: assessment and treatment

51 Breast CancerRecent advances in diagnosis and treatment ofbreast cancer

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Renal cell carcinoma (RCC) is arare disease, with approximately39,000 new cases diagnosed in

2007, accounting for about 2% of allmalignancies in the United States.1 Theincidence of RCC has been increasingby 2% per year for the past 65 years butthe reason for this is unknown.1 In2007, 12,000 deaths were expected fromRCC, and 5-year survival was approxi-mately 40%.1 Ninety percent of casesare of clear cell histology.

RCC commonly metastasizes to liver,lung, bone, brain, and the adrenalglands. Although prognosis is influ-enced by tumor grade and stage, poorperformance status, high lactate dehy-drogenase, low hemoglobin, and highcorrected serum calcium are indicatorsfor a poor prognosis.2

The “classic” presentation of RCC isa symptom triad of flank pain, hema-turia, and a palpable abdominal mass;however, about 50% of cases are foundincidentally on a radiograph in patientswith nonspecific symptoms, includingfatigue, weight loss, and anemia.2 Riskfactors include smoking, obesity, hyper-tension, and acquired cystic kidney dis-ease from chronic kidney disease.1,2

Overview of drug therapyDrug therapy is primarily reserved

for stage IV and relapsed/recurrentRCC. Stages I to III of RCC are surgi-cally resected, and the use of adjuvantdrug therapy is not recommended inclinical practice guidelines.1 External-beam radiation therapy or arterialembolization are reserved for patientswho are not surgical candidates.1 TheTable provides a summary of the dosingand adverse events of the drug thera-pies discussed.

Since the US Food and Drug Admin -istration (FDA) approval of sorafenib in2005, sunitinib in 2006, and tem-sirolimus in 2007, the role of interferonalfa and high-dose interleukin-2 is moreinteresting as a historical treatmentoption for advanced/metastatic RCC.Interferon alfa is not FDA approved forRCC but yields response rates ofapproximately 14%, with short durabil-ity of response, ranging from 6 monthsto 2 years.2 The drug is also poorly toler-ated, causing marked fatigue and severedepression.

High-dose interleukin-2 yields betterresponse rates (21%) with greater dura-bility of response (median duration, 54

months) than interferon alfa but isadministered on telemetry floorsbecause of the risk of capillary leak syn-drome.2 The drug is also contraindicat-ed in patients with significant cere-brovascular disease, cardiac disease,pulmonary disease, renal disease (serumcreatinine >1.5 mg/dL), hepatic disease,abnormal thallium stress test, or abnor-mal pulmonary function test, whichlimits the number of patients who aremedically well enough to qualify fortreatment. A small group of patients arealso known to be cured by high-doseinterleukin-2, but there is no knownway to predict patients who mayrespond to therapy.2

Sunitinib, 50 mg once daily for 4weeks with 2 weeks off, with or withoutfood, has shown a doubling in medianprogression-free survival (PFS) com-pared with active treatment with inter-feron alfa (11 months vs 5 months, P <.001) in a phase 3 trial of 662 previ-ously untreated patients with metastaticRCC.3 The most common adverseevents (>20% of patients) associated

with treatment included liver functiontest elevations, elevated serum creati-nine, myelosuppression, lymphopenia,elevated amylase and lipase, hypophos-phatemia, diarrhea, fatigue, nausea,stomatitis, vomiting, hypertension,hand-foot syndrome, and rash. Themost common grade 3/4 adverse events(>5% of patients) included lipase eleva-tions, lymphopenia, neutropenia, ele-vated uric acid, hypertension, fatigue,hand-foot syndrome, and diarrhea.3

Sorafenib, 400 mg (two 200-mgtablets) twice daily on an empty stom-ach, was shown to double PFS to 167days compared with 84 days withplacebo in a phase 3 trial of 769 ad -vanced RCC patients who were resist-ant to prior therapies (not includingsunitinib).4 The most common sideeffects (>20% of patients) reportedwith sorafenib include diarrhea,fatigue, rash, hand-foot syndrome,alopecia, and nausea; the most com-mon grade 3/4 toxicities (>5% ofpatients and statistically different com-pared with placebo) included hand-

foot syndrome and fatigue.4Both sorafenib and sunitinib were

studied in patients who had good per-formance status, were Memorial Sloan-Kettering Cancer Center (MSKCC)low-intermediate risk, and, for morethan 95%, had been treated withnephrectomy.

Temsirolimus was studied in a phase 3trial of 626 previously untreated pa -tients with advanced RCC who wereMSKCC poor-risk, only two of three ofwhom had been treated with nephrec-tomy.5 Median overall survival (OS)was significantly improved for patientswho were treated with temsirolimus, 25mg intravenous (IV) weekly (10.9months), compared with those treatedwith interferon alfa, 3 million to 18 mil-lion units (depending on tolerability)subcutaneous three times a week (7.3months) (hazard ratio [HR] for death =0.73; P = .008).5

Patients treated with both tem-sirolimus and interferon alfa did not livelonger than those treated with interfer-on alfa alone (median OS = 8.4 months;

Renal Cell Carcinoma: Reviewand Recent AdvancesSarah L. Scarpace, PharmD, BCOPAssistant Professor, Pharmacy Practice, Albany College of Pharmacy and Health Sciences, Albany, New York

Table. Dosing and Adverse Events of Targeted Therapies Used in RCC

Drug Dosing Most common AEsa Most common grade 3/4 AEsb

Sunitinib 50 mg PO daily for 4weeks, then 2-weekbreak without regard to food

LFT elevations; elevated SCr;myelosuppression; lymphopenia; elevated amylase/lipase;hypophosphatemia; diarrhea; fatigue;nausea; stomatitis; vomiting; rash; hand-foot syndrome

Lipase elevations; lymphopenia;neutropenia; elevated uric acid;hypertension; fatigue; hand-footsyndrome; diarrhea

Sorafenib 400 mg (two 200-mgtablets) PO twice daily onan empty stomach

Diarrhea; fatigue; rash; alopecia; hand-foot syndrome; nausea

Hand-foot syndrome; fatigue

Temsirolimus 25 mg IV weekly Asthenia; rash; pain; nausea; anorexia; dyspnea; infection;hyperlipidemia; hypercholesterolemia;peripheral edema; hyperglycemia; fever; abdominal pain

Anemia; asthenia; pain; hyperglycemia; dyspnea

Bevacizumab+ IFN-2a

10 mg/kg IV every 2weeks, 9 million unitssubcutaneously threetimes a week

Fatigue; asthenia; bleeding; anorexia;hypertension; headache; diarrhea; flu-like symptoms

Fatigue; asthenia; proteinuria

Everolimus 10 mg PO daily Stomatitis; rash; fatigue; hyperglycemia; hypercholesterolemia;hypertriglyceridemia; lymphopenia;increased SCr and LFTs;hypophosphatemia; myelosuppression

Lymphopenia; anemia; hyperglycemia

AE indicates adverse events; IFN, interferon; LFT, liver function tests; RCC, renal cell carcinoma; SCr, serum creatinine.a>20% of patients; b>5% of patients.Sources: References 3-5, 7, 10.


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HR = 0.96; P = .70).5 The most com-mon side effects (> 20%) in the tem-sirolimus alone arm included asthenia,rash, anemia, nausea, anorexia, pain,dyspnea, hyperlipidemia and hyper- holesterolemia, infection, periph eraledema, hyperglycemia, fever, andabdominal pain.5 The most commongrade 3/4 adverse events in the tem-sirolimus alone group (>5%) includedanemia, asthenia, hyperglycemia, dysp-nea, and pain.5

Recent advances: General treatment

More than 100 studies on kidney can-cers were presented at the 2008 AnnualMeeting of the American Society ofClinical Oncology (ASCO), represent-ing a wide array of drug therapy optionsfor the disease. Novel therapies includ-ed pazopanib, cediranib, erlotinib, ixab -epilone, meloxicam, gefitinib, beva-cizumab, and everolimus, as well asvaccine therapies.

Two studies that presented outcomedata for bevacizumab and everolimus,a mammalian target of rapamycin(mTOR) inhibitor, were randomizedtrials in which 649 patients withadvanced RCC were randomized tointerferon alfa-2a, 9 million units subcu-taneously three times a week, witheither bevacizumab, 10 mg/kg IV every2 weeks, or placebo, which was stoppedearly after the sorafenib and sunitinibdata became available.6,7 Median PFS atthe time of unblinding was almost dou-bled in patients treated with combina-tion therapy compared with single-agent interferon alfa (10.2 months vs5.4 months; P = .0001).7

The updated results of AVOREN pre-sented at the 2008 ASCO meetingdemonstrate that combination therapywith bevacizumab plus interferon alfa-2a yields significantly better medianPFS than interferon alfa-2a aloneregardless of various risk categories,including those with mixed clear celland nonclear cell histology.7 Fur -thermore, a subgroup analysis of the 131patients who received reduced doses ofinterferon alfa-2a in combination withbevacizumab had comparable medianPFS (12.4 months) as those whoreceived full-dose therapy.8,9

RECORD-1, a randomized, phase 3trial that evaluated best supportive careplus either oral everolimus 10 mg dailyor placebo in 410 patients withadvanced RCC who had progressed onprior sunitinib, sorafenib, or both, wasfirst presented at the 2008 ASCO meet-ing.10 The study was stopped early at thesecond interim analysis after significantimprovements in median PFS wereobserved for the active treatment arm(4.0 months [95% confidence interval(CI), 3.7-5.5 months] vs 1.9 months[95% CI, 1.8-1.9 months]).10 Stomatitis,rash, and fatigue were the most com-monly reported adverse events.10 Thistrial was the first to establish a therapyfor patients who failed prior therapy

with a vascular epithelial growth factorreceptor (VEGFR)-tyrosine kinaseinhibitor (TKI).8 Based on the results ofthis trial, everolimus was approved inMarch for the treatment of advancedRCC after failure of treatment withsunitinib or sorafenib.

Discussion of these findings at the2008 ASCO meeting led to a proposalthat sunitinib or bevacizumab withinterferon alfa be considered as first-linetreatment of good-intermediate riskadvanced RCC, and temsirolimus or

sunitinib as first-line treatment forpatients with poor-risk disease.8 So -rafenib was suggested as second-linetherapy for those who previously failedcytokine therapy, and everolimus, forthose who failed prior VEGFR-TKItherapy. No data or recommendationswere offered for those who failed treat-ment with an mTOR inhibitor.8

Recent advances: Special populations

The subtleties of applying clinical

trial data to real patients frequentlyinvolve consideration of patient charac-teristics. Several trials presented at the2008 ASCO Annual Meeting and the2008 ASCO Genitourinary Symposiuminvestigated the nuances of drug treat-ment in special populations, such asthose with impaired renal function orolder adults with brain metastases.11-13

In a retrospective analysis of 32patients with metastatic RCC who weretreated with sorafenib, 14 patients withcreatinine clearance (CrCl) <60

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mL/min were more likely than their 18counterparts with CrCl >60 mL/min toexperience side effects, such as rash(86% vs 56%), diarrhea (57% vs 33%),and dose interruptions (57% vs 28%) ordose reductions (43% vs 22%).11

Although these adverse events wereincreased in patients with impairedrenal function, there were no differ-ences in response rates or median PFS.12

This would suggest that patients withimpaired renal function could start ther-apy at equivalent doses as those with

normal renal function, but that theymust be more closely monitored foradverse events.

The risk of hemorrhage is a concernfor patients who receive anti-VEGFRtherapy, particularly those with brainmetastases. Similar efficacy and toxicitywere reported in a retrospective analysisof 3997 metastatic RCC patientsenrolled in an expanded access programfor sunitinib regardless of whether brainmetastases were present.12

Of the 298 patients with brain metas-

tases, 6% required dose reduction for anadverse event, and only one patienthad a treatment-related cerebral hemor-rhage (which was grade 1/2).12 Amongpatients with brain metastases, 11% hada partial response and 51% had stabledisease, similar to the results reported inthe literature.12 Although this report didnot find a significant increase in hemor-rhagic events, it would be worthwhile towait for additional experience to accruebefore accepting the safety of this agentin this particular population.

Finally, many practitioners are hesi-tant to prescribe full-dose therapy forolder adult (age > 65 years) patients forfear of an increased risk of adverseevents. A subset analysis of theAdvanced Renal Cell CarcinomaSorafenib (ARCCS) expanded accessprogram in North America found simi-lar rates of adverse events in 1135 olderpatients, including hand-foot syndrome,rash, fatigue, hypertension, diarrhea,nausea, and anorexia, as well as similarresponse rates as their 1469 younger

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counterparts when given the standarddose of sorafenib.13 In this instance, thedose of sorafenib should not be reducedon the basis of age alone.

Recent advances: ToxicitiesThe study of special populations is of

interest for two reasons: first, to ascer-tain whether certain groups of patientsrespond differently than other groupsand second, to see whether certaingroups of patients are more prone to var-ious toxicities. In the absence of popula-

tion-specific data, some investigatorshave attempted to better describe boththe incidence of certain adverse eventsin general and in patients who may rea-sonably be presumed to be predisposedto the toxicity—specifically the car-diotoxicity associated with sunitinib,the risk of hand-foot syndrome withsorafenib, skin toxicities with sunitinib,endocrine complications from tem-sirolimus and sorafenib, and the long-term adverse effects of TKIs.14-19

In a retrospective single-institution

study of 45 patients treated with suni-tinib, seven patients (15%) experiencedsymptomatic grade 3/4 left ventriculardysfunction (LVD); three of five forwhom data were available had persist-ent LVD despite treatment with stan-dard congestive heart failure (CHF)therapy.14 This figure is rather alarmingwhen compared with the 21% overallincidence of LVD reported in the litera-ture.15 The effect was seen even inpatients who had normal heart functionat the initiation of therapy. Significant

predictors of LVD include a history ofCHF (P = .002), coronary artery disease(P = .05), and a low body mass index(P = .03).14 Patients who start sunitinibshould be closely monitored for symp-toms of CHF.

Skin toxicities are a common sideeffect of therapies that target the epider-mal growth factor receptor pathway. Ananalysis of 4883 patients found thatthose who received sorafenib for RCC(n = 3252) experienced more hand-footsyndrome overall than patients treated

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with the drug for non-RCC indications(n = 545).15 The relative risk for allgrades of hand-foot syndrome inpatients treated for RCC compared

with non-RCC was 1.52 (95% CI, 1.32-1.75; P <.001); however, there was no

significant increase in more severe(high grades) hand-foot syndrome.15

The cause of the disparity in this analy-sis is not known, but it might be worth

further investigation because the mech-anism of toxicity may suggest a differ-

ence in mechanism of action for thera-peutic effect in different disease states.The incidence of skin toxicities mayalso be higher in actual practice thanreported in the literature. The 40patients enrolled in clinical trials orthe expanded access programs for suni-tinib reported 46 dermatologic adverseevents.16 Although the rates of skin tox-icities with sunitinib are reported to be10%, the rate was found to be muchhigher in this analysis: 30% of patientsexperienced hair depigmentation, 27%

hand-foot syndrome, 22% acral syn-drome, 15% scrotal erythema, and 12%mucositis.16 These rates are likely morereflective of actual practice and warrantgreater emphasis during patient coun-seling and assessment.

Complete blood cell count and elec-trolyte monitoring are routine in stan-dard oncology practice. For patientstreated with temsirolimus, sorafenib, orsunitinib, endocrine panels must also bemonitored. A subset analysis of the reg-istration trial for temsirolimus indicatesthat hyperglycemia occurs in patientstreated with this agent regardless of aprior history of diabetes. This agent alsoincreases total cholesterol but not otherlipids.17 In patients treated with tem-sirolimus, 16% of patients without dia-betes experienced hyperglycemia com-pared with 3% of those treated withinterferon alfa, and all patients with dia-betes experienced hyperglycemia whileon temsirolimus compared with 36% ofthose on interferon alfa.17

Hypothyroidism attributed to suni-tinib has been reported, but the inci-dence of hypothyroidism with sorafenibwas not previously characterized. Aprospective single-institution study of38 patients treated with sorafenib foundthat seven of 23 patients with normalbaseline thyroid-stimulating hormone(TSH) levels experienced elevations inTSH while being treated, two of 15patients with abnormal baseline TSHlevels experienced elevated TSH, andtwo others experienced thyroiditis.18

Although these rates are lower thanthat reported in the literature for suni-tinib, they are high enough to warrantmonitoring of TSH during therapy.18

Finally, because these newer therapieshave been routinely available only forthe past few years, the long-term rates ofadverse events are not well-described.In a small retrospective review of 16patients who received either sunitinib,sorafenib, or axitinib for at least 16months (median, 24.4 months), 77% ofpatients experienced their worst toxici-ty within the first 12 months of treat-ment, compared with 23% who experi-enced it after 12 months.19 The mediantime to worst toxicity was 5.5 months(range, 0.6-28.3 months), and the ratesof hypothyroidism, anemia, and neu-tropenia were relatively similar within12 months of treatment as after 12months of treatment.19 Thrombocytope -nia and fatigue did seem to be numeri-cally more likely to occur in the first 12months of therapy (56% vs 25% forthrombocytopenia, 56% vs 13% forfatigue), but the small number ofpatients in the analysis preclude draw-ing a stronger conclusion from theresults.20 The issue of long-term therapycertainly warrants additional follow-upwith larger numbers of patients.

SummaryTargeted therapies are now the main-

stay of drug options for advanced and

“The incidence of skin toxicities may alsobe higher in actual practice than reportedin the literature.”

Continued on page 41

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Prostate Cancer 2008Susan Goodin, PharmD, FCCP, BCOPAssociate Director, Clinical Research and Therapeutics, The Cancer Institute of New Jersey, Professor of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey

The natural history of prostatecancer may be prolonged overdecades, thus treatment ad -

vances have not occurred as rapidly asin other common solid tumors, includ-ing breast, lung, and colon cancers.However, in 2008, significant advanceswere made in the understanding of pre-viously published data on finasteride inthe prevention of prostate cancer.Addition ally, safety issues with andro-gen ablation, a long-standing approachto the management of prostate cancer,were reported and a review of theNational Cancer Institute’s Surveil -lance, Epi demiology, and End Results(SEER) database revealed androgenablation is not appropriate for mostpatients with newly diagnosed prostatecancer. Finally, newer therapies arebeing evaluated in patients with bothandrogen-sensitive and -insensitive dis-ease. This article discusses theseadvances with the latest studies de -scribed at each step along the naturalprogression of the disease.

PreventionThe best way to treat cancer is

through prevention; thus efforts todevelop new preventive strategies andto understand recently reported data onolder strategies were a focus in 2008.The Prostate Cancer Prevention Trial(PCPT), which enrolled 19,000 menaged 55 years or older, revealed thatfinasteride reduced the relative risk of adiagnosis of prostate cancer by about25%.1 Although these findings, report-ed in 1993, were significant, the trialalso revealed an increased risk of rapid-ly growing high-grade cancers in mentaking this medication. Because of theseconcerns, this agent has not been wide-ly used in clinical practice for preven-tion of prostate cancer.

Five years later, reanalysis of tissueobtained from the original studyrevealed that the risks were overesti-mated and clear benefits existed for theuse of finasteride.2-4 For the originalanalysis of data, both the tumor gradeand Gleason grade were derived from abiopsy of a small section of the prostate.However, to adequately assess Gleasongrade, the entire prostate must beexamined after surgical removal.Therefore, in 2007, researchers gradedthe entire prostate that was surgicallyremoved in 500 PCPT participants todetermine the Gleason grade in thesespecimens. Data were then mathemati-cally modeled to extend those results tothe entire PCPT cohort.2,3 Both analy-

ses concluded that the rates of high-grade disease were lower in the finas-teride arm compared with the placeboarm (Figure 1). According to the model,8.2% of men in the placebo arm wouldhave been diagnosed with high-gradeprostate cancer compared with 6% inthe finasteride arm, contradicting theearly concerns that finasteride useresulted in high-grade prostate cancer.3

A third new report from PCPT datareexamined the biopsy scores from each

participant found to have prostate can-cer. Using the Epstein criteria (clinicalstage, extent of tumor, and prostate-spe-cific antigen [PSA] density) to deter-mine clinical significance, the research -ers found 75% of cancers in the placebogroup met the criteria for clinical signif-icance—possible cases where finasteridecould have prevented prostate cancer.4These new results have renewed inter-est in finasteride, and other agents inthis class, to potentially reduce the riskof prostate cancer. Appropriate candi-dates for finasteride, such as African-American men and those with a familyhistory of disease, should be evaluatedfor therapy and counseled on the risksand benefits of finasteride.

The recently released AmericanSociety of Clinical Oncology-AmericanUrological Associ ation Clinical Prac -tice Guidelines recommend thatasymptomatic men with a 3.0 ng/mLlevel who are regularly screened withPSA or are anticipating undergoingannual PSA screening for early detec-tion of prostate cancer may benefitfrom a discussion of both the benefitsof 5-alpha reductase inhibitors (ARIs)for 7 years for the prevention ofprostate cancer and the potential risks(including the possibility of high-gradeprostate cancer). Men who are taking5-ARIs for benign conditions may ben-efit from a similar discussion.5

While the news about finasterideexcited the prevention world, disap-pointing news was reported in 2008 forthe Selenium and Vitamin E CancerPrevention Trial (SELECT). The inde-pendent Data and Safety MonitoringCommittee for the trial met on Septem -ber 15, 2008, to review SELECT studydata and found that selenium and vita-min E, taken alone or together for anaverage of 5 years, did not preventprostate cancer.6 In fact, there was a

nonsignificant increased risk of prostatecancer in the vitamin E group (P = .06)and type 2 diabetes mellitus in the sele-nium group (relative risk, 1.07; 99%confidence interval [CI], 0.94-1.22; P =.16), but not in the selenium plus vita-min E group.6 While there is still muchto be learned from these data, neitherselenium nor vitamin E at the doses andformulations used were shown to pre-vent prostate cancer.

Before discussing prevention options,

patients at risk must be identified.Until recently, identification of pa -tients at risk was limited to factors suchas age, race, and family history. Recentgenomewide analyses have identifiedvariants in five chromosomal regionsthat are significantly associated withprostate cancer. Previously, single-nucleotide polymorphisms in each offive chromosomal regions were shownto have only a moderate associationwith prostate cancer. However, datapublished in 2008 revealed that vari-ants in three independent regions—8q24, 17q12, and 17q24.3—in combi-nation with family history, accountedfor 46% of prostate cancer cases in aSwedish population.7 The identifiedassociation did not predict for aggres-siveness of disease; therefore, theassumption is that the genetic variantsact at an early stage. These data are thefirst step in understanding the geneticassociation of prostate cancer andrequire further evaluation in assessingrisk in individual men.

Androgen-deprivation therapyAndrogen-deprivation therapy (ADT),

including gonadotropin-releasing hor-mone agonists, such as leuprolide andgoserelin, and the antiandrogens flu-tamide and bicalutamide, are impor-tant in the management of prostatecancer. Often used as palliative treat-ment for advanced prostate cancer andin patients with early disease at highrisk of progression, these agents havealso been used as first-line treatmentfor patients with T1 or T2 prostatecancer. Clinical outcomes associatedwith this use are not definitive.

In a retrospective analysis of the pop-ulation-based SEER database andlinked Medicare files, 19,271 men aged66 years or older were evaluated for sur-vival based on the management oflocalized (T1 or T2) prostate cancer.8These patients were diagnosed between1992 and 2002, and the data were eval-uated for PSA and overall survivalbased on use of primary ADT (PADT)versus conservative management. Inthis population, 41% (7867) of patientsreceived PADT (median age 77 years),while the remaining 11,404 receivedconservative management. The authorsfound that the PADT group had a lower10-year disease-specific survival thanthose taking no drugs. Specifically,PADT was associated with a lower 10-year prostate cancer–specific survival(80.1% vs 82.6%; hazard ratio [HR],1.17; 95% CI, 1.03-1.33) and noincrease in 10-year overall survival(30.2% vs 30.3%; HR, 1.00; 95% CI,0.96-1.05) compared with conservativemanagement. The only exception tothese results were patients with poorlydifferentiated prostate cancer, in whom

“The best way to treat cancer is throughprevention.”

Figure 1. Prostate cancer detection rates

When your patients experience acute chemotherapy-induced

nausea and vomiting (CINV) during their fi rst cycle of

chemotherapy, they may have an increased risk of CINV on

subsequent days and in subsequent cycles.1-3

ALOXI®:

Starts strong to prevent CINV4

A single IV dose lasts up to 5 days after MEC4,5*

Can be used with multiple-day chemotherapy regimens6†

HELP ESTABLISH A SUCCESSFUL

CINV PREVENTION STRATEGY

FROM THE FIRST CYCLE

STRONG. FROM THE START.

ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information

ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. Most commonly reported adverse reactions include headache (9%) and constipation (5%).

Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved Prevention of Moderately Emetogenic Chemotherapy-induced Nausea and Vomiting with Palonosetron, a Pharmacologically Novel 5-HT3 Receptor Antagonist: Results of a Phase

III, Single-Dose Trial Versus Dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

* Moderately emetogenic chemotherapy.† Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a

7-day interval was removed.

www.ALOXI.com

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc.

© 2008 Eisai Inc.

All rights reserved. Printed in USA. AL348 A 10/08

http://www.ALOXI.com


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PADT was associated with a betterprostate cancer–specific survival but notbetter overall survival, compared withthose receiving no therapy. These data,while retrospective, add to the argu-ment that ADT has little role inimproving outcomes in most men withearly prostate cancer.

ADT is also utilized for patients withbiochemical recurrence, as evidencedby a rising PSA after definitive localtherapy. However, several studies havesuggested an increased risk of fragilityfractures, acute myocardial infarction,

and diabetes mellitus with continuoususe of ADT. Therefore, a retrospectivepopulation-based matched cohortanalysis of 19,709 pa tients receivingADT and 19,709 prostate cancer pa -tients not receiving ADT, 66 years ofage or older in Ontario, Canada, wasconducted using propensity-basedmethods. The analysis revealed thatcontinuous use of ADT for at least 6months was associated with anincreased risk of fragility fracture anddiabetes, but not acute myocardialinfarction or hypercholesterolemia.9

Local recurrenceIn patients who experience biochem-

ical disease recurrence heralded by a ris-ing PSA after definitive local therapy,treatment choices are varied. Salvageoptions include radiation therapy, hor-monal therapy, combined therapy,investigational therapy, or watchfulwaiting. These choices could be delayedor initiated immediately. Conclusiveevidence from randomized trials todetermine which approach prolongs lifeis not available. A review of 18 random -ized clinical trials and 473 observation-al studies revealed little high-qualityprospective evidence that establishesthe superiority of one therapy overanother.10 Additionally, all treatments(ADT, radical prostatectomy, and radio-therapy) were associated with urinary,bowel, or sexual dysfunction; the fre-quency, duration, and severity of theseadverse events varied among treatments.

A recent study has proved salvageradiotherapy, administered within 2years of biochemical recurrence of dis-ease after prostatectomy, offers a significant increase in prostate cancer–specific survival.11 With a medianfollow-up of 6 years after recurrenceand 9 years after prostatectomy, investi-gators analyzed a cohort of 635 menwho experienced biochemical and/orlocal recurrence and received no salvagetreatment (n = 397), salvage radiother-apy alone (n = 160), or salvage radio-therapy combined with hormonal ther-apy (n = 78). Salvage radiotherapyinitiated within 2 years of recurrencewas associated with a significant three-fold increase in prostate cancer–specificsurvival relative to those who receivedno salvage treatment (HR, 0.32; 95%CI, 0.19-0.54; P <.001), and theimprovement was primarily confinedto men with a PSA doubling time ofless than 6 months. How ever, the addi-tion of hormonal therapy to salvageradiotherapy was not associated withan additional in crease in prostate can-cer–specific survival.

Novel agents also have been evaluat-ed in patients with PSA recurrent non-metastatic prostate cancer after localdefinitive therapy. The results of a ran-domized, double-blind, placebo-con-trolled, crossover phase 3 study of inter-mittent hormonal therapy andthalidomide were presented at the 2008American Society of Clinical Oncology

ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI is indicated for:• Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses• Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat coursesDOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and VomitingDosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.Instructions for I.V. AdministrationALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.CONTRAINDICATIONSALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information]WARNINGS AND PRECAUTIONSHypersensitivityHypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT

3

receptor antagonists.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not refl ect the rates reported in practice.In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy:Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.Dermatological: < 1%: allergic dermatitis, rash.Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and fl atulence.

General: 1%: weakness, < 1%: fatigue, fever, hot fl ash, fl u-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fl uctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Postmarketing ExperienceThe following adverse reactions have been identifi ed during postapproval use of ALOXI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

DRUG INTERACTIONSPalonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically signifi cant drug interactions with palonosetron appears to be low.

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not signifi cantly altered (AUC: no change, Cmax: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no signifi cant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the fi ve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Category BTeratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

Labor and DeliveryPalonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

Nursing MothersIt is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric UseSafety and effectiveness in patients below the age of 18 years have not been established.

Geriatric UsePopulation pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in effi cacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI effi cacy in geriatric patients has not been adequately evaluated.Renal ImpairmentMild to moderate renal impairment does not signifi cantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.Hepatic ImpairmentHepatic impairment does not signifi cantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.RaceIntravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.OVERDOSAGEThere is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fi xed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (17.2) in full prescribing informationInstructions for Patients• Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].• Patients should be instructed to read the patient insert.

Rx Only

Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677.

© 2008 Eisai Inc.

All rights reserved. Printed in USA. AL350 10/08

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)

Headache 60 (9%) 34 (8%) 32 (16%)

Constipation 29 (5%) 8 (2%) 12 (6%)

Diarrhea 8 (1%) 7 (2%) 4 (2%)

Dizziness 8 (1%) 9 (2%) 4 (2%)

Fatigue 3 (< 1%) 4 (1%) 4 (2%)

Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%)

Insomnia 1 (< 1%) 3 (1%) 3 (2%)

Figure 2. Chemical structures of (a) abiraterone acetate and (b) pregnenolone

H0

H

H

N

HH

H0

CH3

CH3

H3C 0

b. Pregnenolonea. Abiraterone


PRO

STAT

E CA

NCE

R

meeting.12 At the time of PSA progres-sion, patients received 6 months of aluteinizing hormone-releasing hormone(LHRH) agonist and then were ran-domized to thalidomide or placebo (partA) until a PSA rise to baseline or to ≥5ng/mL, whichever occurred first. Atthat time, the LHRH agonist was reini-tiated for 6 months followed by oraltherapy with the opposite agent (part B[thalidomide patients received placeboand placebo patients received thalido-mide]) until PSA progression. Of 159enrolled patients, 147 received thestudy drug in part A and 103 patientsproceeded to part B; of these, 51patients received thalidomide and 38patients received placebo. There was nodifference in median time to PSA pro-gression in part A (thalidomide 15months, placebo 9.6 months, P = .21),and median progression-free survival(PFS) during part B was 17.1 months forthe thalidomide arm versus 6.6 monthsfor the placebo arm (P = .0002).Although the sample size of this studywas small, the results revealed a possiblerole for thalidomide, whose effects wereindependent of testosterone in this clin-ical stage of pros tate cancer. The differ-ences in outcome in part A versus partB are unclear, but may relate to possiblebiological changes that occur over timein the presence of LHRH-agonist thera-py. Fur ther investigation of the role ofthalidomide in the management ofprostate cancer is ongoing.

Metastatic diseaseIn metastatic disease, much interest is

fo cused on the 17-alpha hydroxylaseC17,20-lyase cytochrome P17 (CYP17)irreversible inhibitor abiraterone ace -tate for the treatment of prostate cancer.CYP17 catalyzes two independentlyreg ulated corticosteroid reactions key toan drogen and estrogen biosynthesis.13

Struc turally similar to pregnenolone(Figure 2), abiraterone in hibits the pro-duction of tes tosterone in the testis,adrenal glands, and the pros tate. Keto -conazole, which also works through theinhibition of CYP17, is less potent thanabiraterone and a competitive inhibitorof several cytochrome en zymes beyond

CYP17. Phase 1 and 2 trials have beencompleted with abiraterone (Table),with responses reported in patients pre-viously treated with multiple hormonaltherapies, chemotherapy, and ketocona-

zole.13-16 Importantly,no pa tients developedclinical adrenocorticalinsufficiency with toxi-cities caused by sec-ondary mineralocorti-coid excess, includinghypertension, hypo -kalemia, and fluidoverload. The additionof a cortico steroid,prednisone, has mini-mized the occurrenceof toxicities associatedwith secondary miner-alocorticoid excess andis being utilized in theongoing phase 3 trialcomparing abiraterone/prednisone to place-

bo/prednisone in patients with priordocetaxel and no ketoconazole.

The impact of che motherapy andanti angiogenic therapy continues to beinves tigated in the metastatic setting

with mixed results. Follow-up datafrom the Satraplatin and PrednisoneAgainst Refractory Cancer (SPARC)trial, a mul tinational, randomized,double-blind, placebo-controlled trialof 950 patients comparing the oralplatinum compound satraplatin plusprednisone to prednisone alonerevealed no improvement in overallsurvival with combination therapy.17

In patients with no prior chemothera-py for metastatic disease, the combina-tion of docetaxel, bevacizumab,thalidomide, and prednisone was asso-ciated with an 88% response rate asmeasured by PSA and a 63% responserate in measurable disease.18 The medi-an estimated PFS was 18.2 months inthis population with unfavorable prog-nostic factors. Al though these datarequire validation in a randomizedphase 3 setting, early results areencouraging for the management ofmetastatic disease.

Table. Phase 1/2 Clinical Trials Involving Abiraterone Acetate

Study Phase Number of patientsAbiraterone

dose (mg/day) Responsea

Attard 1 21 250–2000b 57%

Ryan 2 33 250–1000b 53% prior K 61% no prior K

Reid 230 chemonaïve (arm A)

31 prior docetaxel (arm B)1000

Arm A: 60% Arm B: 52%

Danilla 2 381000 + 5 mg prednisone

40%

aResponse is defined as 50% decrease in prostate-specific antigen, confirmed after 1 month that lasted for more than 3 months.bRecommended phase 2 dose is 1000 mg/day.K indicates ketoconazole.Sources: References 13 through 16.

COMMENTARY

According to American Cancer Society statistics,prostate cancer is the most commonly diagnosedsolid tumor in American men and the second lead-

ing cause of cancer-related death. Although these facts arewithout debate, prostate cancer often progresses at a slowerrate than other solid tumors, and thus treatment advanceshave been slow as well. In 2008, however, significant strideswere made in the approach to identification of high-riskpatients and in prevention and treatment options not onlyfor high-risk patients, but also for patients with locallyrecurring disease and those with metastatic disease.

In February 2008, data were published identifying sin-gle-nucleotide polymorphisms in three independent chro-mosomal regions at 8q24, 17q12, and 17q24.3. This genet-ic information together with family history gives us moredata to better assess a man’s relative risk of being diag-nosed with prostate cancer.

As a result of the data and continuing reports from theProstate Cancer Prevention Trial (PCPT), many articleshave been published that support the benefit of use of finas-teride at a daily dose of 5 mg for prevention of prostate can-cer. Although not approved as a chemoprevention agent,the evidence supports clinical use of finasteride for high-riskmen, such as African Americans or those with a family his-tory of prostate cancer. As for use of dietary supplements forprevention, the Selenium and Vitamin E CancerPrevention Trial (SELECT) showed that neither vitamin Enor selenium taken alone or together provided clinicallysignificant benefit.

Data derived from the Surveillance, Epidemiology, andEnd Results (SEER) program on the management of local-ized T1 and T2 disease showed no survival benefit at 10 yearsfor androgen-deprivation therapy (ADT) as compared withconservative management. Several studies, however, havesuggested an increase in the risk for myocardial infarction,diabetes mellitus, and fragility fractures with ADT. Thesedata suggest that ADT may have little clinical benefit interms of either improvement of patient outcomes or survival.

Patients with disease recurrence after local definitivetherapy, as evidenced by rising prostate-specific antigen(PSA) levels, lack conclusive evidence for treatment choic-es, because little high-quality evidence supports the superi-ority of one treatment choice over another. One recentstudy showed that radiation therapy within 2 years of bio-chemical recurrence after radical prosta tectomy offers asignificant survival benefit over no salvage treatment. Thisbenefit was achieved by men with a PSA doubling time ofless than 6 months. ADT in addition to radiation was notassociated with any survival benefit.

Results of a crossover phase 3 study of intermittent hor-mone therapy and thalidomide were very promising, withmedian time to survival of 17.1 months compared with 6.6months in the placebo arm. The results were achieved bymen with PSA-recurrent, nonmetastatic disease.

For patients with metastatic disease, abirateroneacetate, which inhibits the production of testosterone inthe testis, adrenal glands, and the prostate, has shown aless toxic profile than ketoconazole. Additionally, pred-nisone is being used in phase 3 studies and has furtherreduced the occurrence of mineralcorticoid excess.

PSA continues to be the measure of response used forprediction of overall survival in men with prostate cancer.In 2008, there were considerable advances in the preven-tion and management of prostate cancer. Many findingswere inconclusive, but much promising new informationwith positive results and survival benefits was reported.Carefully assessing risk, implementing preventive measures,educating patients on available treatment options, screen-ing for clinical trial eligibility, and continual PSA monitor-ing are all within the clinical nurse arena. The ongoingquest for results, implementation in clinical practice, andacquisition of the knowledge necessary to follow recom-mendations for trial design and end point assessment, asoutlined by the Prostate Cancer Clinical Trials WorkingGroup, will enable us to further delay disease progressionand enhance survival for men with prostate cancer.

A NURSE’S PERSPECTIVEProstate Cancer 2008: Implications for ClinicalNursing PracticeDoris Pindilli, MS, ANP-BC, OCNColumbia University, New York, New York



SUPPORTIVE CA

RE

Venous Thromboembolism in Patients with Cancer: Current Approaches to Management

Kamakshi V. Rao, BSc Pharmacy, PharmDClinical Specialist, University of North Carolina Hospitals and Clinics, Associate Professor, University of North Carolina School of Pharmacy, Chapel Hill

Acting Surgeon General StevenK. Galson, MD, MPH, issued aCall to Action in September

2008 to reduce the number of cases ofdeep vein thrombosis (DVT) and pul-monary embolism (PE) in the UnitedStates.1 These conditions affect an esti-mated 350,000 to 600,000 Americanseach year and contribute to at least100,000 deaths. The plan as describedby the Surgeon General emphasizes theneed for increased awareness of DVTand PE, evidence-based practices forDVT, and more research on the causes,prevention, and treatment of the condi-tion. In conjunction with thisannouncement, the Agency forHealthcare Research and Quality hasreleased two new guides on the preven-tion of dangerous blood clots—one forpatients and another for healthcareproviders.1 Additionally, under a sub-contract with the National QualityForum, the Joint Commission onAccreditation of Healthcare Orga -nizations is finalizing performancemeasures to evaluate the quality of carefor persons at risk for venous throm-boembolism (VTE).2

VTE is a frequent complication ofcancer,3,4 occurring more often inpatients with cancer than in those with-out cancer. Those with cancer have afour- to six-fold increased risk of devel-oping VTE, and approximately 20% ofall new VTE events in the communityare cancer-related.5,6 Recurrent VTE isalso more common in cancer patientsthan in patients without cancer, despitetreatment with anticoagulants. Moreimportant, it is associated with a poorprognosis in cancer patients. In fact, 1-year mortality rates in cancer patientsdiagnosed with VTE can be as high as90%, making it one of the leading causesof death in cancer patients.7,8

Standard treatment of VTE has beeninitial therapy with unfractionatedheparin (UFH) or low-molecular-weight heparin (LMWH) followed bylong-term therapy with an oral antico-agulant. Recently, increasing data haveemerged regarding alternative optionsfor therapy, particularly in the treat-ment of VTE in patients diagnosed withcancer. These data have led to the pub-lication and revision of a number ofpractice guidelines, including the guide-

lines of the American College of ChestPhysicians (ACCP), the National Com -prehensive Cancer Network (NCCN),the American Society of Clinical On -cology (ASCO), and the AmericanSociety of Health-System Pharmacists(ASHP). Most notable in all of theserecommendations is the expanding roleof LMWH in the initial and extendedtreatment of VTE.

Prevalence of and risk factors forVTE in patients with cancer

The prevalence of first-time DVT orPE in the general population has beenestimated at 17 per 100,000 per year.9,10

Among patients with cancer, risk ofVTE rises dramatically to approxi-mately 1 in 200.5,10 However, this riskdiffers according to type of cancer,tumor stage, and whether a patient isreceiving chemotherapy.11 It is possiblethat the risk of this complication isunderestimated, however, as VTE isfound in at least 50% of cancer patientsat autopsy.12,13 Additionally, the burdenof cancer-associated VTE appears to begrowing as new cancer therapies thatincrease the risk of VTE enter into useand combination therapy using theseagents becomes more common.14

Metastatic disease is a strong predictorof VTE. Compared with patients with lo -calized disease, patients with metastaticcancer have a two- to four-fold in creasein the risk of VTE during the 6 monthsafter initial diagnosis of cancer.15,16

Cancer treatment as a risk factorfor VTE

In addition to the risk conferred bycancer itself or the presence ofmetastatic disease, the treatment of thedisease increases the risk that a patientwill experience VTE. Concomitant useof therapies such as hormonal agents,chemotherapy, invasive procedures,and catheterization add to the consid-erable risk these patients alreadyhave.10 Undergoing surgery as part ofthe overall management of their can-cer places these patients at increasedrisk for development of VTE for up to1 year after the surgical procedure.17

Agents used in the supportive care ofcancer patients such as erythropoietin,granulocyte colony-stimulating factor,and high-dose corticosteroids may also

increase the risk for VTE in thesepatients.11,18

Synergy between the treatment andthe severity of the disease has also beennoted. High rates of thrombosis havebeen noted in patients with advancedcancer receiving some form of antitu-mor therapy, including patients receiv-ing chemotherapy for metastatic breastcancer,19,20 advanced ovarian cancer,21

or those receiving L-asparaginase thera-py for acute lymphoblastic leukemia.22

Both surgery and the use of in -dwelling central venous cathetersincrease the risk of developing VTE inall patients. For cancer patients, this riskis compounded. Postoperative VTE incancer patients occurs at least twice as

often as it does in noncancer patientswho receive similar surgical proce-dures.23 These patients also have athree-fold higher risk of fatal PE thannoncancer patients.24 The risk for VTEassociated with central venous cathetersis approximately 4%, with the highestrisk occurring in patients requiring mul-tiple insertion attempts and those withprior central venous catheterizations.25

VTE as an indicator of occultcancer

While cancer is a risk factor forVTE, the occurrence of VTE in patientswithout other identifiable risk factorscan also suggest the presence of occultcancer.26 In large prospective studies,4% to 5% of patients presenting withVTE have previously undiagnosed can-cer. Smaller studies suggest that therisk for cancer in patients with idio-pathic VTE may be as high as 7% to12%, compared with 2% to 3% inpatients with identifiable risk factorsfor VTE.26 Findings such as these haveled some to suggest that patients pre-senting with VTE, particularly thosewithout evident risk factors, should be

carefully screened for underlying can-cer; however, such an approach wouldneed to be verified and validated in thecontext of a clinical trial.24

Risk of recurrent VTEThe risk of recurrent VTE is

increased in cancer patients comparedwith patients without cancer, evenwith appropriate prophylaxis.27 In aprospective study of 355 patients withDVT who were treated with heparinfollowed by warfarin, 10.3% of thosewith cancer experienced a recurrenceof VTE in the 3-month follow-up peri-od compared with 4.7% of patientswithout cancer.27 In the subgroup ofpatients who had achieved interna-

tional normalized ratios (INRs) of 2.0to 3.0, 8.6% of cancer patients and1.3% of patients without cancer expe-rienced a recurrence (P <.01).28

Risk assessment for VTE inpatients undergoing cancertreatment

While it is evident that cancerpatients are at an increased risk forVTE, the risk differs from one patient tothe next, and can vary in an individualpatient over the course of the illness.Cancer patients constitute a heteroge-neous population with a wide variety ofrisk factors, ranging from age and diseasestage to chemotherapy and surgical pro-cedures. Thus, risk assessment requires adynamic approach.12 Table 1 presentsselected risk factors for cancer-associat-ed thrombosis.

Biomarkers and laboratory parame-ters may also help stratify patient riskfor VTE. Cancer patients with elevat-ed levels of markers for hemostaticactivation are at increased risk for pri-mary and recurrent VTE.12 D-dimer iselevated in patients with cancer com-pared with normal controls, and tissue

“In addition to the risk conferred bycancer itself or the presence of metastaticdisease, the treatment of the diseaseincreases the risk that a patient willexperience VTE.”


SUPP

ORT

IVE

CAR

E

factor expression has been associatedwith increased angiogenesis. VTEoccurs four times more often in pa -tients with high tissue-factor express-ing carcinomas (20%) than in thosewith low tissue-factor expressing carci-nomas (5.5%) (P = .04).12 Additionally,elevated prechemotherapy plateletcounts have been correlated with anincreased risk for VTE.12

Although there are ample data tosuggest the use of thromboprophylaxisin cancer patients requiring hospitaliza-tion, as of yet there is not enough evi-dence to support the systematic use ofsuch therapy in cancer patients under-going chemotherapy, radiotherapy, orthe insertion of a central venouscatheter.29 The decision as to whetherthromboprophylaxis should be adminis-tered to a particular patient or not, andthe duration of such therapy, is left tothe clinical judgment of the physician.29

The patient’s personal and family med-ical history, comorbidities, the presenceof thrombophilia, and patient prefer-ences must be carefully assessed andconsidered in the context of thepatient’s overall VTE risk factors.29

Prevention and treatment ofVTE in patients undergoing cancer treatment

As early as 1960, trials indicated thatanticoagulation reduced mortality inpatients with VTE.30,31 A seminal studyby Barritt and Jordan demonstrated thatuntreated patients with PE had a highmortality rate, while patients treatedwith anticoagulation therapy experi-enced a reduction in mortality.31 Anti -coagulant therapy should be started assoon as a diagnosis of DVT can beobjectively substantiated; it should alsobe initiated in cases where DVT is high-ly suspected but results of diagnostictests are not yet available. Both UFHand LMWH are indicated for the initialtreatment of DVT, and these agents aswell as oral vitamin K antagonists suchas warfarin are recommended for long-term treatment of DVT.30

Unfractionated heparin therapy. UFHhas long been considered to be the stan-dard of care for initial treatment ofDVT. Most hospitals use standardizednomograms for the initiation and main-tenance of heparin dosing. The shorthalf-life of UFH allows rapid adjustmentof doses and makes reversal of anticoag-ulation rather easy. There are, however,a number of factors that make the use ofUFH unattractive and difficult. It hasan unpredictable dose response, requir-ing frequent monitoring and doseadjustments. Also, it has a relativelynarrow therapeutic window, and re -quires prolonged inpatient hospitaliza-tion for administration. Even with theadvent of bridging therapy, the initia-tion of warfarin on the first day of UFHtherapy, patients must remain in thehospital for a minimum of 5 days toreceive combination therapy until a sta-ble therapeutic INR has been attained.

In contrast, LMWHs offer a numberof advantages over UFH for the initialmanagement of patients with VTE.These agents do not require laboratorymonitoring, although plasma anti-Xalevel monitoring may be used in a smallnumber of patients, such as those whoare pregnant, obese, or have significantrenal impairment. The LMWHs can beadministered on a weight-adjusted basisand given subcutaneous (SC) once ortwice daily. Evidence from studies com-paring LMWH SC without monitoringto UFH with monitoring indicates thatLMWH therapy may result in fewerrecurrent VTE and bleeding eventsthan UFH.32,33

Because of these advantages, LMWHshave replaced UFH as the first-lineagents of choice in many hospitals.Randomized trials have demonstratedthat outpatient LMWH therapy is aseffective and safe as inpatient UFH forthe management of VTE, especiallywhen started concomitantly with anoral anticoagulant that is to be takenon a long-term basis.34-36 Ambulatorytreatment with LMWH is possiblebecause of its convenient SC adminis-tration. This, in turn, allows early hos-pital discharge of patients, resulting incost savings and improved quality oflife.30 Current ACCP guidelines actual-ly recommend initial treatment withSC LMWH once or twice a day insteadof UFH on an inpatient basis when

needed (grade 1A) or otherwise on anoutpatient basis (grade 1C) in patientswith acute DVT.30

Warfarin therapy in cancer patients. Asfor long-term treatment of acute DVT,extended anticoagulant treatment isrecommended to prevent both sympto-matic progression of thrombosis andrecurrence of DVT. In most patientswith DVT of the legs, treatment with avitamin K antagonist such as warfarin isrecommended for long-term therapy.

The use of warfarin, especially incancer patients, is particularly prob-lematic. Patients receive multiple med-ications for the treatment of the malig-nancy itself and the management oftreatment side effects and complica-tions of the disease. Furthermore, can-cer therapy changes depending onwhere the patient is in the particularcycle. Thus, at any one time, a patientmay be tak ing an antiemetic forchemotherapy-induced nausea andvomiting, an antibiotic for neutropenicfever, growth factors, an anthracycline,a purine analog, and/or a monoclonalantibody or tyrosine kinase inhibitorfor the malignancy.

Each of these interventions can havean effect on warfarin, often necessitat-ing frequent monitoring and dose mod-ifications to maintain a therapeuticINR. The inability to maintain a thera-peutic INR can result in recurrence ofVTE and potential bleeding complica-tions from anticoagulation. In aprospective cohort study, the risk ofrecurrent VTE for patients with cancerwho received long-term warfarin thera-py was as high as 21% during the firstyear of anticoagulation, compared with7% in patients who did not have can-cer.37 Major bleeding events occurred in12% of cancer patients versus 5% ofthose without cancer, and the risk ofthis event remained higher throughoutthe course of warfarin therapy.37

Warfarin has proved to be subopti-mal therapy in cancer-related VTE forother reasons as well. Cancer patientsmay have unpredictable anticoagulantresponses caused by gastrointestinalproblems, malnutrition, vomiting, andliver dysfunction associated with thecancer.10,38-40 Interruption of anticoagu-lant therapy as the result of chemother-apy-related thrombocytopenia or inva-sive procedures is a greater problemwith warfarin than heparin because ofthe former drug’s slow onset and offsetof action.10,38,39 Thrombocytopenia alsoincreases bleeding risk in these pa -tients.37 Finally, the need for frequentmonitoring to maintain the INR with-in the therapeutic range is a quality-of-life issue that becomes greater inpatients with cancer because of poorvenous access.10,38,39 As a result, patientswith cancer spend less time within thetherapeutic INR range than patientswithout cancer and are thus at greaterrisk for recurrent VTE.39,41 Notably,rates of VTE recurrence are highthroughout oral anticoagulation thera-

py, even when the INR is within thera-peutic range.37,39,41

The Role of LMWHAs mentioned before, compared

with UFH, LMWHs have a more pre-dictable anticoagulant effect, requireless monitoring, and allow for outpa-tient management of VTE. Because ofthese benefits, LMWHs have become awidely accepted option for initial ther-apy (first 5-7 days) in the managementof VTE.

It is important to note that LMWHsmust be used with caution in patientswith renal insufficiency and failure andthat dose adjustments may be requiredin patients with creatinine clearance<30 mL/min.42

Compared with warfarin, LMWHsalso hold some significant advantages.LMWHs have far fewer drug–drug anddrug–food interactions than warfarinand require much shorter interruptionsin therapy for invasive procedures.Additionally, the time to elimination ofdrug in the event of a serious bleedingevent is significantly shorter withLMWHs compared with the washouttime for warfarin. A number of investi-gators have evaluated the potential foruse of LMWHs as long-term therapy totreat VTE and prevent recurrent VTE,especially in the cancer population.

CANTHANOX. Comparison ofLow-Molecular-Weight Heparin andWarfarin for the Secondary Preven tionof Venous Thromboembolism in Pa -tients with Cancer (CANTHANOX),the first published trial of an LMWHin cancer, compared 3 months of war-farin therapy with enoxaparin in 146cancer patients with proximal DVT,PE, or both. An open-label trial,CANTHANOX evaluated whether afixed dose (1.5 mg/kg) of enoxaparinSC given once daily was superior tostandard warfarin therapy for the pre-vention of recurrent cancer-relatedVTE.43 All patients were started onenoxaparin 1.5 mg/kg once daily, andthen randomized to either enoxaparinor oral anticoagulant warfarin for theremainder of the 3-month trial. Theprimary outcome measure was a com-bined end point of major bleeding orrecurrent VTE within 3 months.

The trial was stopped after 4 years dueto an inability to recruit subjects. Atthat time, 146 patients had been ran-domized to the study. Of these patients,71 in the warfarin group and 67 in theLMWH group were considered evalu-able for the primary end point. Duringthe study period, 15 patients (21.1%)receiving warfarin compared with seven(10.%) receiving enoxaparin experi-enced recurrent VTE or major hemor-rhage (P = .09).43 Although this was notstatistically significant, enoxaparin wasfound to be significantly more effectivein delaying time to a primary event (P =.04). The majority of combined endpoint events involved major bleeding:12 (80%) of 15 in the warfarin group

Demographics

• Older age• Gender• Race: higher in African-Americans,

lower in Asians

Cancer-related factors

• Site of cancer: brain, pancreas,kidney, stomach, lung, bladder,gynecologic, hematologic

• Advanced stage of cancer• Initial period after diagnosis

Treatment-related factors

• Major surgery• Hospitalization• Cancer therapy• Chemotherapy• Hormonal therapy• Antiangiogenic agents: thalidomide,

lenalidomide, bevacizumab• Erythropoiesis-stimulating agents

Biomarkers• Elevated prechemotherapy

platelet count• D-dimer• Tissue factor expression by

tumor cellsReprinted with permission from Reference 13.

Table 1. Selected Risk Factorsfor Cancer-associatedThrombosis


SUPPORTIVE CA

RE

and five (71%) of seven in the enoxa-parin group. Over the 3-month treat-ment period, 17 patients (22.7%)receiving warfarin and eight (11.3%)receiving enoxaparin died (P = .07).43

In the warfarin group, six deaths (35%)were attributable to bleeding comparedwith none in the enoxaparin group. Nosignificant difference was observedbetween the groups for the progressionof cancer or in cancer-related deaths.43

Although these results indicate an asso-ciation between warfarin and increasedbleeding in patients with cancer-relatedVTE and provide initial safety data onextended treatment with an LMWH,no definitive conclusions could bedrawn from this trial because the diffi-culties in patient recruitment resultedin the study being underpowered.

LITE. A second trial comparing theefficacy and safety of an LMWH to war-farin in cancer-related VTE en rolledpatients with and without cancer whohad a diagnosis of DVT. In this multi-center trial, 737 patients with a proxi-mal DVT were randomized to tinza-parin, given SC for 84 days, or UFH for5 days plus long-term warfarin for 84days.44 Slightly more than one quarter ofthe patients in each group had cancer.Follow-up took place at the completionof treatment and at 1 year followingrandomization. In the overall group, 18patients (4.9%) in the tinzaparin grouphad recurrent VTE, compared with 21(5.7%) in the UFH/warfarin group. At1 year, the rate of recurrent VTE was4.3% for both groups.44

In the subset of patients with cancer(n = 200), recurrent VTE within 3months occurred in 6% of patients whoreceived tinzaparin and 10% of thosereceiving UFH/warfarin.44 At 1 year,this difference was maintained, with 7%of patients receiving tinzaparin com-pared with 16% receiving UFH/war-farin experiencing recurrent VTE (P =.044). While there were no significantdifferences in mortality or bleedingevents between the two groups, thesedata support the finding of improvedoutcomes for recurrent VTE with long-term LMWH in cancer patients withthrombosis.

ONCENOX. The effectiveness oflong-term enoxaparin therapy to pre-vent recurrent VTE in cancer patientswas also evaluated in the open-label,parallel-design Initial Profiling of Can -cer Patients Entering in a SecondaryPrevention of Venous Thrombosis withEnoxaparin (ONCENOX) trial. Aswith CANTHANOX, this trial wasclosed due to poor recruitment.45,46

However, results are available for the102 patients who received 1 mg/kg ofenoxaparin SC twice daily for 5 daysand then were randomized to either 1.0mg/kg enoxaparin SC twice daily for175 days (group 1; n = 32), 1.5 mg/kg ofenoxaparin SC once daily for 175 days(group 2; n = 36), or initial treatmentwith enoxaparin as described above,with bridging to therapeutic doses of

warfarin, which was begun on day 2and continued for a total of 180 days(group 3; n = 34).45,46 The primary effi-cacy measure was the incidence ofobjectively documented recurrent VTEup to the end of the 180-day study peri-od, and the main safety outcome meas-ures were major and minor bleedingevents.45,46

The compliance rates were high in allthree groups, with mean rates of 97.6%,94.1%, and 92.8% for groups 1, 2, and 3,respectively. Recurrent VTE was experi-enced by 7.1% of the lower-dose enoxa-parin group, 3.2% of the higher-doseenoxaparin group, and 10.3% of thewarfarin group. No significant differ-ences in major or minor bleeding rateswere noted between the three groups,and there were no fatal or intracranialbleeding events.45,46

As with the earlier CANTHANOXtrial, the results of ONCENOX supportthe safety and efficacy of enoxaparin aslong-term therapy, but again, the failureto enroll a large patient population hin-ders the ability to draw conclusionsfrom these data.

CLOT. The Randomized Comparisonof Low-Molecular-Weight Heparin ver-sus Oral Anticoagulant Therapy forthe Prevention of Recurrent VenousThromboembolism in Patients withCancer (CLOT) study is the definitivetrial to date involving extendedLMWH treatment in patients with can-cer-associated thrombosis.38,47 This 6-month, international, multicenter,open-label trial randomized 676 cancerpatients with proximal DVT, PE, orboth to either dalteparin 200 IU/kg(maximum: 18,000 IU) SC given once

daily for 5 to 7 days, followed by long-term warfarin therapy (or aceno-coumarol in a few countries) titrated toachieve a target INR of 2.0 to 3.0, or toinitial therapy with dalteparin 200IU/kg SC (maximum: 18,000 IU) oncedaily, continued for the first month,then followed by long-term dalteparintherapy given in prefilled syringes at75% to 80% of the full dose (approxi-mately 150 IU/kg) for the remaining 5months.38 The primary efficacy endpoint was objectively documented,symptomatic, recurrent DVT, PE, orboth during the 6-month study period.Secondary outcome events were majorbleeding, any bleeding, and mortality at6 and 12 months.38

Unlike previous trials, adequaterecruitment to this trial was successful.Baseline characteristics of both groups

were well matched, 90% of patientshad solid tumors, and 67% had metasta-tic disease at trial entry.38 Eightypatients experienced a recurrent VTEduring the 6-month treatment period:27 in the dalteparin group and 53 in theoral anticoagulant group. The relativerisk reduction was 52%, favoring dal-teparin (P = .002).38 In the oral antico-agulant group, only 38% of thromboticevents occurred when the INR wasbelow 2.0, so a subtherapeutic INR didnot ac count for these events in themajority of patients in that group. Thehazard ratio for recurrent VTE in thedalteparin group versus the oral antico-agulant group was 0.48 (95% confi-dence interval, 0.30-0.77). Kaplan-Meier estimates of the probability ofrecurrent VTE at 6 months were 9% forpatients treated with dalteparin and

17% for those with anticoagulant.38

Over the course of the study, 6% ofpatients in the dalteparin group and4% in the oral anticoagulant group hada major bleeding event (P = .27).38

Overall, more bleeding events occurredin the oral anticoagulant group (19%)than in the dalteparin group (14%) (P =.09). There was no correlation betweenmajor bleeding events and a suprathera-peutic INR in the anticoagulantgroup.38 Major bleeds occurred at criti-cal sites (intracranial, retroperitoneal,or pericardial) in seven patients: threein the dalteparin group and four in theoral anticoagulant group.38 Most otherbleeds occurred in the gastrointestinalor genitourinary tracts.

As for mortality, 39% of patients inthe dalteparin group and 41% in theoral anticoagulant group had died atthe 6-month follow-up (P = .53).38

Progressive cancer was the cause ofdeath in 90% of cases in each group;however, there were five fatal PEs inthe dalteparin arm and seven in theoral anticoagulant arm. Although nosignificant difference in mortality wasfound between the two groups at 6 or12 months, a post hoc analysis of the12-month mortality data showed a sur-vival benefit for dalteparin in patientswithout metastatic cancer.48 Table 2summarizes the four LMWH trials dis-cussed here.

As a result of the trials describedabove, guidelines from several groups,including ACCP and NCCN, includerecommendations for long-term treat-ment of cancer-associated VTE withan LMWH.

Guidelines on the managementof VTE

Guidelines on the treatment of acuteVTE and prophylaxis of VTE inpatients with cancer have been issuedby a number of organizations, including

Table 2. LMWH vs Warfarin for Treatment and Secondary Prevention of VTE

Trial Name Study design

Number of

patients Treatment

Recurrent

VTE rate, % P value Mortality rate, %

ONCENOX Open-label, paralleldesign, randomized

102 Enoxaparin:Low-dose High-dose

7.1 10.3

NS—

CANTHANOX Open-label, multicenter,randomized

138 EnoxaparinWarfarin

10.5 21.1 NS

11.3 22.7 at 3 mo

LITE Open-label, multicenter,randomized

200a Enoxaparin

Warfarin

6 at 3 mo 7 at 1 yr 10 at 3 mo 16 at 1 yr

NS at 3 mo

.044 at 1 yr

20

19 at 12 wk

47 for bothgroups at 1 yr

CLOT Open-label, multicenter,randomized

676 DalteparinCoumarin derivative

8 15.7

.002 39 41 at 6 mo

a200 patients represent those with cancer only; total patient population included patients with and without cancer (n = 737).LMWH indicates low-molecular-weight heparin; NS, not significant; VTE, venous thromboembolism.Adapted with permission from Newcomb T, Sheth S. Therapeutic approaches to coagulopathy in cancer patients. US Pharmacist. 2007;32:5-10.

“Overall, more bleeding events occurredin the oral anticoagulant group (19%) thanin the dalteparin group (14%) (P = .09).”


=bpan�iu�>]hhkkj�Guldklh]opu(��EÐi�s]hgejc�l]ej)bnaa�]c]ej*

Tom Callaghan

Attorney, Age: 58

Diagnosis: Multiple

myeloma-induced

fracture

A vertebral compression fracture (VCF) occurs when

the vertebral body collapses because the bone is too weak due

to primary bone cancer, metastatic bone disease, and cancer

and chemotherapy-related osteoporosis.

Tom Callaghan experienced debilitating pain due to spinal fractures caused by multiple myeloma. “I couldn’t stand for more than a couple of minutes without pain.”

Tom underwent a minimally invasive procedure, Balloon Kyphoplasty, to treat his collapsed vertebrae. “It was truly remarkable,” he says. “Within two days of being discharged from the hospital, I was back on the golf course and playing tennis with my son. I could stand up straight and walk pain-free. It was as though it never happened.”

Tom’s cancer is in remission and he remains pain-free to this day.

To learn more about Balloon Kyphoplasty, visit our website at www.kyphon.com.

Although the complication rate with Balloon Kyphoplasty has been demonstrated to be low, as with most surgical procedures, there are risks associated with Balloon Kyphoplasty, including serious complications. For complete information regarding indications for use, warnings, precautions, adverse events and methods of use, please reference the devices’ Instructions for Use. Kyphon and KyphX are registered trademarks and Ahead of the Curve is a trademark of Kyphon Inc. © 2007 Kyphon Inc. All rights reserved. 16000846-01

Balloon Kyphoplasty

http://www.kyphon.com


SUPPORTIVE CA

RE Although great strides have been

made in the management ofchemotherapy-induced nausea

and vomiting (CINV), it remains afeared side effect of cancer treatment.CINV is classified into three primarycategories: acute, delayed, and antici-patory. Acute CINV is thought to bemostly serotonin related and occurswithin 24 hours of administration ofchemotherapy. Delayed CINV is, inpart, substance P related and occurs 24hours to several days after initial treat-ment. Anticipatory CINV is a learnedor conditioned response that can betriggered by taste, odors, sight, thoughts,or anxiety related to therapy. It is usual-ly secondary to a history of poorresponse to antiemetic agents or inade-quate antiemetic prophylaxis in previ-ous cycles of chemotherapy.

OverviewCancer chemotherapy is thought to

elicit nausea and vomiting through acti-vation of the chemoreceptor triggerzone, the gastrointestinal (GI) tract, thecerebral cortex, and other areas in theemetic center in the central nervoussystem (CNS).1 The emetic center sendsout signals to the esophagus, stomach,and abdominal muscles to cause emesis.1Multiple neurotransmitters are involvedin the emetic pathway; however, sero-tonin, substance P, and dopamine arebelieved to be the most important.These neurotransmitters are found inthe vagal nerve complex, the chemore-ceptor trigger zone, and the GI tract.Other receptors involved include corti-costeroid,2 histamine, cannabinoid, ace -tylcholine, gabaminergic, and opiate re -ceptors. Combinations of antiemetics arenecessary to target multiple neurotrans-mitters for adequate relief of CINV.1

Although the neurochemical systemsand pathways mediating che motherapy-induced emesis are reasonably wellunderstood, the neurochemical pro -cesses for nausea are less well de fined.The 5-hydroxytryptamine (HT3)-recep-tor antagonists are believed to play apivotal role in the mechanism of acuteemesis but have lesser impact ondelayed emesis. The mechanism ofdelayed emesis is thought to result fromseveral nonserotonergic mechanisms.Delayed emesis is also believed to bethe result of visceral inflammationinvolving mediators that activate theemetic reflex, such as prostaglandins,histamine, and substance P.2

The symptoms of nausea and vomit-ing are usually considered under theumbrella term, CINV, but actually twoseparate phenomena are occurring,which many believe are caused by sep-arate processes and respond differentlyto pharmacologic intervention. Someresearchers contend that whereas theserotonin antagonists have been very

successful at controlling chemothera-py-induced vomiting, the incidence ofposttreatment nausea may have actual-ly increased.3 The lack of adequatecontrol of CINV may be partly due tothe fact that antiemetic treatments arebased on risk factors such as level ofemetogenicity of chemotherapy agents.In a recent study by Cohen and associ-ates, as many as 13% of patients receiv-ing chemotherapy experienced acutevomiting and 33% experienced de -layed vomiting during cycles 1 to 3.4Acute and delayed nausea were moresignificant problems, with up to 35% ofpatients experiencing acute nausea and62% experiencing delayed nausea dur-ing cycles 1 to 3. Patients who devel-oped CINV during cycle 1 were morelikely to develop CINV at cycle 2.4

The neuropharmacologic mechanismof delayed CINV is not well under-stood. Despite improvements in emesiscontrol, nausea, which is less wellunderstood at the neurochemical level,continues to be a problem for patientsreceiving chemotherapy.

CINV affects patients’ quality of life(QOL); in fact, nausea has a strongernegative impact on QOL than vomit-ing.4,5 In addition, delayed nausea has agreater impact on QOL than acute nau-sea.6 Even infrequent episodes of emesisare associated with significant declinein QOL and in physical and cognitivefunctioning, and can eventually causepatients to delay or refuse potentiallycurative therapy.7 Uncontrolled CINVcan lead to decreased morale anddecreased ability to participate in activ-ities of daily life, such as work, personalcare, or recreational activities. In addi-

tion, uncontrolled symptoms are morelikely to lead to depression and fatigue.1

Chemotherapeutic agents are classi-fied into four emetic risk groups basedon the percentage of patients havingemetic episodes when no prophylacticantiemetic protection is provided. Therisk groups are: high (90%), moderate(30%-90%), low (10%-30%), and min-

imal (<10%).8 The risk of CINV isinfluenced by dosage of the chemo -therapeutic drug, duration of its infu-sion, and patient characteristics.Patient-related risk factors includefemale sex, younger age, a history ofmotion sickness, consumption of mini-mal amounts of alcohol (<1.5 ouncesof alcohol per day), emesis during preg-nancy, impaired QOL, and previousexperience with chemotherapy.8

Pharmacologic management ofCINV

Pharmacologic interventions to pre-vent and manage CINV are the onlymodalities supported by enough evi-

dence to be recommended for prac-tice9 (Table 1). With the correct use ofantiemetics, CINV can be preventedin at least 70% to 80% of patients.Nonpharmacologic interventions lacksufficient evidence to be recommend-ed for practice.9 Pharmacologic inter-ventions are recommended based onthe type of nausea and vomiting andthe level of emetogenicity of thechemotherapy. Oral and intravenous(IV) antiemetics are equally effective.The specific antiemetic used should bebased on the level of emetogenicityanticipated by the chemotherapy regi-men the patient is to receive. Theperiod when nausea and vomiting areanticipated, based on the chemothera-py regimen received, should be cov-ered by the antiemetics provided.However, the lowest effective doseshould be used. Contributing factorsthat may enhance nausea and vomit-ing include reflux, the patient’s under-lying disease, comorbid conditions,and other medications.9

Serotonin antagonists. The 5-HT3-receptor antagonists are the most effec-tive antiemetics for prophylaxis ofacute CINV (Table 2). Ondansetron,granisetron, dolasetron, and palon -osetron are serotonin antagonists thatare useful in the prevention of acutenausea and vomiting. Although gra -nisetron and dolasetron have differentpharmacologic profiles, including dif-ferences in binding affinity for the 5-

Chemotherapy-induced Nausea and VomitingBarbara Barnes Rogers, CRNP, MN, AOCN, ANP-BCAdult Hematology-Oncology Nurse Practitioner, Fox Chase Cancer Center, Philadelphia, Pennsylvania

“Even infrequent episodes of emesis areassociated with significant decline in QOLand in physical and cognitive functioning,and can eventually cause patients to delayor refuse potentially curative therapy.”

Table 1. Interventions for Nausea and Vomiting Supported byEmpirical Studies

Recommended for practice• Pharmacologic interventions, including benzodiazepines, 5-HT3-receptor

antagonists, corticosteroids, and NK-1 receptor antagonists

Likely to be effective• Acupuncture • Music therapy

• Acupressure • Progressive muscle relaxation

• Guided imagery • Psychoeducational support and information

• Hypnosis

Benefits balanced with harm• Virtual reality

Effectiveness not yet established• Exercise • Acustimulation with wristband device

• Massage • Ginger

• AromatherapySources: References 9 and 13.


SUPP

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CAR

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HT3-receptor, serum half-life, andmetabolism, they do not offer improvedcontrol of acute or delayed emesis orvomiting over ondansetron.2 Becausepalonosetron is effective in preventionof delayed CINV, the theory that sero-tonin receptors have little impact inthis area has been questioned. Pa -lonsetron has distinct structural fea-tures that may give it a different modeof binding to 5-HT3-receptors. In addi-tion, it exhibits a substantially higherbinding affinity and longer half-lifecompared with other serotonin recep-tor antagonists.7

The major routes of administrationof serotonin antagonists are oral or IV.Oral forms have been shown to be aseffective as IV forms.1 In October2008, a granisetron transdermal patchwas approved for the management ofCINV and can offer 5 days of protec-tion.10 In a noninferiority randomizedstudy, the patch provided equivalentcontrol of nausea and vomiting; 60.2%of patients receiving the patch and64.8% of patients receiving oralgranisetron achieved complete controlof CINV. Tropisetron is an additional5-HT3-receptor antagonist but is notavailable in the United States. As sin-gle agents, the serotonin antagonistshave a response rate of 60% to 80%;when combined with corticosteroids,however, the response rates are higher.The primary side effect of 5-HT3-receptor antagonists is headache.Change in bowel habits with eitherconstipation or diarrhea also has beenreported.7,11

Neurokinin-1-receptor antagonists.Substance P induces vomiting andbinds to neurokinin (NK)-1 receptors.Agents that block NK-1 receptorslessen emesis. Aprepitant, an NK-1-receptor antagonist, is the firstantiemetic in this class to be approved.Its delayed antiemetic activity isthought to be due to inhibition of theaction of substance P in the emeticpathways in both the central andperipheral nervous systems. Aprepitantis approved for prevention of bothacute and delayed emesis in combina-tion with 5-HT3-receptor antagonists.It may also exert some effect at thelevel of the gut. Current NationalComprehensive Cancer Network(NCCN) guidelines include the use ofaprepitant along with a serotoninantagonist and dexamethasone for theprevention of CINV associated withhighly emetogenic chemotherapy.12

Aprepitant is a moderate inhibitor ofcytochrome P450 (CYP) 3A4, andtherefore, the dexamethasone doseadministered along with aprepitant islowered because aprepitant may reducethe elimination of dexamethasone andother corticosteroids.8

Dexamethasone. Dexamethasone playsa major role in the prevention of acuteand delayed CINV and is included inalmost all antiemetic regimens. Corti -costeroids are potent antiemetics and

are often combined with otherantiemetics for enhanced benefit.When dexamethasone is added to sero-tonin antagonists, the complete re -sponse rates are about 15% to 20%higher. Dexamethasone is important inthe prevention and management ofCINV secondary to both moderate andhighly emetic chemotherapy agents.While dexamethasone is effective inmanaging acute CINV, it is particularlyactive in the management of delayedCINV. The most common side effects of

corticosteroids are insomnia, jitteriness,increased appetite, hyperglycemia, andheartburn or other GI distress.1

Cannabinoids. Cannabinoid-receptoragonists are known to exert antiemeticeffects. Although two cannabinoidreceptors have been identified (CB 1and CB 2), CB 1 is believed to play theimportant role in CINV. The mecha-nism of action of the CB 1 agonists(dronabinol and nabilone) is not clear-ly defined, but it is thought to actthrough the CB 1 receptors in thebrain stem. The efficacy of cannabi-noids in CINV, along with potentiallybeneficial side effects such as sedationand euphoria, may make cannabinoidsa useful adjunct to other antiemetics.

Their usefulness may be limited, how-ever, by the relatively high incidenceof bothersome side effects such as dizzi-ness, dysphoria, and hallucinations.8

Dopamine-receptor antagonists. Theseagents represent an older class of anti -emetics. Examples of agents that impactdopamine receptors include pheno -thiazines (eg, prochlorperazine andpromethazine), butyrophenones (eg,haloperidol and droperidol), and a ben-zamide (eg, metoclopramide). Theseagents are used for breakthrough CINV

and for refractory nausea and vomiting.Metoclopramide may be effective inmoderate doses in the delayed periodbut can cause sedation and extrapyra-midal side effects.7 Although listed inprevious guidelines, it is not currentlyrecommended and should be reservedfor special circumstances, such as intol-erance to 5-HT3-receptor antagonistsor corticosteroids. All these medica-tions cause more sedation, extrapyra-midal symptoms, and adverse effectsthan other antiemetics. Their useful-ness is due in part to their oral and par-enteral availability.

Benzodiazepines. Lorazepam is avail-able in both oral and parenteral forms.It is approved as an antianxiety agent

but is widely used as an antiemetic,especially in patients with break-through nausea and vomiting. Itsaction on nausea and vomiting may bethrough inhibition of impulses fromthe cerebral cortex to the emetic cen-ter in the CNS. Lorazepam reducessymptoms of anticipatory nausea andvomiting but causes CNS depression.1

Gabapentin. Gamma-aminobutyricacid (GABA) is the major inhibitorytransmitter in the brain, and GABA-receptor agonists are used clinically forseizure disorders and as sedatives. Theirmechanism of action involves calciumchannels that control neurotransmitterrelease.1 Gabapentin, a cyclic analog ofGABA, has been shown to improveCINV in an open-label study of patientswith breast cancer. Gabapentin has alsobeen studied in patients receiving high-ly emetogenic and moderately emeto-genic chemo therapy regimens. In thisgroup of patients who had significantprevious CINV, gabapentin used inaddition to a 5-HT3-antagonist anddexamethasone enhanced control ofnausea and vomiting. Further researchis necessary to determine the usefulnessof gabapentin in CINV.

Olanzapine. Olanzapine is an atypicalantipsychotic used to treat mania andschizophrenia. It also antagonizes sever-al neurotransmitters involved in CINV,such as serotonin, dopamine cate-cholamines, acetylcholine at muscarinicreceptors, and histamine.11 Olanzapineappears to be an effective alternative fortreating refractory CINV. It is well tol-erated, and few side effects have beenreported. The major side effects includefatigue, drowsiness, and dry mouth.1

Table 2. Doses of Antiemetics for Prevention or Breakthrough Nausea and Vomiting

Antiemetic Prevention Breakthrough

Aprepitant 125 mg PO day 1, then 80 mg PO days 2-3

Dexamethasone 12 mg PO or IV day 1, then 8 mg PO or IV days 2-4 12 mg PO or IV daily

Dolasetron 100 mg PO or 1.8 mg/kg IV or 100 mg IV day 1 100 mg PO daily or 1.8 mg/kg IV or 100 mg IV

Dronabinol 5 mg-10 mg PO every 3-6 hr

Granisetron 1 mg-2 mg PO or 1 mg PO bid or 0.01 mg/kg(max: 1 mg) IV day 1 or transdermal patchcontaining 34.3 mg applied 24-48 hr prior to first dose of chemotherapy

1 mg-2 mg PO daily or 1 mg PO bid or 0.01 mg/kg IV (max: 1 mg) or transdermalpatch containing 34.3 mg granisetron

Haloperidol 1 mg-2 mg PO every 4-6 hr

Lorazepam 0.5 mg-2 mg PO or IV or sublingual either every 4 or every 6 hr

0.5 mg-2 mg PO every 4-6 hr

Metoclopramide 10 mg-40 mg PO or IV every 4-6 hr 10 mg-40 mg PO or IV every 4-6 hr

Nabilone 1 mg-2 mg PO bid

Olanzapine 2.5 mg-5 mg bid

Ondansetron 8 mg-24 mg PO or 8 mg-12 mg IV 16 mg PO or 8 mg IV daily

Palonosetron 0.5 mg PO or 0.25 mg IV day 1

Prochlorperazine 10 mg PO or IV every 4-6 hr 25-mg suppository every 12 hr or 10 mg POor IV every 4-6 hr

Promethazine 12.5 mg-25 mg PO or IV every 4 hrIV indicates intravenous; PO, by mouth.Source: Reference 12.

“The efficacy of cannabinoids in CINV,along with potentially beneficial sideeffects such as sedation and euphoria,may make cannabinoids a useful adjunctto other antiemetics.”


SUPPORTIVE CA

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Casopitant. Casopitant is a newpotent and selective oral NK-1-receptor antagonist that has shownefficacy in managing CINV in patientsreceiving highly emetogenic chemo -therapy regimens. Overall, it has beenwell tolerated.1

Midazolam. Midazolam is a short-acting benzodiazepine with a rapidonset of action. It decreases dopamineinput at the chemoreceptor triggerzone and serotonin release by bindingto the GABA-benzodiazepine com-plex. Midazolam is generally well tol-erated, sedation being the most com-mon side effect.

Nonpharmacologic interventionsIn a review of the evidence for inter-

ventions to manage CINV, Tipton andcolleagues concluded that there wasinsufficient empirical evidence to rec-ommend nonpharmacologic interven-tions for CINV for use in clinical prac-tice.9 Based on the data, however,acupuncture, acupressure, guided im -agery, music therapy, progressive mus-cle relaxation, and psychoeducationalsupport were judged likely to be effec-

tive. The data also suggested that exer-cise, massage, aromatherapy, acustimu-lation with a wrist device, andconsumption of ginger did not yet haveestablished effectiveness, and that hyp-nosis was not sufficiently efficacious tosupport its use.9

Hypnosis. Richardson and colleaguesconducted a meta-analysis of six ran-domized controlled trials, five of whichfocused on CINV in children.13 Al -though these studies tended to havesmall samples, they revealed a largeeffect size of hypnotic treatment com-pared with treatment as usual. Thesefindings suggest that hypnosis is likelyto be beneficial, especially in children,but additional trials are needed to clar-ify its benefit.

Acupuncture/acupressure. Acupunc -ture at P6 (Figure) is frequently used totreat nausea and vomiting. The P6acupoint is located on the anterior sur-face of the forearm approximatelythree finger-widths from the wristcrease. P6 acupuncture plus antiemet-ics has been shown to be more effectivethan antiemetics alone or antiemeticswith placebo acupuncture. Electro -acpuncture with antiemetics has alsoproved more effective in controlling

emesis than placebo acupuncture withantiemetics or antiemetics alone.14 In ameta-analysis, Ezzo and associatesfound that acupuncture was effectivein reducing the incidence of acute

vomiting but not the severity of acutenausea.15 In a randomized trial, Dibbleand associates showed that acupressure(ie, the application of pressure to acu-points digitally or with acustimulation

bands) at P6 is useful for managingdelayed nausea and vomiting.16

Other interventions. In a meta-analy-sis of 15 studies of guided imagery, aclinically significant reduction of nau-

Figure. Acupuncture at the P6 pointReprinted with permission from Reference 9.

COMMENTARY

As outlined in the accompanying article by Rogers,there have been significant developments in con-trolling chemotherapy-induced nausea and vomit-

ing (CINV) but less progress has been made in the controlof nausea. The availability of neurokinin-1 antagonists hasimpacted the rate of delayed emesis with cisplatin and bothacute and delayed emesis for regimens, such as doxorubicinplus cyclophosphamide for breast cancer.1,2 With these andother advances in recent years come a new set of questions.Three important questions for patient care are:

• How should clinicians apply current CINV guidelines?• What is the place of serotonin and dopamine antago-

nists in current antiemetic therapy?• How should antiemetics be dosed for multiday

chemotherapy regimens?Guidelines for the prevention of CINV have become

commonplace from both a general patient care and an insti-tutional or health-system perspective. Some aspects of thedifferent guidelines are outlined in the Table.3-6 Generallyspeaking, the American Society of Health-SystemPharmacists guidelines, although old and missing informa-tion on newer medications, offer the most thorough reviewof medication dosing. The American Society of ClinicalOncology guidelines offer the best evidence basis forantiemetic use and comprehensive clinical guidance. TheNational Com pre hensive Cancer Network guidelines,while the most up-to-date, are most likely to be influencedby common practice without clinical evidence. TheMultinational Association of Supportive Care in Cancerguidelines offer a more international perspective on thecontrol of CINV. Depending on the clinician’s needs, eachhas useful information to offer but must always be inter-preted in the above-mentioned contexts when designinginstitutional guidelines.

Serotonin antagonists are clearly the mainstay of acuteCINV prophylaxis, with multiple studies showing clinicalevidence for separation of the acute, serotonin-driven anddelayed, substance P–driven phases of CINV.7,8 Despitecontinued use by community oncologists, the use of theseagents in the delayed setting continues to be controversialbecause of inadequately controlled trials.9,10 In contrast,dopamine antagonists, which were once favored for controlof acute emesis, have been relegated to use in the delayedor salvage settings because of their lower efficacy and high-

er adverse event rates compared with serotonin antagonists.In this setting, they continue to show patient benefit.

Additional study of CINV prophylaxis for patients re -ceiving multiday chemotherapy is needed. Current guide-lines provide minimal guidance regarding multiday thera-pies, although recent trials support the need for dailyadministration of serotonin antagonists, dexamethasone,and potentially aprepitant or dopamine antagonists. Doseand duration of dose generally are individualized based onlimited study data or local treatment norms.11-13

There has been slow, continuous improvement in ourclinical and scientific understanding of the prevention ofCINV, but many questions remain unresolved and there ismuch room for improvement in our understanding of howto best utilize new therapies.

References1. Polo-Bigelli S, Rodrigues-Pereira J, Carides AD, et al. Addition of the neu-

rokinin 1 receptor antagonist aprepitant to standard antiemetic therapyimproves control of chemotherapy-induced nausea and vomiting: resultsfrom a randomized double-blind, placebo-controlled trial in LatinAmerica. Cancer. 2003;97:3090-3098.

2. Warr DG, Hesketh PJ, Gralla RJ, et al. Efficacy and tolerability of aprepi-tant for the prevention of chemotherapy-induced nausea and vomiting inpatients with breast cancer after moderately emetogenic chemotherapy.J Clin Oncol. 2005;23:2822-2830.

3. Naeim A, Dy SM, Lorenz KA, et al. Evidence-based recommendations forcancer nausea and vomiting. J Clin Oncol. 2008;26:3903-3910.

4. ASHP Therapeutic guidelines on the pharmacologic management of nau-sea and vomiting in adult and pediatric patients receiving chemotherapyor radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:729-764.

5. Kris MG, Hesketh PJ, Herrstedt J, et al. Consensus proposals for the pre-vention of acute and delayed vomiting and nausea following high-emetic-risk chemotherapy. Support Care Cancer. 2005;13:85-96.

6. NCCN Clinical Practice Guidelines in Oncology: Antiemesis, V.3.2009.www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. AccessedJanuary 27, 2009.

7. Hesketh PJ, Van Belle S, Aapro M, et al. Differential involvement of neu-rotransmitters through the time course of cisplatin-induced emesis asrevealed by therapy with specific receptor antagonists. Eur J Cancer. 2003;39:1074-1080.

8. Schmoll HJ, Aapro MS, Polo-Bigelli S, et al. Comparison of an aprepitantregimen with a multiple-day ondansetron regimen, both with dexametha-sone, for antiemetic efficacy in high-dose cisplatin treatment. Ann Oncol.2006;17:1000-1006.

9. Saito M, Aogi K, Sekine I, et al. Palonosetron plus dexamethasone versusgranisetron plus dexamethasone for prevention of nausea and vomitingduring chemotherapy: a double-blind, double-dummy, randomised, com-parative phase III trial. Lancet Oncol. 2009;10:115-124.

10. Geling O, Eichler HG. Should 5-hydroxytryptamine receptor antagonistsbe administered beyond 24 hours after chemotherapy to prevent delayedemesis? Systematic re-evaluation of clinical evidence and drug cost impli-

cations. J Clin Oncol. 2005;23:1289-1294.11. Einhorn LH, Brames MJ, Dreicer R, et al.

Palonosetron plus dexamethasone for preventionof chemotherapy-induced nausea and vomiting inpatients receiving multiple-day cisplatin chemo -therapy for germ cell cancer. Support Care Cancer.2007;15:1293-1300.

12. Bubalo JS, Leis JF, Curtin PT, et al. A randomized,double-blinded, pilot trial of aprepitant added tostandard antiemetics during conditioning therapyfor hematopoietic stem cell transplant (HSCT). JClin Oncol. 2007;25(suppl 18):Abstract 9112.

13. Herrstedt J Sigsgaard TC, Nielson HA, et al.Randomized, double-blind trial comparing theantiemetic effect of tropisetron plus metopi-mazine with tropisetron plus placebo in patientsreceiving multiple cycles of multiple-day cis-platin-based chemotherapy. Support Care Cancer.2007;15:417-426.

A PHARMACIST’S PERSPECTIVEChemotherapy-induced Nausea and VomitingJoseph S. Bubalo, PharmDKnight Cancer Institute, Oregon Health & Science University, Portland, Oregon

Table. Antiemetic Guidelines

Guideline Last updated CommentsAmerican Society of Health-System Pharmacists

1999 Need substantial updating

American Society of ClinicalOncology

2008

National ComprehensiveCancer Network

2009 Updated multiple times peryear. Criteria for updateunclear

Multinational Association ofSupportive Care in Cancer

2004 Due for review and update inJune 2009

http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf

A Newsletter Series for Cancer Care Professionals

Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, will proudly offer the multidisciplinary cancer team at your center a series ofnewsletters focusing on the challenges in treating patientswith multiple myeloma.

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At the completion of this educational activity, participants should be able to:• Describe how standard therapy may be improved with novel agents and treatment

approaches for patients with relapsed and refractory multiple myeloma (MM)• Summarize new data from clinical trials in relapsed/refractory MM as reported at the

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• Retreatment Settings

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SUPPORTIVE CA

RE

sea was found17; the effect on vomitingcould not be analyzed, however,because of its low incidence. Virtualreality has been shown to be a possibleintervention for nausea and vomiting,but it may have adverse effects. Thiscomputer-simulated technique allowsindividuals to hear and feel stimuli thatcorrespond with a visual image. It isinteractive and engages multiple sensessimultaneously. Although virtual reali-ty can decrease emesis following che -motherapy, it also can cause motionsickness, which can increase nauseaand vomiting. In addition, its prohibi-tive cost can limit its usefulness.17

Progressive muscle relaxation candecrease the duration of nausea andvomiting considerably. Meta-analyseshave shown a consistent positive effecton reduction of nausea and vomiting aswell as other symptoms, but limiteddata are available.17

Psychosocial support and information.Psychosocial support and informationcan be effective in managing CINV.Williams and Schreier assessed thelevel of CINV in 70 women with breastcancer and found that informationalaudiotapes on self-care behaviors andthe occurrence and intensity of sideeffects of treatment were helpful inmanaging the side effects that womenoften have with breast cancer treat-ment.18 A meta-analysis of 116 inter-vention studies showed that psychoed-ucational and psychosocial care havebeneficial effects in managing nauseaand vomiting in patients with cancer.19

Clinician interventionsA significant component of preven-

tion and management of CINV relatesto patient education regarding whichantiemetics to use and when to takeoral medications at home. Antiemeticsshould be taken early enough beforemeals to ensure that the effect is pres-ent during and after meals. Althoughnot supported by sufficient data,dietary interventions may also be ben-eficial. Exposure to aromas of food andother substances, such as perfumes,should be minimized. Patients shouldbe instructed to eat small, more fre-quent meals and to avoid foods that arespicy, fatty, or highly salty, becausethese foods may enhance nausea andvomiting.9

ConclusionDuring the past two decades, many

advances have been made in theunderstanding and control of CINV.Although acute emesis is well con-trolled with the use of 5-HT3-antagonists, delayed nausea is less wellunderstood and not optimally con-trolled with modern antiemetic thera-py. Continued research is necessary tobetter understand this symptom.Currently, only pharmacologic inter-ventions have sufficient data to sup-port their use. Although data exist onthe use of some nonpharmacologic

interventions (such as acupuncture,acupressure, guided imagery, musictherapy, progressive muscle relaxation,and psychoeducational support), addi-tional evidence is necessary before theycan be recommended as a componentof CINV therapy. Anecdotal evidencesupports the efficacy of lemon, pepper-mint, ginger, and chamomile, but thereis no research that examines the use ofthese herbal products in the manage-ment of CINV.9

Clinicians must have an attitude ofzero tolerance for nausea and vomitingin patients receiving cancer therapy.With an emphasis on open communi-cation about CINV and ongoing mod-ifications in interventions, optimalcontrol of CINV can be achieved forthe majority of patients receivingchemotherapy.

References1. Lohr L. Chemotherapy-induced nausea and

vomiting. Cancer J. 2008;14:85-93.2. Rubenstein E, Slusher B, Rojas C, Navari RM.

New approaches to chemotherapy-induced nau-sea and vomiting: from neuropharmacology toclinical investigations. Cancer J. 2006;12:341-347.

3. Roscoe J, Morrow G, Hickok J, Stern RM.Nausea and vomiting remain a significant clini-cal problem: trends over time in controllingchemotherapy-induced nausea and vomiting in1413 patients treated in community clinical prac-tices. J Pain Symptom Manage. 2000;20:113-121.

4. Cohen L, de Moor CA, Eisenberg P, et al.Chemotherapy induced nausea and vomiting:incidence and impact on patient quality of life atcommunity oncology settings. Support CareCancer. 2007;15:497-503.

5. Bloechl-Daum B, Deuson R, Mavros P, et al.Delayed nausea and vomiting continue toreduce patients’ quality of life after highly andmoderately emetogenic chemotherapy despiteanti emetic treatment. J Clin Oncol. 2006;24:4427-4478.

6. Ballatori E, Rolla F, Ruggeri B, et al. The impactof chemotherapy-induced nausea and vomitingon health-related quality of life. Support CareCancer. 2007;15:179-185.

7. Navari R. Prevention of emesis from multiple-day and high-dose chemotherapy regimens. J NatCompr Canc Netw. 2007;5:51-59.

8. Jordan K, Sippel C, Schmoll H-J. Guidelines forantiemetic treatment of chemotherapy-inducednausea and vomiting: past, present, and future rec-ommendations. Oncologist. 2007;12:1143-1150.

9. Tipton JM, McDaniel RW, Barbour L, et al.Putting evidence into practice: evidence-basedinterventions to prevent, manage, and treatchemotherapy-induced nausea and vomiting.Clin J Oncol Nurs. 2007;11:69-78.

10. Grunberg S, Gabrial NY, Clark G. Phase III trialof transdermal granisetron patch (Sancuso)compared with oral granisetron in the manage-ment of chemotherapy-induced nausea andvomiting (CINV). Multinational Associationof Supportive Care in Cancer; June 18, 2007;Poster 18.

11. Roila F, Garassino M, Fatigoni S. New anti-emetic treatments. Ann Oncol. 2007;18(suppl9): 43-47.

12. NCCN Clinical Practice Guidelines in On -colo gy: Antiemesis, V.3.2009. www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf.Accessed January 27, 2009.

13. Richardson J, Smith JE, McCall G, et al.Hypnosis for nausea and vomiting in cancerchemotherapy: a systematic review of theresearch evidence. Euro J Cancer Care (Engl).2007;16:402-412.

14. Shen J, Wenger N, Glaspy J, et al. Electro -acupuncture for control of myeloablativechemotherapy-induced emesis: a randomizedcontrolled trial. JAMA. 2000;284:2755-2761.

15. Ezzo J, Vickers A, Richardson MA, et al.Acupuncture-point stimulation for chemothera-py-induced nausea and vomiting. J Clin Oncol.2005;23:7188-7198.

16. Dibble S, Luce J, Cooper BA, et al. Acupressurefor chemotherapy-induced nausea and vomiting:a randomized clinical trial. Oncol Nurs Forum.2007;34:813-820.

17. Luebbert K, Dahme B, Hasenbring M. The effec-tiveness of relaxation training in reducing treat-ment-related symptoms and improving emotion-al adjustment in acute non-surgical cancertreatment: a meta-analytical review. Psychooncol -ogy. 2001;10:490-502.

18. Williams S, Schreier A. The effect of educationin managing side effects in women receivingchemotherapy for treatment of breast cancer.Onocol Nurs Forum [online exclusive]. 2004.http://ons.metapress.com/content/b366435101rv1712/fulltext.pdf. Accessed March 10, 2009.

19. Devine E, Westlake S. The effects of psychoedu-cational care provided to adults with cancer:meta-analysis of 116 studies. Oncol Nurs Forum.1995;22:1369-1381.

COMMENTARY

A NURSE’S PERSPECTIVE

Chemotherapy-inducedNausea and VomitingAmy Ford, RN, BSN, OCNClinical Education Specialist, Creative Cancer Concepts, Inc, Rockwall, Texas

Many significant advances have been made in the past 20 years thathave improved the care of patients with chemotherapy-induced nau-sea and vomiting (CINV). Delayed nausea is still an issue, however.

Rogers explains the physiologic reasons for this symptom in the accompany-ing article, but there are psychosocial and financial issues to consider as well.For example, does the patient take the antiemetics as prescribed? Does thepatient have prescription insurance issues, such as a high copayment for themedication? Does the patient actually purchase the drug if there are monetaryconcerns? Taking a proactive approach and assigning a nurse to call allpatients on day 3 of the treatment cycle can improve management of delayednausea.

Palonosetron, the only intravenous (IV) 5-HT3-receptor antagonistapproved for delayed CINV, works on both acute and delayed CINV.¹ Bothpalonosetron and aprepitant are now available in IV and oral formulations.²,³Oral antiemetics are effective only if the patient has adequate absorption or afunctioning gut. The 5-HT3 granisetron transdermal patch presents an excit-ing new route of antiemetic delivery. The patch may be a good option forthose with oral intake issues or those who forget to take medications. Otherroutes being researched are novel formulations of ondansetron in a lingualspray and a quick-dissolving film.4

Many patients are taking some type of oral therapy for their cancer. Patientsmay believe that side effects may not be “as strong” with these agents. It isimportant to explain that the emetic risk applies to all agents—regardless ofroute of administration. Scripps Cancer Center has added the relative emeto-genicity of chemotherapeutic agents along with those associated with delayedemesis on the back of the chemotherapy order sheet to serve as a second checkfor the oncology nurse to ensure that appropriate antiemetics are orderedaccording to medication administered. Education must be provided to bothclinician and patient proactively to reduce the risk of CINV.

Enrollment of patients in supportive care trials is critical to our knowledgeof CINV. Research helps to improve patient care. For example, Grunberg andcolleagues reviewed the use of palonosetron (25 mg), dexamethasone (20 mg),and aprepitant (285 mg) in a single dose on day 1, avoiding the multiday reg-imen. One hundred percent (n = 41) were emesis free in the acute phase, and97% in the delayed phase.5 As Rogers pointed out, it is particularly critical fornonpharmacologic interventions to be studied because of the lack of research.Nurses must have an open relationship with patients to ensure that they dis-close use of herbal, over-the-counter, and complementary therapies.

As Rogers explained, there must be zero tolerance for CINV. Oncologynurses are at the forefront of managing CINV and educating patients aboutzero tolerance. Nurses must be proactive instead of reactive in terms of choos-ing the best medications from the current armamentarium in this battle. Wemust ask ourselves what antiemetic regimen would I want if that were me?

References1. Aloxi (palonosetron HCl) [package insert]. Switzerland: Helsinn Healthcare SA; 2008.2. Palonosetron: the long-lasting antiemetic action finds its basis [news release]. September 2008.

www.helsinn.com/media/news/ex/3360_esmo2008release-final_1.pdf Accessed December 16, 2008.3. Emend (aprepitant) [package insert]. Whitehouse Station, NJ: Merck & Co; 2008.4. Strativa Pharmaceuticals. Pharmaceuticals in late stage development as of December 2008.

www.strativapharma.com/pipeline.php. Accessed December 16, 2008.5. Grunberg SM, Dugan M, Muss HB, et al. Efficacy of a 1-day 3-drug antiemetic regimen for pre-

vention of acute and delayed nausea and vomiting induced by moderately emetogenicchemotherapy. J Clin Oncol. 2007;25(suppl 18):Abstract 9111.

http://ons.metapress.com/content/b366435101rv1712/fulltext.pdf

http://www.helsinn.com/media/news/ex/3360_esmo2008release-final_1.pdf

http://www.strativapharma.com/pipeline.php




NO

N-H

OD

GKI

N’S

LYM

PHO

MA

Despite the fact that non-Hodgkin’s lymphomas (NHLs)represent only 4% of all newly

diagnosed cancers, they remain themost common hematologic malignancyin adults, with an estimated 66,000 newcases diagnosed in the United States in2008.1,2 The current front-line standardof care for NHL utilizing the combina-tion chemotherapy regimen of cyclo -phosphamide, doxorubicin, vincristine,and prednisone (CHOP) has resulted ininitial re sponse rates of 60% to 80%, yetmost patients will ultimately relapse anddie of their disease.3,4 For this reason,research has focused on the develop-ment of new therapies, including themonoclonal antibodies (Table 1).5 Thisreview focuses on some of the newernonchemotherapy treatments for NHL.

RituximabRituximab is a murine chimeric mono -

clonal antibody directed against theCD20 cell-surface antigen found prima-rily on pre-B and mature B lympho-cytes.6 Physiologically, it is believed thatCD20 plays a role in B-cell activation,

proliferation, and differentiation, whichmay be essential to the expansion oflymphoma cells. Because as many as85% of all adult cases of NHL are of B-cell origin, CD20 has become an impor-tant target for improving the efficacy ofNHL treatment regimens.7 Multiplestudies have demonstrated that the addi-tion of rituximab to CHOP chemother-apy improves overall survival and event-free survival in patients with newlydiagnosed diffuse large B-cell lymphoma(DLBCL).8 Infusion-related toxicitiesare relatively common with rituximaband include fever, chills, orthostatichypotension, bronchospasm, and rigors.Although these toxicities affect as manyas 80% of patients, they are typicallylimited to the infusion period.5

OfatumumabOfatumumab is a fully human CD20

monoclonal antibody developed as analternative for patients who do notrespond or become resistant to ritux-imab. It differs from rituximab by target-ing a novel epitope of CD20 and havinga very slow release from the target thatappears to be related to an increase incomplement-dependent cytotoxicity.5,9

As a result, ofatumumab may have effi-cacy in patients with relapsed or refrac-tory NHL who have previously beentreated with rituximab.10 Additionally,preclinical data have shown thatpatients who express high levels ofCD59, a complement-regulatory pro-tein, in addition to CD20, derive thegreatest benefit from ofatumumab.11

Phase 2/3 studies demonstrated efficacyin patients with follicular lymphomaand relapsed or refractory B-cell chron-ic lymphocytic leukemia (CLL), withan overall response rate of 63%, includ-ing a 57% response rate in patients pre-viously treated with rituximab.9,10,12

Furthermore, the adverse event profileof ofatumumab is very similar to that of

rituximab, and toxicities (or hypersensi-tivity) appear primarily during the infu-sion period.9,10

GaliximabCD80 is a mediator of B-cell and T-

cell activation and frequently is consti-tutively activated in a variety of NHLs,including follicular lymphoma.13 Galix -imab is a primate–human chi meric anti-body, which upon binding CD80 resultsin an upregulation of apoptosis, antipro-liferation, and induction of antibody-dependent cellular cytotoxicty.14 Addi -tionally, preclinical models havedemonstrated the potential for galix-imab to sensitize resistant B-cell malig-nancies, resulting in the synergisticallyenhanced cytotoxicity of traditional

chemotherapeutic drugs.15 Galiximabhas been evaluated alone and in combi-nation with rituximab in patients whohad relapsed or failed primary therapyfor follicular NHL. Phase 2/3 studiesreported superior results with the com-bination therapy than with singleagents, including a 66% overall re -sponse rate for patients receiving galix-imab (500 mg/m2) and rituximab (375mg/m2).16 Structurally, galiximab isindistinguishable from human antibod-ies because of its human constantregions and primate variable regions,rendering the antibody unlikely toinduce immunogenicity in humans.This results in minimal adverse events,which include primarily nausea, fatigue,and headache.17

EpratuzumabEpratuzumab is a humanized antibody

targeting the CD22 surface antigen.CD22 appears to be preferentiallyexpressed on the surface of mature Bcells and has been identified in 60% to80% of B-cell malignancies.18 Althoughthe function of CD22 is not fully under-stood, it is believed to function in celladhesion and B-cell activation, makingit a novel target for antibody thera-py.19,20 In contrast to its murine antibodypredecessor, LL2, epratuzumab wasdeveloped with the goal of reducingimmunogenicity, prolonging half-life,and increasing effector function.21

Efficacy has been demonstrated withepratuzumab as both a single agent andin combination with rituximab for

patients with relapsed or refractory B-cell NHL.4 In a recent international,multicenter study of epratuzumab plusrituximab in patients with recurrentindolent NHL, 24% of patients exhibit-ed a complete response (CR) that wasmaintained at a median follow-up of44.3 months. These results confirm thatthis combination shows promising effi-cacy for patients with indolent NHL,the adverse event profile for the combi-nation being no more severe than forrituximab alone.22 Ongoing studies arecurrently evaluating the combinationregimen as initial therapy for indolentNHL (CALGB 50701) and for DLBCLin combination with CHOP plus ritux-imab (NCCTG N0489).

LumiliximabFollicular lymphoma and CLL B cells

overexpress CD23. When CD23 is tar-geted by lumiliximab, a primatized anti-body, immunoglobulin E production isinhibited and cellular apoptosis is stim-ulated.23 In single-agent trials, lumilix-imab was observed to have limitedeffectiveness in patients with CLL.24

However, a phase 1/2 study evaluatingthe combination of lumiliximab withfludarabine, cyclophosphamide, andrituximab (FCR) for patients withrelapsed CLL resulted in a 71% overallresponse rate with 48% CR. Theseresults suggest a higher response ratefor FCR plus lumiliximab than for FCRalone. Common toxicities includednausea, pyrexia, chills, neutropenia,and fatigue.25

Beyond Chemotherapy: Non-Hodgkin’s Lymphoma UpdateSteve Stricker, PharmD, MSAssistant Professor of Pharmacy Practice, Samford University McWhorter School of Pharmacy, Birmingham, Alabama

Jolynn K. Sessions, PharmD, BCOPOncology Clinical Pharmacist Specialist, Charles George Asheville Veterans Administration, Asheville, North Carolina

Table 1. Monoclonal Antibodies for B-cell Non-Hodgkin’sLymphoma

Antibody Target Phase of developmentRituximab CD20 Commercially available

Ofatumumab CD20 Phase 1/3

Galiximab CD80 Phase 2/3

Epratuzumab CD22 Phase 2

Lumiliximab CD23 Phase 3

Radioimmunotherapy90Y-ibritumomab tiuxetan CD20 Commercially available131I-tositumomab CD20 Commercially availableSource: Reference 5.

“Because as many as 85% of all adultcases of NHL are of B-cell origin, CD20has become an important target forimproving the efficacy of NHL treatmentregimens.”


NO

N-H

OD

GKIN

’S LYMPH

OM

A

Radioimmunotherapy With the long-term success of mono-

clonal antibodies such as rituximab inthe treatment of patients with NHL,anti-CD20 antibodies have been com-bined with radioisotopes in an attemptto “home” radiation therapy to CD20-positive B cells to improve efficacy.Studies have demonstrated radiationsensitivity of lymphoma cell lines,making radioimmunotherapy an at -tractive option for patients withNHL.26 In addition to the direct effectof killing cells by targeted radiation,these drugs have the potential to killsurrounding cells that may not ade-quately express surface antigen or maybe poorly vascularized.27 Two radioim-munotherapy drugs are currently com-mercially available.

90Y-labeled ibritumomab tiuxetan.Ibritumomab tiuxetan is a murine,anti-CD20 antibody that is the parentcompound of rituximab and acts by tar-geting the same CD20 epitope as ritux-imab. It has been combined with yttri-um-90 (90Y), a beta emitter, resultingin an 80% overall response rate inpatients with follicular or low-gradeNHL, without the toxicity of totalbody irradiation.28 Furthermore, ibritu-momab therapy has been demonstratedto be efficacious in patients with ritux-imab-refractory follicular lymphoma,with response rates of 74% and a CRrate of 15%.29 Recent studies evaluat-ing the use of ibritumomab as consoli-

dation therapy in patients withadvanced stage follicular lymphoma infirst remission resulted in an 87%unconfirmed CR rate and a prolonga-tion of progression-free survival (PFS)of 2 years.30 Adverse reactions withibritumomab include severe cutaneousand mucocutaneous skin reactions.

131I-labeled tositumomab. Similar toibritumomab, tositumomab is a murineanti-CD20 antibody conjugated to aradioactive isotope, iodine-131 (131I).Dosing of tositumomab occurs over thecourse of a week and must be accompa-nied by drugs to protect the thyroid,given the avidity of the thyroid glandfor iodine. The pivotal phase 3 trialevaluating the efficacy of tositumomabin patients with chemotherapy-refracto-ry NHL reported a 65% response rate,with 20% CR.31 Additionally, treatmentwith tositumomab has shown to resultin a 20% complete remission rate inpatients with rituximab-refractory lym-phoma.32 A recent phase 3 study evalu-ating the effect of tositumomab versusR-CHOP on PFS rates in newly diag-nosed patients with follicular NHL hascompleted enrollment and may create aparadigm shift in front-line therapy forthis patient population. Hyper -sensitivity reactions and severe or life-threatening cytopenias have beenreported in patients treated with tositu-momab. For this reason, exclusion crite-ria include patients with greater than25% bone marrow involvement, less

than 15% bone marrow cellularity,platelet counts of less than 100,000cells/mm3 or neutrophil counts of lessthan 1500 cells/mm3, extensive previ-ous radiation therapy, pregnancy (dueto potential fetal risk), lactation, or pre-vious stem-cell transplantation (due tounknown safety).5

Bortezomib and other proteasome inhibitors

The body of literature for the use ofbortezomib in NHL continues to growand may have the most compelling dataas compared with other nonchemother-apy, nonmonoclonal agents. The bulkof study results are on the use of borte-zomib for mantle-cell lymphoma(MCL). This is in part due to theDecember 2006 US Food and Drug Ad -ministration (FDA) approval of borte-zomib for the treatment of patients withMCL who have received at least oneprior therapy. This approval has height-ened the interest in using bortezomib incombination with other agents. Table 2summarizes some of the newer data onuse of bortezomib for MCL.33-37

Bortezomib is also being studied inother forms of NHL. As a single agent,it has shown a response rate of 50% inpatients with relapsed or refractory gas-tric marginal zone B-cell lymphoma.38

An interesting phase 1 trial ongoing inKorea has “replaced” rituximab withbortezomib when given with dose-denseCHOP as first-line therapy in DLBCL.39

In this study, doses of bortezomib usedwere 1 mg/m2, 1.3 mg/m2, or 1.6 mg/m2

on days 1 and 4, with a 1-week recoveryperiod. Eight of nine evaluable patientshad CR. The authors concluded thatfirst-line bortezomib plus dose-denseCHOP every 2 weeks was safe and hadpromising antitumor activity. Furthertesting in phase 2 trials is under way.Study results are now emerging for newproteasome inhibitors, such as carfil-zomib, in lymphomas and other hemato-logic malignancies. These newer agentsmay offer minimal cross-reactivity withother catalytic sites within the proteo-some as compared with bortezomib.

Acetylase inhibitorsIn October 2006, vorinostat, the first

of a new class of agents, was approved bythe FDA for cutaneous T-cell lym-phoma (CTCL). Vorinostat is a histonedeacetylase (DAC) inhibitor. Histone isthe major protein component, or frame-work, that DNA wraps around. Histoneacetylase is an enzyme that acts to cre-ate a less compact and more transcrip-tionally active DNA/protein structure,thus allowing easier replication. Con -versely, histone DAC works to create acondensed and transcriptionally si -lenced chromatin. By altering the struc-ture of a chromosome, gene transcrip-tion can also be altered. A histoneDAC inhibitor would allow genes thathave been previously silenced, forexample a gene that helps to suppress

Table 2. Recent Trials of Bortezomib in Mantle-cell Lymphoma

Reference Phase N Bortezomib dose Plus chemotherapy Response Toxicities

Goy A et al 2 155 1.3 mg/m2, days 1, 4, 8, 11

None 1-y OS = 69% 1-y survival in responders = 91%Refractory patients, median survival = 17.3 mo ORR = 31% CR + Cru = 8%

Neuropathy, fatigue,thrombocytopenia

Drach J et al 2 16 1.3 mg/m2, days 1, 4, 8, 11

Rituximab 375 mg/m2, day 1; dexamethasone 40 mg orally days1–4; repeat every 21 days for 6cycles; rituximab maintenance;BORID

ORR = 69% (11/16) CR = 38% (6/16)

Zoster, bacterialpneumonia, mucosalcandidiasis, peripheralneuropathy, vasculitic skin infiltrates

Guariglia R et al 2 6 > 75 years 1.3 mg/m2, days 1, 4, 8, 11

Rituximab 375 mg/m2, day 1,hyperfractionated cyclophos-phamide 600 mg/m2/d as doubleinfusion, days 1–3; repeat every 21 days; RBC

ORR = 66.6% PR = 1/6 (17%)CR = 3/6 (50%)

Thrombocytopenia,neutropenia

Gerecitano JF et al

1 Total = 27 MCL = 9

1.3–1.8 mg/m2, days 2 and 8 or 1.1–1.5 mg/m2, days 2,5, 9, 12

Rituximab 375 mg/m2, day 1,cyclophosphamide 750 mg/m2 or1000 mg/m2, day 1; oral prednisone 100 mg, days 2–6; up to 8 cycles R-CB or P

Combined: CR = 5/27 (19%) PR = 13/27 (48%)SD = 8/27 (30%)ORR = 96%

Neutropenic fever,diarrhea, dehydration,neuropathy

Agathocleous A et al

1/2 Total = 45 MCL = 18

1.3 mg/m2, days 1, 4, 8, 11 of 21-daycycle (arm A) or 1.6 mg/m2, days 1, 8,15, 22 of 35-day cycle

Rituximab 375 mg/m2, day 1 for 8 cycles (arm A) or rituximab 375 mg/m2, days 1, 8, 15, 22,cycles 1 and 4 for 6 cycles (arm B)

ORR = 56% ORR in MCL = 46%

Neutropenia,thrombocytopenia, fatigue, nausea, diarrhea,lethargy, neurotoxicity

BORID indicates bortezomib, rituximab, and dexamethasone; CR, complete response; Cru = complete response unconfirmed; MCL, mantle-cell lymphoma; OS, overall survival; ORR, overall rate of response; PR, partial response;RBC, rituximab, bortezomib, and hyperfractionated cyclophosphamide; R-CB or P, bortezomib with rituximab, cyclophosphamide, prednisolone; SD, stable disease.Sources: References 33 through 37.

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malignant growth, to be available fortranscription.

In a recently published phase 2 trial,33 patients with CTCL were random-ized into three arms of various dosingschemas of vorinostat.40 Most patients(69%) had either stage III or IV disease,and had received a median of five previ-ous systemic therapies for CTCL. Theoverall intent-to-treat response rate was24.2% (eight of 33 patients); all werepartial responses (PRs). The mediantreatment duration for all patients was 8weeks, with a range of 1 to 67 weeks.Nineteen percent of patients discontin-ued vorinostat because of an adverseevent, and 68% discontinued because ofprogressive disease. Time-to-treatmentresponse (in patients who responded)ranged from 3.6 to 21.9 weeks. Fourteenof 31 patients (45%) had symptomaticrelief of their baseline pruritus: 73% ingroup 1, 18% in group 2, and 44% ingroup 3. Common toxicities of this ther-apy included fatigue (78%), diarrhea(60%), nausea (60%), thrombocytope-nia (54%), dysgeusia (51%), and dry

mouth (38%). Toxicity-related reasonsfor discontinuation of therapy includedanemia, drug eruption, fatigue, tingling,pulmonary embolism, thrombocytope-nia, pyrexia, and subdural hematoma.The authors concluded that there was aclinical benefit to 19 of the 33 patients,58% had either symptom relief or dis-ease response. A dose of 400 mg per daywas recommended, which is now theFDA-approved dosing for adults.

Now, data are emerging using vorino-stat in combination with other agentsfor CTCL. At the 2008 AmericanSociety of Clinical Oncology AnnualMeeting, Hymes and colleagues report-ed on a phase 1 dose-finding study ofthe combination of bexarotene andvorinostat in advanced CTCL.41 Nin -teen patients have been enrolled toreceive vorinostat in doses from 200 mgto 400 mg daily with bexarotene dosesfrom 150 mg per day to 300 mg/m2/day.Preliminary data indicate encouragingresults, with 18 evaluable patients and16 patients having at least stabilizationof disease (one CR, three PR, 12 stabledisease). The maximum tolerated doseshad not been reached. Hypertriglyc -eridemia (50%), hypercholesterolemia(28%), hypothyroidism (28%), andlethargy/fatigue (28%) were the mostcommon toxicities. Additionally, a fewcase studies have emerged indicatingresponses of advanced CTCL with thecombination of vorinostat to other ther-apies, including interferon and ultravio-

let-light-B therapy.42

Other DAC inhibitors are beingstudied in lymphoma. In T-cell lym-phoma, belinostat and panobinostat arein phase 2 trials. Both of these agentsare pan-DAC inhibitors. In a trial ofintravenous (IV) belinostat thatenrolled patients with refractory periph-eral T-cell lymphoma (PTCL) or CTC,seven of 11 PTCL patients had at leaststable disease (two with CRs), and fourof 16 responders were CTCL patientsfor a median duration of 10 weeks.43

Belinostat was well tolerated with mostof the toxicities reported as grade 1 and2. Grade 3 toxicities included peripher-al edema, apraxia, ileus, pruritus, rash,and infection. One grade 4 thrombocy-topenia was reported. Oral panobino -stat, 20 mg on days 1, 3, and 5 weekly,was given to patients with CTCL.44 Inthe 25 patients who were previouslytreated with bexarotene (group 1),three patients have had a PR and fourhad stabilization of disease. The mediannumber of prior therapies for CTCL ingroup 1 was 5. Based on current data,

response rates to the DAC inhibitors inpreviously treated CTCL are between20% and 30%; however, an additionalnumber of patients showed sympto-matic improvement with minimal toxi-cities from this class of drug.

The DAC inhibitors are also beingstudied in DLBCL, follicular lym-phoma, and Hodgkin’s lymphoma. Inheavily pretreated DLBCL, a 23.5%response rate (PR + CR) has beenreported to an oral histone DAC with aPFS in the responders ranging from 112to 336 days or better.45 With at least sixagents in this intriguing new drug class,much more data will be emerging in thenear future.

TemsirolimusInitially marketed for renal cell carci-

noma, temsirolimus is being studied fortreatment of NHL. The bulk of infor-mation to date is in MCL. Temsirolimusis the first mammalian target ofrapamycin inhibitor (mTOR) marketedin the United States. These agents arecritical in the initiation of mRNAtranslation and thus cell replication.Twenty-nine patients were enrolled in aphase 2 trial using temsirolimus 25 mgweekly in relapsed MCL.46 Eighty-sixpercent of patients had stage IV diseaseand had received a median of four pre-vious therapies (range 1-9). Half of thepatients were deemed refractory to pre-vious treatment. The overall responserate of this therapy was 41% (11 of 27

patients) with one CR and 10 PRs. Inthose who responded, the tumorresponse was rapid, with a median timeto response of 1 month; however,responses were also observed at 6months or more of therapy. Both themedian duration of response and medi-an time to progression was 6 months inthis poor-prognosis group. Dose reduc-tions or treatment delays were warrant-ed in 19 patients due to thrombocytope-nia (five patients), neutropenia (twopatients), both thrombocytopenia andneutropenia (two patients), and surgery(one patient). The primary toxicity inthis trial was reversible myelosuppres-sion. The most common toxicitiesincluded thrombocytopenia (82%),fatigue (75%), hyperglycemia (71%),hypertriglyceridemia (71%), anemiaand neutropenia (57%), nausea (39%),and stomatitis (39%). In a recent reportof a phase 3 trial, comparing two dosingschemas of temsirolimus with “investi-gator’s choice” of therapy for MCL,increased PFS and objective responserate was shown in the increased-dosetemsirolimus arm.47 One hundred sev-enty-seven patients were randomized1:1:1 to receive: temsirolimus 175 mgweekly × 3 followed by 75 mg (arm 1),25 mg (arm 2) weekly, or investigator’schoice (arm 3). Investigator’s choiceincluded single-agent gemcitabine 42%,single-agent fludarabine 26%, otherchemotherapies, such as thalidomide,alemtuzumab, and lenalidomide, madeup the remainder of the choices. Half ofthe patients had received more thanthree previous therapies for MCL,which had to include rituximab, analkylating agent, and an anthracycline.Based on the results of 162 patients, themedian PFS in arms 1, 2, and 3 were 4.8(P = .0009), 3.4, and 1.9 months, re -spectively. Overall survival in the threegroups was not significant at 10.9, 8.5,and 5.8 months, respectively. Theobjective response rates were 22% inarm 1, 6% in arm 2, and 2% in arm 3,indicating that in this study the higherdose of temsirolimus is more effective intreating refractory MCL.

In a study by Smith and associates, 82patients with non-MCL were given tem-sirolimus 25 mg IV weekly for 8 weeks.48

Early results including patients withDLBCL, follicular lymphoma, and smalllymphocytic lymphoma/CLL show anoverall response rate of 46% (26 of 56evaluable patients) in patients complet-ing two or more cycles of temsirolimus.Another 25 of the 82 patients had stabledisease. More mature results from thisphase 2 trial are anticipated. There isalso a growing body of literature on theuse of everolimus (RAD001), anothermTOR inhibitor that is administeredorally, for treatment of lymphomas.

LenalidomideLenalidomide is being studied in a

variety of lymphoma subtypes, includ-ing aggressive and indolent NHL. Theoption of an active oral medication is

attractive to many patients andproviders. Based on safety data from twophase 2 trials of lenalidomide inrelapsed or refractory aggressive NHL,Habermann and associates concludedthat 25 mg per day for days 1 through 21of a 28-day cycle is a tolerable regimenin the majority of these patients.49 Of131 patients evaluable for safety of thisdrug, adverse effects that occurred in> 10% included fatigue, neutropenia,rash, thrombocytopenia, constipation,anemia, diarrhea, pyrexia, nausea,peripheral edema, decrease white bloodcell count, anorexia, and cough. Seriousadverse effects included febrile neu-tropenia, pyrexia, pneumonia, backpain, deep-vein thrombosis, dehydra-tion, and diarrhea. This toxicity profileis not dissimilar to previous findings inpatients with myelodysplastic syn-dromes. Lenalidomide’s activity in oneof the above-mentioned studies wasreported by Czuczman and colleagues.50

These authors reported an objectiveresponse rate of 28% (13 of 46 evaluablepatients), with stable disease in another10 patients. Lenalidomide response wasassociated with a low tumor burden andshorter duration from the last rituximabdose to lenalidomide treatment.

In the more indolent small lympho-cytic NHL, 25 mg per day for days 1 to21 of a 28-day cycle has similarly dem -onstrated a 22% objective response ratein 18 patients, and stable disease wasseen in an additional seven of these 18patients.51 In this study, the PFS is 6.5months or more and ongoing. Of note,three (14%) of the 18 patients experi-enced grade 1 or 2 tumor flare. All theabove trials conclude that lenalidomideoral monotherapy has activity in NHLwith manageable toxicities.

ConclusionMany available nonchemotherapy

agents are emerging that have activityin NHL and frequently a more favorabletoxicity profile than chemotherapy.Whether used as monotherapy or com-bination therapy, these classes of drugswill continue to change the standard ofcare in NHL treatment. These agentshelp us move away from a “shot-gun”approach to cancer therapy to a moretargeted, rational therapy. Although thephase 1 and 2 data currently availableare intriguing, confirmation of activityversus accepted standard therapies inphase 3 trials is warranted.

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“A histone DAC inhibitor would allowgenes that have been previously silenced,for example a gene that helps to suppressmalignant growth, to be available fortranscription.”


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18. Coleman M, Goldenberg D, Siegel AB, et al.Epratuzumab: targeting B-cell malignanciesthrough CD22. Clin Cancer Res. 2003;9(10 pt 2):3991-3994.

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22. Leonard JP, Schuster SJ, Emmanouilides C, et al.Durable complete responses following therapywith epratuzumab plus rituximab: final efficacyresults of a multicenter study in recurrent indo-lent non-Hodgkin’s lymphoma (NHL). Blood.2007;110(suppl):Abstract 3419.

23. Pathan NI, Chu P, Hariharan K, et al. Mediationof apoptosis by and antitumor activity of lumil-iximab in chronic lymphocytic leukemia cellsand CD23+ lymphoma cell lines. Blood. 2008;111:1594-1602.

24. Byrd JC, O’Brien S, Flinn IW, et al. Phase 1study of lumiliximab with detailed pharmacoki-netic and pharmacodynamic measurements inpatients with relapsed or refractory chronic lym-phocytic leukemia. Clin Cancer Res. 2007;13:4448-4455.

25. Byrd JC, Castro J, O’Brien SO, et al. Comparisonof results from a phase 1/2 study of lumiliximab(anti-CD23) in combination with FCR forpatients with relapsed CLL with published FCRresults. Blood. 2006;108(suppl):Abstract 32.

26. Witzig TE, Gordon LI, Cabanillas F, et al.Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunother-apy versus rituximab immunotherapy forpatients with relapsed or refractory low-grade,follicular, or transformed B-cell non-Hodgkin’slymphoma. J Clin Oncol. 2002;20:2453-2463.

27. Fanale M, Younes A. Monoclonal antibodies inthe treatment of non-Hodgkin’s lymphoma.Drugs. 2007;67:333-350.

28. Witzig TE, White CA, Wiseman GA, et al.Phase I/II trial of IDEC-Y2B8 radioim-munotherapy for treatment of relapsed or refrac-tory CD20(+) B-cell non-Hodgkin’s lymphoma.J Clin Oncol. 1999;17:3793-3803.

29. Witzig T, Flinn IW, Gordon LI, et al. Treatmentwith ibritumomab tiuxetan radioimmunothera-py in patients with rituximab-refractory follicu-lar non-Hodgkin’s lymphoma. J Clin Oncol.2002;20:3262-3269.

30. Hagenbeek A, Bischof-Delaloye A, Radford JA,

et al. 90Y-ibritumomab tiuxetan (Zevalin®) con-solidation of first remission in advanced stagefollicular non-Hodgkin’s lymphoma: first resultsof the international randomized phase 3 first-lineindolent trial (FIT) in 414 patients. Blood. 2007;110(suppl):Abstract 643.

31. Kaminski MS, Zelenetz AD, Press OW, et al.Pivotal study of iodine 131I tositumomab forchemotherapy-refractory low-grade or trans-formed low-grade B-cell non-Hodgkin’s lym-phomas. J Clin Oncol. 2001;19:3918-3928.

32. Horning SJ, Younes A, Jain V, et al. Efficacyand safety of tositumomab and iodine-131 tosi-tumomab (Bexxar) in B-cell lymphoma, pro-gressive after rituximab. J Clin Oncol. 2005;23:712-719.

33. Goy A, Bernstein S, Kahl B, et al. Durableresponses with bortezomib in patients withrelapsed or refractory mantle cell lymphoma(MCL): updated time-to-event analysis of themulticenter PINNACLE study. Blood. 2007;110(suppl):Abstract 125.

34. Drach J, Kaufmann H, Pichelmayer O, et al.Bortezomib, rituximab, and dexamethasone(BORID) as salvage treatment in relapsed/refractory mantle cell lymphoma: sustained dis-ease control in patients achieving a completeremission. Blood. 2007;110(suppl):Abstract 2578.

35. Guariglia R, Pietrantuono G, Villani O, et al.Combination of rituximab, bortezomib, andhyper-fractionated cyclophosphamide (RBC) in“true” elderly patients with advanced mantle celllymphoma. Blood. 2007;110(suppl):Abstract 4448.

36. Gerecitano JF, Portlock C, Hamlin P, et al. Aphase I study evaluating two dosing schedules ofbortezomib (Bor) with rituximab (R), cyclophos-phamide (C), and prednisone (P) in patientswith relapsed/refractory indolent and mantle celllymphomas. J Clin Oncol. 2008;26(suppl 20):Abstract 8512.

37. Agathocleous A, Rule S, Johnson S, et al.Preliminary results of a phase I/II study of week-ly or twice weekly bortezomib in combinationwith rituximab, in patients with follicular lym-phoma, mantle cell lymphoma, and Walden -ström’s macroglobulinemia. Blood. 2007;110(suppl):Abstract 2559.

38. Spadaro P, Pitini V, Toscano G, et al. Clinicalactivity of bortezomib in relapsed or refractorygastric marginal zone B-cell lymphoma of malttype. J Clin Oncol. 2008;26(suppl 20):Abstract8567.

39. Jang G, Sym S-J, Kim S, et al. A phase I trial ofbortezomib plus CHOP every 2 weeks in patientswith advanced stage diffuse large B-cell lym-phomas. Blood. 2007;110(suppl):Abstract 4446.

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oral vorinostat (suberoylanilide hydroxamicacid, SAHA) for refractory cutaneous T-celllymphoma (CTCL). Blood. 2007;109:31-39.

41. Hymes K, Dummer R, Sterry W, et al. Phase Itrial of oral vorinostat in combination withbexarotene in patients with advanced cutaneousT-cell lymphoma. J Clin Oncol. 2008;26(suppl20):Abstract 8613.

42. Geskin LJ. Vorinostat in combination with otheragents for therapy of cutaneous T-cell lym-phomas: a case series. Blood. 2007;110(suppl):Abstract 4482.

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47. Hess G, Romaguera JE, Verhoef G, et al. PhaseIII study of patients with relapsed, refractorymantle cell lymphoma treated with temsirolimuscompared with investigator’s choice therapy.J Clin Oncol. 2008;26(suppl 20):Abstract 8513.

48. Smith SM, Pro B, Cisneros A, et al. Activity ofsingle agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes.J Clin Oncol. 2008;26(suppl):Abstract 8514.

49. Habermann TM, Witzig TE, Lossos IS, et al.Safety of lenalidomide monotherapy in patientswith relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(suppl 20):Abstract 8603.

50. Czuczman MS, Reeder CB, Polikoff J, et al.International study of lenalidomide in relapsed/refractory aggressive non-Hodgkin’s lymphoma.J Clin Oncol. 2008;26(suppl):Abstract 8509.

51. Witzig TE, Vose JM, Justice G, et al.Lenalidomide oral monotherapy in relapsed/refractory small lymphocytic non-Hodgkin’slymphoma. J Clin Oncol. 2008;26(suppl):Abstract 8573.

ACCP, NCCN, and ASCO. TheACCP Guidelines on Antithromboticand Thrombolytic Therapy recommendthe use of an LMWH for the manage-ment of VTE events in cancer for thefirst 3 to 6 months (grade 1A), followedby treatment with LMWH or a vitaminK antagonist as long as the cancer isactive (grade 1C).30 Cancer patientsundergoing surgical procedures shouldreceive prophylaxis that is appropriateto their current risk state, as should hos-pitalized cancer patients who arebedridden (both grade 1A).23 Routineprophylaxis is not recommended, how-ever, for prevention of thrombosis relat-ed to long-term indwelling centralvenous catheters in cancer patients(grade 2B). Specifically, cliniciansshould not use LMWH (grade 1B) orminidose warfarin (grade 1B) for thisindication.23

The most recent version of theNCCN guidelines regarding VTE inpatients with cancer recommends thatLMWH be used as monotherapy forlong-term treatment of proximal DVT(3-6 months) or PE (6-12 months), and

prevention of recurrent VTE in patientswith advanced or metastatic cancerwho do not have contraindications toanticoagulation (grade 2A).49 Theguidelines stop short, however, of solelyrecommending LMWHs for long-termmanagement; they do state that war-farin may be given in place of LMWH,with a target INR of 2.0 to 3.0.Continuation of anticoagulation for anindefinite period should be considered ifthe patient has active cancer or persist-ent risk factors. For catheter-associatedthrombosis, anticoagulation therapyshould be continued as long as thecatheter is in place and for 1 to 3months after it is removed.

Initial prophylaxis is recommendedfor the high-risk hospitalized cancerpopulation, using either anticoagula-tion therapy or mechanical prophylax-is (ie, pneumatic venous compressiondevice). In patients who have under-gone surgery, the NCCN guidelinesrecommend that primary VTE prophy-laxis be continued for up to 4 weekspostoperatively. In medical oncologypatients, VTE prophylaxis should be

considered in high-risk settings. Rec -ommended anticoagulant options forboth inpatient and outpatient settingsinclude LMWH (dalteparin, enoxa-parin, or tinzaparin), factor Xa antago-nist (fondaparinux), or UFH.49

ASCO guidelines recommend thatall hospitalized cancer patients be con-sidered for VTE prophylaxis with anti-coagulants in the absence of bleeding orother contraindications.50 They do not,however, recommend the routine pro-phylaxis of ambulatory cancer patientswith anticoagulation therapy, with theexception of patients receiving thalido-mide or lenalidomide plus chemothera-py and/or dexamethasone. Patients whoare undergoing major surgery for malig-nant disease should be considered forpharmacologic thromboprophylaxis.Prophylaxis should be initiated preoper-atively or as early as possible in the post-operative period and continued for atleast 7 to 10 days postoperatively.Prolonged prophylaxis for up to 4 weeksmay be considered in patients undergo-ing major abdominal or pelvic surgeryfor cancer who have high-risk features

such as residual malignant disease afterthe operation, obesity, or a history ofVTE. LWMHs are the preferred agentfor both the initial and continuingtreatment of cancer patients with estab-lished VTE. Vitamin K antagonists witha targeted INR of 2.0 to 3.0 are accept-able for long-term therapy if LMWH isnot available. After 6 months, indefi-nite anticoagulant therapy should beconsidered for selected patients withactive cancer, such as those withmetastatic disease and those receivingchemotherapy.

Antitumor effects of LMWHsAlthough current guidelines do not

recommend the use of LMWHs or anti-coagulation therapy to improve sur-vival in cancer patients withoutVTE,48,50 there are some intriguing datasuggesting that anticoagulation withLMWH may have antitumor effects.42

Although the mechanisms involved inthese possible antitumor effects haveyet to be elucidated, inhibition ofangiogenesis, inhibition of release ofcoagulation proteases, immunomodula-

Venous Thromboembolism Continued from page 16


SUPPORTIVE CA

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tory effects, and apoptosis are all pro-posed theories.42 Higher survival rateshave been reported in patients receiv-ing prophylactic doses of LMWH com-pared with no treatment or placebo.51-53

A meta-analysis of randomized trials incancer patients found that the additionof prophylactic LMWH to convention-al cancer treatment resulted in anincreased overall survival time as com-pared with placebo or no anticoagula-tion (relative risk, 0.87; 95% CI, 0.77-0.99; P = .04).54 Despite the promiseoffered by these studies, further investi-gation is required before any conclu-sions regarding the antineoplasticeffects of LMWHs can be made.42

Practical considerationsLMWHs provide patients with a

medication that unlike warfarinrequires no monitoring and no specialdiet. Notably with this class of agent,the prospect of patients self-administer-ing injections on a daily basis does notappear to present a problem. In theONCENOX trial, the compliance ratefor daily administration of enoxaparinwas 94% to 97%.45 In the CLOT trial,patients found long-term self-injectionof dalteparin to be acceptable. Fur -thermore, only 21 patients (6%) receiv-ing dalteparin stopped taking the studymedication before the end of the trialcompared with 14 patients (4%) in theoral anticoagulant group.55

Despite the advantages in terms ofpatient convenience and clinical effica-cy as demonstrated in the CLOT trial,cost of therapy with LMWHs has longbeen a concern for practitioners, phar-macists, and patients. When evaluatingthe cost-effectiveness of LMWH versusUFH in the initial management ofpatients with DVT or PE, investigatorsin one study found that use of dalteparinresulted in less anticoagulant monitor-ing and shorter hospital stays than UFH,making dalteparin a less expensive regi-men for initial treatment of DVT.56

The concern over cost has not beenas well studied in the prolonged-usesetting. None of the four trialsdescribed previously included econom-ic implications of long-term LMWHtherapy. In one study, investigatorsdesigned a decision-analytic model tocompare a 6-month regimen with dal-teparin to a similar regimen with war-farin.57 Pharmacy costs constituted46% of total costs associated withLMWH. While LMWH therapyachieved higher incremental quality-adjusted life expectancy than warfarin,this clinical benefit was offset by a sub-stantial cost increase of $7609.57

ConclusionCancer carries a considerable risk for

VTE. The disease itself contributes tothis risk, as do the treatment regimensand invasive procedures that many can-cer patients endure. More important,the presence of VTE in a cancer patientimplies a poor prognosis, including

increased rates of VTE recurrence,worsened quality of life, and a greaterrisk of death. Available treatmentoptions, while effective, are limited by anumber of important issues, includingtoxicities, complications, and intensityof monitoring.

The emergence of LMWHs as a treat-ment option for DVT and PE has dra-matically changed the landscape ofVTE treatment. In the acute setting,LMWHs are more cost-effective thanUFH, despite higher initial acquisitioncosts, due to the shortened hospitalstays associated with LMWH therapy.LMWHs have demonstrated greaterefficacy than and comparable safety towarfarin, and are now widely consideredto be the treatment of choice in extend-ed settings to prevent recurrent, cancer-associated thrombosis. The cost ofextended therapy with LMWH must bebalanced against its increased efficacy inpreventing VTEs and the better qualityof life associated with this medicationclass as compared with warfarin.

The possibility that LMWHs mayhave substantial antineoplastic effectsremains a theory that has yet to be thor-oughly explored. More clinical trials arenecessary to determine whether the sur-vival benefit seen in earlier studies isrobust enough to warrant a broadeningof indications for these agents.

References1. US Department of Health and Human Services

Office of the Surgeon General. Acting SurgeonGeneral issues “Call to Action to prevent deepvein thrombosis and pulmonary embolism.”September 15, 2008. www.surgeongeneral.gov/news/pressreleases/pr20080915.html. AccessedNovember 11, 2008.

2. National Quality Forum. National consensusstandards for the prevention and care of venousthromboembolism (including deep vein throm-bosis and pulmonary embolism). www.qualityforum.org/projects/completed/vte/comments/index.asp. Accessed November 12, 2008.

3. Donati MB. Cancer and thrombosis. Haemosta -sis. 1994;24:128-131.

4. Arkel YS. Thrombosis and cancer. Semin Oncol.2000;27:362-374.

5. Heit JA, Silverstein MD, Mohr DN, et al. Riskfactors for deep vein thrombosis and pulmonaryembolism: a population-based case-control study.Arch Intern Med. 2000;160:809-815.

6. Heit JA, O’Fallon WM, Petterson TM, et al.Relative impact of risk factors for deep veinthrombosis and pulmonary embolism: a popula-tion-based study. Arch Intern Med. 2002;162:1245-1248.

7. Levitan N, Dowlati A, Remick SC, et al. Ratesof initial and recurrent thromboembolic diseaseamong patients with malignancy versus thosewithout malignancy: risk analysis usingMedicare claims data. Medicine (Baltimore). 1999;78:285-291.

8. Khorana AA, Francis CW, Culakova E, et al.Thromboembolism is a leading cause of death incancer patients receiving outpatient chemother-apy. J Thromb Haemost. 2007;5:632-634.

9. Silverstein MD, Heit JA, Mohr DN, et al. Trendsin the incidence of deep vein thrombosis andpulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585-593.

10. Lee AY, Levine MN. Venous thromboembolismand cancer: risks and outcomes. Circulation.2003;107(23 suppl 1):117-121.

11. Linkins LA. Management of venous thromboem-bolism in patients with cancer: role of dalteparin.Vasc Health Risk Manag. 2008;4:279-287.

12. Peuscher FW. Thrombosis and bleeding in can-cer patients. Neth J Med. 1981;24:23-25.

13. Thompson CM, Rodgers RL. Analysis of theautopsy records of 157 cases of carcinoma of thepancreas with particular reference to the inci-dence of thromboembolism. Am J Med Sci. 1952;223:469-476.

14. Khorana AA, Rao MV. Approaches to risk-strat-ifying cancer patients for venous thromboem-bolism. Thromb Res. 2007;120(suppl 2):S41-S50.

15. Blom JW, Doggen CJ, Osanto S, et al. Malignan -cies, prothrombotic mutations, and the risk ofvenous thrombosis. JAMA. 2005;293:715-722.

16. Blom JW, Vandershoot JP, Oostindier MJ, et al.Incidence of venous thrombosis in a large cohortof 66,329 cancer patients: results of a record link-age study. J Thromb Haemost. 2006;4:529-535.

17. Chew HK, Wun T, Harvey D, et al. Incidence ofvenous thromboembolism and its effect on sur-vival among patients with common cancers.Arch Intern Med. 2006;166:458-464.

18. Haddad TC, Greeno EW. Chemotherapy-induced thrombosis. Thromb Res. 2006;118:555-568.

19. Goodnough LT, Saito H, Manni A, et al.Increased incidence of thromboembolism instage IV breast cancer patients treated with afive-drug chemotherapy regimen: a study of 159patients. Cancer. 1984;54:1264-1268.

20. Levine M, Hirsh J, Gent M, et al. Double-blindrandomized trial of a very-low-dose warfarin forprevention of thromboembolism in stage IVbreast cancer. Lancet. 1994;343:886-889.

21. Von Tempelhoff GF, Dietrich M, Niemann F, etal. Blood coagulation and thrombosis in patientswith ovarian malignancy. Thromb Haemost.1997;77:456-461.

22. Gugliotta L, Mazzucconi MG, Leone G, et al, forthe GIMEMA Group. Incidence of thromboticcomplications in adult patients with acute lym-phoblastic leukaemia receiving L-asparaginaseduring induction therapy: a retrospective study.Eur J Haematol. 1992;49:63-66.

23. Geerts WH, Pineo GF, Heit JA, et al. Preventionof venous thromboembolism: the Eighth ACCPConference on Antithrombotic and Throm -bolytic Therapy. Chest. 2008;133:381-453.

24. Kakkar AK, Haas S, Wolf H, et al. Evaluation ofperioperative fatal pulmonary embolism anddeath in cancer surgical patients: the MC-4 can-cer substudy. Thromb Haemost. 2005;94:867-871.

25. Lee AY, Levine MN, Butler G, et al. Incidence,risk factors, and outcomes of catheter-relatedthrombosis in adult patients with cancer. J ClinOncol. 2006;24:1404-1408.

26. Falanga A, Zacharski L. Deep vein thrombosis incancer: the scale of the problem and approachesto management. Ann Oncol. 2005;16:696-701.

27. Rickles FR, Levine MN. Epidemiology of throm-bosis in cancer. Acta Haematol. 2001;106:6-12.

28. Prandoni P, Lensing AWA, Cogo A, et al. Thelong-term clinical course of acute deep venousthrombosis. Ann Intern Med. 1996;125:1-7.

29. Prandoni P, Samama MM. Risk stratification andvenous thromboprophylaxis in hospitalized med-ical and cancer patients. Br J Hamaetol. 2008;141:587-597.

30. Kearon C, Kahn SR, Agnelli G, et al. Anti -thrombotic therapy for venous thromboembolicdisease: American College of Chest Physi ciansEvidence-Based Clinical Practice Guide lines(8th ed). Chest. 2008;133(6 suppl):454S-545S.

31. Barritt DW, Jordan SC. Anticoagulant drugs inthe treatment of pulmonary embolism: a con-trolled trial. Lancet. 1960;1:1309-1312.

32. Lensing AW, Prins MH, Davidson BL, et al.Treatment of deep vein thrombosis with low-molecular-weight heparins: a meta-analysis. ArchIntern Med. 1992;155:601-607.

33. Dolovich LR, Ginsberg JS, Douketis JD. A meta-analysis comparing low-molecular-weight hepa -rins with unfractionated heparin in the treat-ment of venous thromboembolism: examiningsome unanswered questions regarding location oftreatment, product type, and dosing frequency.Arch Intern Med. 2000;160:181-188.

34. Levine M, Gent M, Hirsh J, et al. A compari-son of low-molecular-weight heparin adminis-tered primarily at home with unfractionatedheparin administered in the hospital for proxi-mal deep-vein thrombosis. N Engl J Med. 1996;334:667-681.

35. Koopman MM, Prandoni P, Piovella F, et al, forthe Tasman Study Group. Treatment of venousthrombosis with intravenous unfractionatedheparin administered in the hospital as com-pared with subcutaneous low-molecular-weightheparin administered at home. N Engl J Med.1996;334:682-687.

36. The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients withvenous thromboembolism. N Engl J Med. 1997;337:657-662.

37. Prandoni P, Lensing AW, Piccioli A, et al.Recurrent venous thromboembolism and bleed-ing complications during anticoagulant treat-ment in patients with cancer and venous throm-bosis. Blood. 2002;100:3484-3488.

38. Lee AY, Levine MN, Baker RI, et al, for theRandomized Comparison of Low-Molecular-Weight Heparin versus Oral AnticoagulantTherapy for the Prevention of Recurrent VenousThromboembolism in Patients with Cancer(CLOT) Investigators. Low-molecular-weightheparin versus a coumarin for the prevention ofrecurrent venous thromboembolism in patientswith cancer. N Engl J Med. 2003;349:146-153.

39. Hutten BA, Prins MH, Gent M, et al. Inci -dence of recurrent thromboembolic and bleed-ing complications among patients with venousthromboembolism in relation to both malig-nancy and achieved international normalizedratio: a retrospective analysis. J Clin Oncol.2000;18:3078-3083.

40. Deitcher SR. Dalteparin reduced recurrentvenous thromboembolism more than oral anti-coagulation in patients with cancer. ACP J Club.2004;140:10.

41. Bona RD, Sivjee KY, Hickey AD, et al. The effi-cacy and safety of oral anticoagulation inpatients with cancer. Thromb Haemost. 1995;74:1055-1058.

42. Khorana AA. The NCCN Clinical PracticeGuidelines on venous thromboembolic disease:strategies for improving VTE prophylaxis in hos-pitalized cancer patient. Oncologist. 2007;12:1361-1370.

43. Meyer G, Marjanovic Z, Valcke J. Comparisonof low-molecular-weight heparin and warfarinfor the secondary prevention of venous throm-boembolism in patients with cancer: a random-ized controlled study. Arch Intern Med. 2002;162:1729-1735.

44. Hull RD, Pineo GE, Mah AF, et al. A random-ized trial evaluating long-term low-molecular-weight heparin therapy for three months versusintravenous heparin followed by warfarin sodi-um. Blood. 2002;100:Abstract 148.

45. Deitcher SR, Kessler CM, Merli G, et al.Secondary prevention of venous thromboembol-ic events (VTE) in patients with active malig-nancy: a randomized study of enoxaparin sodiumalone vs. initial enoxaparin sodium followed bywarfarin for a 180-day period. J Thromb Haemost.2003;1(suppl 1):OC194.

46. Deitcher SR, Kessler CM, Lyons RM, et al.Treatment of venous thromboembolic events(VTE) in patients with active malignancy: a ran-domized study of enoxaparin alone versus initialenoxaparin followed by warfarin for a 180-dayperiod. Blood. 2003;102:Abstract 1158.

47. Bick RL. Cancer-associated thrombosis. N Engl JMed. 2003;349:109-111.

48. Lee AY, Rickles FR, Julian JA, et al. Randomizedcomparison of low molecular weight heparin andcoumarin derivatives on the survival of patientswith cancer and venous thromboembolism. JClin Oncol. 2005;23:2123-2129.

49. NCCN. Venous thromboembolic disease.V.2.2008. www.nccn.org/professionals/physician_gls/PDF.vte.pdf. Accessed September 26, 2008.

50. Lyman GH, Khorana AA, Falanga A, et al.American Society of Clinical Oncology guide-line: recommendations for venous thromboem-bolism prophylaxis and treatment in patientswith cancer. J Clin Oncol. 2007;25:5490-5505.

51. Altinbas M, Coskun HS, Er O, et al. A random-ized clinical trial of combination chemotherapywith and without low-molecular-weight heparinin small cell lung cancer. J Thromb Haemost.2004;2:1266-1271.

52. Kakkar AK, Levine MN, Kadziola Z, et al. Lowmolecular weight heparin, therapy with dal-teparin and survival in advanced cancer: thefragmin advanced malignancy outcome study(FAMOUS). J Clin Oncol. 2004;22:1944-1948.

53. Klerk CP, Smorenburg SM, Otten HM, et al.The effect of low molecular weight heparin onsurvival in patients with advanced malignancy.J Clin Oncol. 2005;23:2130-2135.

54. Lazo-Langner A, Goss GD, Spaans JN, et al. Theeffect of low-molecular-weight heparin on can-cer survival. A systematic review and meta-analysis of randomized trials. J Thromb Haemost.2007;5:729-737.

55. Hull JH, Hull PJ. Dalteparin compared with anoral anticoagulant for thromboprophylaxis inpatients with cancer. N Engl J Med. 2003;349:1385-1387.

56. Avritscher EB, Cantor SB, Shih YC, et al. Cost-minimization analysis of low-molecular-weightheparin (dalteparin) compared to unfractionatedheparin for inpatient treatment of cancerpatients with deep venous thrombosis. SupportCare Cancer. 2004;12:531-536.

57. Aujesky D, Smith KJ, Cornuz J, et al. Cost-effectiveness of low-molecular-weight heparinfor secondary prophylaxis of cancer-relatedvenous thromboembolism. Thromb Haemost.2005;93:592-599.

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Evaluating and Treating Patientswith Multiple MyelomaElizabeth Bilotti, RN, MSN, APNcAdvanced Practice Nurse, John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey

The 49th annual meeting of theAmerican Society of Hematology(ASH) in December 2007 mark -

ed a decisive turning point in the wayclinicians care for patients with multi-ple myeloma (MM). The stage was setto embark on patient-centered carewith the presentation of numerousabstracts showing promising outcomesfor the treatment of patients in both thenewly diagnosed and relapsed-diseasesetting. Scientific presentations focusedon both genomics and prognostics in aneffort to customize care and improveknowledge about the anticipated courseof the disease. The 45th annual meetingof the American Society of ClinicalOncology (ASCO) was a follow-up toASH, with presentations that focusedon updated response data and subgroupanalysis of previously reported studies.This article provides an overview of ourprogress in the treatment of MM andhighlights our course for the future.

Multiple myeloma: an overviewMM is characterized by an abnormal

proliferation of clonal B cells within thebone marrow.1 The average age at diag-nosis is 70 years, and symptomatic dis-ease can manifest with any or all of thefollowing: osteolytic lesions, anemia,hypercalcemia, renal insufficiency, andinfection1 (Table 1). During the pasttwo decades, the incidence of myelomahas increased, but the mortality rateremains relatively stable.2 It accountsfor 1% of all malignancies, and it wasestimated that 19,920 new patientswould be diagnosed with MM in 2008,with more than 10,000 deaths attrib-uted to the disease annually.3

Although MM is an incurable dis-ease, according to a recent study pub-lished by a group from the Mayo Clinic,patients diagnosed in the past decadehad a median overall survival (OS) of44.8 months versus those diagnosedbefore the past decade (29.9 months).4The introduction of novel therapiesinto the treatment paradigm and anevolving understanding of the diseasehave played key roles in OS and qualityof life improvements. The use of noveltherapeutics in combination with stan-dard and investigational agents willcontinue to be explored in the setting ofclinical trials.

Therapy options in the setting ofnewly diagnosed disease

The focus of myeloma therapy is notonly on the development of new thera-

peutic agents, but also on the combina-tion of standard chemotherapy agentsand novel agents that have proven suc-cess rates. Research presented at theASH 2007 and ASCO 2008 meetingsrevealed many combination regimens

that were efficacious and tolerable, with1-year survival rates of at least 80%.Response criteria used in those studiesare shown in Table 2.

Harousseau and colleagues presentedupdated data from the IntergroupeFrancophone du Myélome (IFM) 2005-01 trial.5 In this study, patients were ran-domized to induction therapy witheither vincristine-doxorubicin-dexa -methasone (VAD) or bortezomib-dex-amethasone (VD), followed by a secondrandomization to either receive or notreceive dexamethasone-cyclophospha -mide-etoposide-cisplatin (DCEP) priorto stem-cell mobilization followed byeither single or tandem autologousstem-cell transplantation (ASCT) asdetermined by response. The overallresponse rate (ORR) was significantlyhigher following induction with VD(80%) versus VAD (62.8%), with agreater than or equal to very good par-tial response (VGPR) of 46.7% and18.6%, respectively. This improvementwas maintained in the posttransplantevaluation with ORR of 89.4% and72.8%, and a greater than or equal toVGPR of 61.7% versus 41.7%, respec-tively. The occurrence of grade 3/4adverse events was comparable in botharms, although the increase in the num-ber of neurological events was higher inthe VD induction arm.

The Gruppo Italiano MalattieEmatologiche dell'Adulto (GIMEMA)group, led by Cavo also presented dataregarding pretransplant induction ther-apy.6 Patients were randomized toreceive bortezomib-thalidomide-dex -amethasone (VTD) or VD prior to tan-dem ASCT. The ORR favored induc-tion with VTD (93%) over VD (80%),with a notable improvement in VGPRpretransplant/posttransplant (60%/77%) versus (27%/54%) maintained.

The adverse event profile was similar inboth arms, except for an increased fre-quency of rash and peripheral neuropa-thy noted in the bortezomib arm.

An analysis revealed that theimprovement of response depth

occurred independent of prognostic fac-tors such as beta-2 microglobulin leveland cytogenetic risk in both studies. Ofnote, these are also the first studies thatdemonstrate a correlation between

depth-of-response postinduction andimproved depth-of-response posttrans-plant. Although more follow-up timeis required to evaluate time-to-progression (TTP) and OS, we can usethese data to help answer the question,“Does the depth of response matter?”

Both the Eastern CooperativeOncology Group (ECOG) and theSouthwest Oncology Group (SWOG)evaluated the use of lenalidomide-dex-amethasone in the front-line setting.The treatment schema differed, but sim-ilar results were seen, supporting it use.

Rajkumar presented the ECOG4A03 data, including pertinent sub-group analysis.7 The trial was designedto compare differences in outcomesrelated to dexamethasone dose. Pa -tients were randomized to receivedlenalidomide (L) plus high-dose (D) orlow-dose (d) dexamethasone. The trial

Table 1. Diagnostic Work-up for Multiple Myeloma with Expected Findings

Test Finding(s) with multiple myeloma

CBC with differential counts ↓ HB, ↓ WBC, ↓ platelets

Chemistries Creat, Ca+, Uric acid, Alb

Serum electrophoresis with quantitative immunoglobulins

M-protein in serum, may have ↓ levels ofnormal antibodies

Immunofixation Identifies light-/heavy-chain types M-protein

Beta-2 microglobulin Levels (measure of tumor burden)

C-reactive protein Levels (marker for myeloma growth factor)

24-hour urine protein electrophoresis Monoclonal protein (Bence Jones)

Serum free light chain Free light chains

Bone marrow biopsy and cytogenetics ≥ 10% plasma cells

Skeletal survey Osteolytic lesions, osteoporosis

MRI Evaluation of involvement of disease

Alb indicates albumin; CBC, complete blood cell count; Creat, creatinine; Hgb, hemoglobin; MRI, magneticresonance imaging; WBC, white blood cell.Sources: Abella. Oncology News International. 2007;16:27; Barlogie B, Shaughnessy J, Munshi N, Epstein J.Plasma cell myeloma. In: Williams Hematology. 7th ed. New York, NY: McGraw Hill; 2006:1501; Durie BG,Kyle RA, Belch A, et al. Myeloma management guidelines: a consensus report from the Scientific Advisors ofthe International Myeloma Foundation. Hematol J. 2003;4:379-398; MM Research Foundation. MM: DiseaseOverview. 2006. www.multiplemyeloma.org; Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free lightchain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812-817.Reprinted with permission from Forging ahead for optimal management of multiple myeloma (MM). AVIDEducational Concepts.

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“The introduction of novel therapies intothe treatment paradigm and an evolvingunderstanding of the disease have playedkey roles in OS and quality of lifeimprovements.”

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MULTIPLE M

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ended early because of a significant dif-ference in 1-year OS seen in the Ld arm,despite an improvement in responserate with LD (71% vs 83%) (Table 3).The toxicity profile showed a significantdifference in grade 3 or greater deep-vein thrombosis (DVT)/pulmonaryembolism, infection, and nonhemato-logic adverse events. l

The SWOG data were presented byZonder comparing lenalolidomide plusD with D alone for three 35-day induc-tion cycles, followed by a 28-day main-tenance schedule.8 Although no signifi-cant 1-year OS difference was seenbetween arms (93% vs 91%), the dex-amethasone dosing was decreased fol-lowing the release of the ECOG 4A03survival data. The ORR was 85.3% ver-sus 51.3% favoring the combinationarm. The most common grade 3/4 toxi-cities reported were neutropenia andinfection, and, based on a high inci-dence of thrombosis in the combinationarm seen early, daily oral aspirin, 325mg, was mandated.

Three studies presented were under-taken in an effort to improve upon theOS and response rates in nontransplant-eligible patients. Hulin and associatesreported data from the IFM 01/01 studyof melphalan-prednisone with or with-out thalidomide in patients aged 75

years or older.9 A twofold increase inORR was noted, 62% versus 31%, inthe thalidomide-containing arm withan increase in a VGPR or better from

8% to 29%. The median OS wasincreased by more than 1.5 years, from27.7 months to 45.3 months. This isconsistent with the data published byFacon and colleagues in patients 65 to75 years of age.10 Although there was nosignificant difference in rate of throm-bosis or somnolence, both of whichwould be worrisome in the elderly pop-ulation, there were significant increasesin rates of peripheral neuropathy, neu-tropenia, and depression in the thalido-mide-containing arm.

San Miguel, on behalf of the VEL-CADE as Initial Standard Therapy inmultiple myeloma: Assessment withmelphalan and prednisone (VISTA)trial investigators, presented data onmelphalan-prednisone with or withoutbortezomib.11 The researchers reportedan ORR of 71% with the bortezomib-containing regimen versus 35% with

the other. The improvement in TTPfavored the bortezomib arm, 24 monthsversus 16.6 months. The benefit wasseen in this group independent of age,

renal function, and high-risk cytogenet-ics. The toxicity profiles were consistentwith the reported profiles for melpha-

lan-prednisone and bortezomib, with ahigher incidence of grade 3 events seenin the bortezomib arm.

The third study by the NationalCancer Institute of Canada ClinicalTrials Group represented by White,evaluated the potential feasibility ofcombining two myelosuppresive agents,melphalan plus lenalidomide, in a dex-amethasone-sparing regimen.12 Al -though no response results have beenreported, hematologic dose-limitingtoxicities (DLT) with various dosagecombinations have led to a single-armstudy design. The plan is to study safetyand efficacy with oral melphalan 5mg/m2 on days 1 to 4, plus daily orallenalidomide, 10 mg on days 1 to 21 ina 28-day cycle.

The oral combination regimen ofcyclophosphamide-lenalidomide-dexamethasone was studied by Kumarand associates, and early data were pre-sented on the first 19 evaluablepatients.13 The ORR was 79% with aVGPR or better of 10%. One fifth ofthe patients experienced a grade 4hematologic toxicity and that, alongwith early withdrawal of five of 19patients, led to the exploration of use oflower cyclophosphamide doses. Thenonhematologic toxicities of grade 3 ormore reported were fatigue, thrombosis,and renal failure.

Another regimen containing cyclo -phosphamide together with novelagents was reported by Jagannath andcolleagues.14 The combination of borte-zomib-cyclophosphamide-thalidomide-dexamethasone achieved a 100% ORRin the first 13 patients enrolled. Thetoxicity profile included neutropenia,hyperglycemia, pneumonia, perforatedviscus, and neuropathy with a severityof grade 2 or more. Patients receivedthrombosis prophylaxis with 325 mgaspirin, and no DVT has been reportedto date.

The last front-line trial, presented byRichardson and colleagues, combinedtwo novel therapeutics, lenalidomideand bortezomib with dexamethasone.15

The phase 1 portion was a dose-findingstudy that showed that dexamethasonewas the source of DLT (grade 3 hyper-glycemia) at a dose of 40 mg on days 1,

Table 2. International Myeloma Working Group Uniform Response Citeria: CR and Other Response Categories

Response subcategory Response criteriaa

sCR CR as defined below plus: Normal FLC ratio and absence of clonal cells in bone marrowb by immunohistochemistry or immunofluorescencec

CR Negative immunofixation on the serum and urine Disappearance of any soft-tissue plasmacytomas ≤ 5% plasma cells in bone marrowb

VGPR Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100 mg per 24 hr

PR ≥ 50% reduction of serum M-protein and reduction in 24-hr urinary M-protein by ≥ 90%or to < 200 mg per 24 hr If the serum and urine M-protein are unmeasurable, ≥ 50% decrease in the differencebetween involved and uninvolved FLC levels is required in place of the M-protein criteria If serum and urine M-protein are unmeasurable, and serum free light assay is alsounmeasurable, ≥ 50% reduction in plasma cells is required in place of M-protein,provided baseline bone marrow plasma cell percentage was ≥ 30% In addition to the above listed criteria, if present at baseline, ≥ 50% reduction in the sizeof soft-tissue plasmacytomas is also required

SD (not recommended for use as an indicator of response;stability of disease is bestdescribed by providing the time-to-progression estimates)

Not meeting criteria for CR, VGPR, PR, or progressive disease

CR indicates complete response; FLC, free light chain; PR, partial response; SD, stable disease; sCR, stringent complete response; VGPR, very good partial response.aAll response categories require two consecutive assessments made at any time before the institution of any new therapy; all categories also require no known evidenceof progressive or new bone lesions if radiographic studies were performed. Radiographic studies are not required to satisfy these response requirements.bConfirmation with repeat bone marrow biopsy not needed.cPresence/absence of clonal cells is based upon the κ:λ ratio. An abnormal κ:λ ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ:λ of > 4:1 or < 1:2.Reprinted with permission from Durie BGM, Harousseau J-L, Miguel JS, et al. International uniform response criteria for MM. Leukemia. 2006;20:1467-1473.

Table 3. Survival Data from ECOG 4A03 Based on Age

N

1-year survivalprobability

2-year survivalprobability

Age < 65 years

LD 104 92% 85%

Ld 108 97% P = .13

91% P = .16

Age ≥ 65 years

LD 119 84% 67%

Ld 114 95% P = .01

82% P = .009

LD indicates lenalidomide plus high-dose dexamethasone (40 mg PO days 1-4, 9-12, 17-20); Ld, lenalidomideplus low-dose dexamethasone (40 mg PO days 1, 8, 15, and 22).

“The median OS was increased by morethan 1.5 years, from 27.7 months to 45.3months.”


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2, 4, 5, 8, 9, 11, and 12. The DLT cohortwas safely treated with the followingschema: oral lenalidomide, 25 mg ondays 1 to 14, bortezomib, 1.3 mg/m2

intravenous (IV) push on days 1, 4, 8,and 11 with oral dexamethasone 20 mgor IV on days 1, 2, 4, 5, 8, 9, 11, and 12.The response data were reported forphase 1; with phase 2 enrollment ongo-ing. The ORR was 89%, with 35%

achieving a VGPR or better. The toxic-ity profile was manageable, with reportsof one grade 4 thrombocytopenia, onegrade 3 DVT treated with low-molecu-lar-weight heparin, and no grade 3 ormore peripheral neuropathy reported.

Although many ASCO presentersupdated the front-line studies alreadymentioned, Reeder and associates pre-sented new data on the combination ofcyclophosphamide (oral), bortezomib,and dexamethasone (CyBorD) prior toASCT.16 The ORR seen following fourcycles of induction therapy was 100%,with 71% achieving VGPR or betterand 46% achieving near completeresponse (nCR)/complete response(CR). The reported adverse events witha severity of grade 3/4 included anemia,neutropenia, thrombocytopenia, hyper-glycemia, diarrhea, hypokalemia, pe -ripheral neuropathy, and thrombosis. Inview of the considerable response data,including excellent depth of response,but less than ideal toxicity profile, thestudy was reopened with a change inbortezomib frequency to once weeklyand a reduction of the dexamethasonedose following the completion of twocycles. The plan is to proceed with athree-arm study to compare three novelcombinations in a randomized fashion,cyclophosphamide/lenalidomide/borte-zomib/dexamethasone versus lenalido-mide/bortezomib/dexamethasone versusCyBorD, to evaluate whether one issuperior to the others in safety.

Therapy options in the setting ofrelapsed and/or refractory disease

Although the focus this year was onthe newly diagnosed MM therapy, sev-eral studies in the relapsed and/orrefractory setting were also presented.Data were presented on a wide array ofinvestigational agents, either alone orin combination, that are targetingnovel pathways in an effort to identifyunique areas of cell proliferation, sur-vival, and migration that can be targetsfor therapy.

Carfilzomib (PR-171), a novel pro-teosome inhibitor that is both struc-turally and functionally different from

bortezomib, was studied in hematologicmalignancies, including MM, on differ-ent dosing schedules. Orlowski and col-leagues presented safety and efficacydata from a phase 1 study of 29 patientsreceiving PR-171 at variable doses IVpush daily for 5 days every 14 days.17

Preclinical studies showed that consec-utive-day dosing with continuous pro-teosome inhibition was superior to split

dosing, as used with bortezomib. Thiswas the rationale for the dosing sched-ule used in this study. Of six MMpatients treated, one achieved a partialresponse (PR), and two achieved minorresponses (MRs) when treated at a dosegreater than or equal to the establishedminimal effective dose (MED) of 11mg/m2. The DLTs that established themaximum tolerated dose (MTD) werefebrile neutropenia and grade 4 throm-bocytopenia. The majority of thereported grade 3/4 adverse events werehematologic. Of note, the withdrawalswere mainly attributed to either pro-gressive disease or inconvenience oftreatment schedule.

The second dosing schedule for PR-171 studied twice-weekly, consecutive-day dosing at variable doses as an IVpush on days 1, 2, 8, 9, 15, and 16 on a28-day cycle.18 Alsina and colleaguesreported three PR, one MR, and twostable disease (SD) in the 13 MMpatients treated at the MED dose of 15mg/m2 or greater. The DLTs reported at27 mg/m2 were one hypoxic event andreversible grade 4 thrombocytopenia. Apotentially significant finding was theobservance of a reversible grade 2 crea-tinine (≥ 2 mg/dL) following day-2 dos-ing with a rapid reduction in serum M-protein without associated tumor lysissyndrome in three of five MM patientstreated at a dose of 27 mg/m2. The effi-cacy and safety data thus far in trialswith PR-171 demonstrate the potentialfor a promising new proteosomeinhibitor that does not appear to causeperipheral neuropathy.

Weber and colleagues presented anupdate on the long-term follow-up dataavailable from the MM-009/010 studies,which showed a significant improve-ment in TTP, ORR, CR, and medianOS in patients with relapsed or refracto-ry MM when given lenalidomide plusdexamethasone versus dexamethasonealone.19 The median OS as of January2007 was 35 months in the combina-tion arm and 31 months in the controlarm; the median OS of those who hadonly one prior line of therapy had notbeen reached in the combination arm.

The TTP was 11.2 versus 4.7 months;ORR, 60.6% versus 21.9%; and CR,15% versus 2%, all favoring the combi-nation arm.

Orlowski and associates previouslyreported an improved TTP in a phase 3study comparing pegylated liposomaldoxorubicin plus bortezomib versusbortezomib alone, one of the first corti-costeroid-sparing regimens in therelapsed/ refractory setting to do this.20

Blade and coworkers analyzed the datato determine whether prior anthracy-cline exposure (naïve vs median dose of144 mg/m2) or the number of prior ther-apies (1 vs ≥ 2) had an effect on theresults.21 It was determined that theimprovement in TTP was maintainedacross all four subgroups with no signifi-cant difference in observed toxicities.

ASCO 2008 updatesRajkumar presented information on

behalf of the ECOG 4A03 trial investigators, who sought to determinewhether the high OS seen was due tothe primary induction therapy, or theresult of ASCT.22 Although only a smallcohort of patients continued on therapyafter 4 months without transplant, thereis a suggestion that novel therapies, inthe setting of an ORR of 89% (CR 22%and ≥VGPR 56%) and an OS of 93% at2 years, may provide a rationale not toincorporate ASCT as part of front-linemanagement. This will require furtherinvestigation with a direct comparisonof novel agent therapy versus ASCT inthe form of a randomized trial in newlydiagnosed MM patients.

Zonder and associates assessed datafrom SWOG S0232 to determinewhether cytogenetic abnormalities hadan impact on LD efficacy.23 The analysisshowed that abnormal karyotypes thatincluded a deletion of chromosome 13and/or 17 by fluorescence in situ

hybridization did affect outcomes, withinferior progression-free survival (PFS)and OS at 1 year, regardless of whichtherapy the patient was randomized toreceive. It is important to note, howev-er, that those with abnormal karyotypesreceiving LD did better than thosereceiving D alone.

Richardson and colleagues presentedupdated response data on both thephase 1 and phase 2 portions of thelenalidomide-bortezomib-dexameth -asone front-line setting study.24 Thirty-five patients were evaluable for responsein the MTD (4M) cohort (phase 2).The reported ORR was 100%, with72% achieving VGPR or better, similar

to the results seen in phase 1. The final analysis of MM-014, single-

agent lenalidomide in the relapsed andrefractory setting, was presented byHussein and colleagues.25 Based on theintention-to-treat population, the ORRwas 44%, with a duration of response of13 months and a median TTP of 5.2months. The PFS was 4.9 months andthe median OS was 23.2 months. Themost common grade 3/4 toxicities weremyelosuppression, all of which were eas-ily managed by dose delay, reduction, orgrowth factor support.

Two studies presented evaluated dif-ferences in efficacy and safety of noveltherapies in the relapsed–refractorysetting in patients with varying degreesof renal insufficiency. . Weber present-ed a subset analysis of patients in theMM-009/010 studies receiving lena -lidomide.26 The degree of renal impair-ment was defined by creatinine clear-ance (CrCl) levels. The analysisrevealed that with increasing renalinsufficiency, dose reductions occurredmore frequently, as did an increasedincidence of thrombocytopenia. Within4 months of therapy, 68% of patientshad at least a one-level improvementin their renal function, with 47% ofpatients who had any degree of renalimpairment achieving a level of norenal impairment. Lenalidomide im -proved TTP, PFS, and OS in allpatients, regardless of renal impair-ment, although those with severe renalimpairment tended to gain a lesserdegree of benefit.

Blade presented data on behalf of theDOXIL-MMY-3001 study investigatorsfrom a subgroup analysis of patientswith renal insufficiency (defined as aCrCl ≤ 60 mL/min).27 The analysisshowed a significant increase in TTPfor patients with inadequate renalfunction treated with pegylated liposo-

mal doxorubicin plus bortezomib ver-sus bortezomib alone, 331 days versus190 days. An improvement in meanCrCl for those with renal insufficiencywas seen in both arms. The only toxic-ities noted to be higher in the arm withrenal insufficiency were grade 3/4 ane-mia and diarrhea.

Badros and collegues presented datafrom a phase 1 trial of vorinostat plusbortezomib in relapsed/refractory MM.28

The MTD was 400 mg of oral dailyvorinostat on days 4 to 11 plus borte-zomib 1.3 mg/m2 IV push on days 1, 4,8, and 11. The DLTs of vorinostat at 500mg were prolonged QTc and fatigue.There were 21 patients evaluable for

“68% of patients had at least a one-levelimprovement in their renal function,with 47% of patients who had any degreeof renal impairment achieving a level ofno renal impairment.”

“The efficacy and safety data thus far intrials with PR-171 demonstrate thepotential for a promising newproteosome inhibitor that does notappear to cause peripheral neuropathy.”


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response following two cycles of thera-py, with ORR 42%, including seven PRand two VGPR, with SD seen in 10patients. The common grade 3/4 toxici-ties included myelosuppression andfatigue, with diarrhea, shingles, andpneumonia occurring to a lesser extent.This agent shows promising activity

with a manageable toxicity profile andis currently being investigated innumerous combinations with otheragents known to be effective in MM.

New prognostic considerationsAs our knowledge of MM and tech-

nology improves, we need to identify

prognostic values that can help inunderstanding the disease process andthe development of successful therapies.

The Mayo Clinic group, based oncurrent knowledge of the prognosticvalue of the serum free light chain(sFLC) ratio in determining the risk ofconversion from monoclonal gammo -pathy of undetermined significance,29

studied the peripheral blood of 790patients; diagnosed with MM.30 Serum-free kappa (κ)- and lambda (λ)-concen-trations were quantified in thesepatients; the κ:λ ratio was then calcu-lated. The normal reference range forthe ratio was 0.26-1.65. Of the patientstested, 95.1% had FLC ratios outsidethe reference range. Patients were thendivided into two groups—those with asFLC ratio between 0.03 and 32 andthose falling below 0.03 or above 32.The patients outside the new referencerange had a significant decrease inmedian OS of 30 months versus 39months for those within range. ThesFLC ratio made the most significantcontribution to predicting prognosis inpatients with International StagingSystem (ISS) stage II disease; 5-year OSwas 20.5% in those outside the refer-ence range compared with 35.2% inthose within the range. When the ratiowas incorporated into the ISS, andpatients were evaluated based on thenumber of risk factors 0, 1, 2, and 3 (lowalbumin: < 3.5 g/dL, high beta-2microglobulin: ≥ 3.5 g/dL, and sFLCratio: < 0.03 or > 32), the median OSrates in months were 51, 39, 30, and 22,respectively. Although this factor hasnot yet been incorporated into the ISS,it will continue to be evaluated and maylead to a change in the future.

In addition, the Mayo Clinic re -searchers explored whether restaging atthe time of relapse would be predictiveof median OS from that timepoint inthe course of the disease.31 They evalu-ated a uniform group of 131 patientswho relapsed (according to EuropeanBlood and Marrow Transplant Registrycriteria) following ASCT and obtainedserum albumin and beta-2 microglobu-lin levels within 30 days of relapse. Ofthe patients evaluated at the time ofrelapse, 49% were stage I, 38% werestage II, and 13% were stage III, withpredicted OS from that timepoint of27.3, 17.8, and 12.3 months, respective-ly. Based on this evaluation, levels ofbeta-2 microglobulin and albumin atthe time of relapse appear to have prog-nostic value, and it may be useful toincorpoate these values into clinical tri-als in the relapsed setting.

The study of genomics is constantlyunder investigation in an effort to helpdetermine the right course of treatmentfor the right type of disease, based onknowledge of how it works. Everypatient’s disease is different, and anunderstanding of that will help to per-sonalize treatment in the future in theeffort to improve outcomes.

Hyperdiploid (H)-MM is character-

ized by an increased number of chromo-somes seen in cytogenetic testing.32

Nonhyperdiploid (NH)-MM is charac-terized not by the number of chromo-somes seen on genetic testing, but bythe number of structural changes thatoccur within the normal chromosomecomplement. Chng and associates per-formed cytogenetic testing on 194patients with MM and looked at notonly the ploidy, but also the number ofgenomic aberrations. They found thatboth H-MM and NH-MM had a highnumber of genomic aberrations, with amean of 15.8 ± 7.5 versus 20.6 ± 17.0,respectively. The patients were thensegregated into two distinctively differ-ent groups with respect to OS based onnumber of aberrations per tumor(NAPT). Those with fewer than 20NAPT had a median OS of 88 months,and those with more had a significantlyshorter median OS of 20 months. Thisinformation enables us to identify asmall subset of patients who would beconsidered high-risk/low-risk based ontheir ploidy, but who may actually fallinto the opposite risk category based onthe NAPT in their disease.

Clinical implicationsAs we continue to identify new tar-

gets for therapy that affect differentpathways and act by different mecha-nisms, we have the potential to subjectpatients to new side effects that theyhave not encountered in the past. Thecurrent tendency when treating MM iscombination therapy with novel agents,standard chemotherapies, and investi-gational drugs. Being able to predict thepotential toxicities and understandingthe treatment interventions will enableus to optimize response and quality oflife by minimizing toxicity. Educatingpatients about potential toxicities asso-ciated with their treatment and theneed for prompt reporting is our besttool for improving patient outcomes.

Each individual with MM has aunique profile of supportive-care needsrelated to his or her diagnosis, comor-bidities, and therapeutic choice. Aneeds assessment must be performed oneach and must take into account psy-chosocial fitness, including but not lim-ited to support network, psychologicalwellness, and access to care (transporta-tion/financial). We also need to evalu-ate the patient’s overall health to deter-mine what existing or potentialcomorbid conditions must be managedor screened for to facilitate the bestquality care a patient can receive.

References1. De Roos AJ, Baris D, Weiss NS, Herrington L.

Epidemiology of multiple myeloma. In: MalpasJS, Bergsagel DE, Kyle RA, Anderson KC, eds.Myleoma Epidemiology, Biology and Management.3rd ed. Philadelphia, PA: Saunders; 2003:117-157.

2. National Cancer Institute. A Snapshot ofMyeloma. Bethesda, MD: National Institutes ofHealth; 2008.

3. Jemal A, Siegel R, Ward E, et al. Cancer statis-tics, 2008. CA Cancer J Clin. 2008;58:71-96.

4. Kumar S, Rajkumar V, Dispenzieri A, et al.

COMMENTARY

As pharmacists, we have a very important role to play as a reference notonly for patients and caregivers but for practitioners as well. Withincreasing numbers of new therapies and combination therapies avail-

able, overall survival for patients with cancer has increased. At the same time,however, the management of bothersome and sometimes severe side effects isbecoming a more prevalent concern in clinical practice. Peripheral neu-ropathies (with the immunomodulators [IMiDs] and bortezomib), severe con-stipation (specifically with thalidomide), rashes (primarily with liposomaldoxorubicin or IMiDs, deep-vein thromboses (DVTs)/pulmonary embolisms(PEs) (with IMiDs and steroids), anemia, diarrhea, herpes zoster virus (HSV)(with bortezomib), pneumonia, and thrombocytopenia are just a few of themajor adverse events requiring possible prevention and management.Pharmacists must advise whether agent A or B would be more suitable foreach patient based on current or anticipated side effects, such as peripheralneuropathies or hyperglycemia.

With some medications, proper timing of doses can help. We need to bevery specific in telling patients with multiple myeloma (MM) when to taketheir medications such as thalidomide or dexamethasone; for example, bothshould be taken in the evening.

We also must counsel patients about the possibility of liposomal doxoru-bicin–induced palmar-plantar erythrodysesthesias, which are charactherizedby abnormal sensation in the hands and feet, edema, and fissuring and ulcer-ation of fingers, toes, palms, and plantar aspects of the feet that can progress,causing severe pain. Dose reduction and delayed administration of liposomaldoxorubicin is sometimes needed, but in our institute, we find that treatmentwith topical Biafin, vitamin B6 (50 mg-200 mg daily), and application of icepacks at the first signs of redness or tingling is effective.

Because drug–drug interactions are so important and there is sometimesminimal information about potential interactions with the newer therapies,pharmacists must consider theoretical interactions and discuss them with thehealthcare team.

With agents such as liposomal doxorubicin, is also important to monitorliver function tests and hematologic parameters. Adjustments of some drugregimens are clearly indicated when certain combinations of drugs are used.For example, published guidelines recommend reducing the dose of bortez -omib when it is used with liposomal doxorubicin or avoiding it altogether,depending primarily on the absolute neutrofil count, fever, and other non-hematologic toxicities.

As pharmacists, we can predict what side effects are most likely to occur andhelp our patients avoid them. For example, we can help prevent peripheralneuropathies and HSV with bortezomib and possible DVTs/PEs and constipa-tion with thalidomide, dexamethasone, and other IMiDs. For example, we canensure that patients who are taking bortezomib also take acyclovir at theappropriate dose for HSV prevention. Patients with MM are usually takingmany medications, most of them following complicated regimens. In our clin-ic, each patient with MM has a consult with a clinical pharmacist. We havefound that meeting with patients and their families and giving them writteninformation about their drug combinations has greatly improved compliance.

With the increased number of oral and intravenous medications now avail-able to treat MM (in both transplant- and nontransplant-eligible patients),more onus is placed on patients to take their medications correctly.Pharmacists in the clinic can play a huge role in preventing and managingdrug toxicity as well as increasing patient compliance.

A PHARMACIST’S PERSPECTIVEEvaluating and TreatingPatients with MultipleMyelomaAnjana Elefante, PharmD, BScPhm, RPhRoswell Park Cancer Institute, Buffalo, New York

www.COEXM.com strives to provide the most up-to-date clinical information that willimprove cancer care and outcomes for patients through specialty products, across

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Improved survival in multiple myeloma and theimpact of novel therapies. Blood. 2008;111:2516-2520.

5. Harousseau JL, Mathiot C, Attal M, et al. VEL-CADE/dexamethasone (Vel/D) versus VAD asinduction treatment prior to autologous stemcell transplantation (ASCT) in newly diag-nosed multiple myeloma (MM): updated resultsof the IFM 2005/01 trial. Blood. 2007;110:139a.Abstract 450.

6. Cavo M, Patriarca F, Tacchetti P, et al. Bortezomib(Velcade)-thalidomide-dexamethasone (VTD)vs thalidomide-dexamethasone (TD) in prepara-tion for autologous stem-cell (SC) transplatation(ASCT) in newly diagnosed mulitple myeloma(MM). Blood. 2007;110:30a. Abstract 73.

7. Rajkumar SV, Jacobus S, Callander N, et al. Arandomized trial of lenalidomide plus high-dosedexamethasone (RD) versus lenalidomide pluslow-dose dexamethasone (Rd) in newly diag-nosed multiple myeloma MM (E4A03): a trial co -ordinated by the Eastern Cooperative OncologyGroup. Blood. 2007;110:31a. Abstract 74.

8. Zonder JA, Crowley J, Hussein MA, et al.Superiority of lenalidomide (Len) plus high-dosedexamethasone (HD) compared to HD alone astreatment of newly-diagnosed multiple myeloma(NDMM): results of the randomized, double-blinded, placebo-controlled SWOG trial S0232.Blood. 2007;110:32a. Abstract 77.

9. Hulin C, Facon T, Rodon P, et al. Melphalan-prednisone-thalidomide (MP-T) demonstrates asignificant survival advantage in elderly patients≥75 Years with multiple myeloma compared withmelphalan-prednisone (MP) in a randomized,double-blind, placebo-controlled trial, IFM01/01. Blood. 2007;110:32a. Abstract 75.

10. Facon T, Mary JY, Hulin C, et al. Melphalan andprednisone plus thalidomide versus melphalanand prednisone alone or reduced-intensity autol-ogous stem cell transplantation in elderly

patients with multiple myeloma (IFM 99-06): arandomised trial. Lancet. 2007;370:1209-1218.

11. San Miguel JF, Schlag R, Khuageva NK, et al.Bortezomib plus melphalan and prednisone forinitial treatment of multiple myeloma. N Engl JMed. 2008;359:906-917.

12. White DJ, Kovacs MJ, Belch A, et al. Phase 2testing of lenalidomide plus melphalan for previ-ously untreated older patients with multiplemyeloma: toxicity data from the NCIC CTGMY.11 trial. Blood. 2007;110:32a. Abstract 189.

13. Kumar S, Hayman SR, Buadi FK, et al. Phase IItrial of lenalidomide, cyclophosphamide, anddexamethasone (CRd) for newly diagnosedmyeloma. Blood. 2007;110:32a. Abstract 190.

14. Jagannath S, Bensinger B, Vescio B, et al. Aphase II study of bortezomib (Velcade), cy -clophosphamide (Cytoxan), thalidomide(Thalomid) and dexamethasone as first-linetherapy for multiple myeloma. Blood. 2007;110:32a. Abstract 188.

15. Richardson P, Jagannath S, Raje N, et al.Lenalidomide, bortezomib and dexamethasone(Rev/Vel/Dex) as front-line therapy for patientswith multiple myeloma (MM): preliminaryresults of a phase 1/2 study. Blood. 2007;110:32a.Abstract 187.

16. Reeder CB, Stewart AK, Hentz JG, et al.Efficacy of induction with CyBorD in newlydiagnosed mulitple myeloma. J Clin Oncol.2008;26:(20 suppl):Abstract 8517.

17. Orlowski RZ, Stewart K, Vallone M, et al. Safetyand antitumor efficacy of the proteosomeinhibitor carfilzomib (PR-171) dosed for fiveconsecutive days in hematologic malignancies:phase 1results. Blood. 2007;110:32a. Abstract 409.

18. Alsina M, Trudel S, Vallone, M, et al. Phase 1sngle agent antitumor activity of twice weeklyconsecutive day dosing of the proteosomeinhibitor Carfilzomib (PR-171) in hematologicmalignancies. Blood. 2007;110:32a. Abstract 411.

19. Weber DM, Chen C, Niesvizky R, et al.Prolonged overall survival with lenalidomideplus dexamethasone compared with dexametha-sone alone in patients with relapsed or refracto-ry multiple myeloma. N Engl J Med. 2007;357:2133-2142.

20. Orlowski RZ, Nagler A, Sonneveld P, et al.Randomized phase III study of pegylated liposo-mal doxorubicin plus bortezomib compared withbortezomib alone in relapsed or refractory multi-ple myeloma: combination therapy improves timeto progression. J Clin Oncol. 2007;25:3892-3901.

21. Blade J, San Miguel J, Nagler A, et al. The pro-longed time to progression with pegylated lipo-somal doxorubicin + bortezomib versus borte-zomib alone in relapsed and refractory multiplemyeloma is unaffected by extent of prior therapyor previous anthracycline exposure. Blood.2007:110;32a. Abstract 410.

22. Rajkumar SV, Jacobus S, Callander N, et al.Randomized trial of lenalidomide plus high-dose dexamethasone versus lenalidomide pluslow-dose dexamethasone in newly diagnosedmyeloma (E4A03), a trial coordinated by theEastern Cooperative Oncology Group: analysisof response, survival, and outcome with primarytherapy and with stem cell transplantation.J Clin Oncol. 2008;26:(20 suppl):Abstract 8504.

23. Zonder JA, Crowley JJ, Bolejack V, et al. A ran-domized Southwest Oncology Group study com-paring dexamethasone (D) to lenalidomide +dexamethasone (LD) as treatment of newly-diagnosed multiple myeloma (NDMM): impactof cytogenetic abnormalities on efficacy of LD,and updated overall study results. J Clin Oncol.2008;2620(suppl 20):Abstract 8521.

24. Richardson PG, Lonial S, Jakubowiak A, et al.Safety and efficacy of lenalidomide (Len), borte-zomib (Bz), and dexamethasone (Dex) inpatients (pts) with newly diagnosed multiplemyeloma (MM): a phase I/II study. J Clin Oncol.

2008;26(suppl 20):Abstract 8520.25. Hussein MA, Richardson PG, Jagannath S, et al.

Final analysis of MM-014: single-agent lenalido-mide in patients with relapsed and refractorymultiple myeloma. J Clin Oncol. 2008;26(suppl20):Abstract 8524.

26. Weber DM, Spencer A, Wang M, et al. The effi-cacy and safety of lenalidomide plus dexametha-sone in relapsed or refractory multiple myelomapatients with impaired renal function. J ClinOncol. 2008;26(suppl 20):Abstract 8542.

27. Blade J, Sonneveld P, San Miguel J, et al. Theeffect of pegylated liposomal doxorubicin plusbortezomib in multiple myeloma patients withrenal insufficiency. J Clin Oncol. 2008;26(suppl20):Abstract 8562.

28. Badros AZ, Philip S, Niesvizk R, et al. Phase Itrial of vorinostat plus bortezomib (bort) inrelapsed/refractory multiple myeloma (mm)patients (pts). J Clin Oncol. 2008;26(suppl 20):Abstract 8548.

29. Rajkumar SV, Kyle RA, Therneau TM, et al.Serum free light chain ratio is an independentrisk factor for progression in monoclonal gam-mopathy of undetermined significance. Blood.2005;106:812-817.

30. Snozek C, Katzmann JA, Kyle RA, et al. Prog -nostic value of the serum free light chain ratio inpatients with newly diagnosed myeloma: poposedincorporation into the International StagingSystem. Blood. 2007;110:32a. Abstract 659.

31. Verma R, Kumar S, Lacy MQ, et al. MyelomaInternational Staging System retains its prognos-tic value at disease relapse. Blood. 2007;110:32a.Abstract 1474.

32. Chng WJ, Keats JJ, Braggio E, et al. Multiplemyeloma (MM) is characterized by genomicinstability regardless of ploidy categories anddegree of karyotypic complexity is an impor-tant prognostic factor. Blood. 2007;110:32a.Abstract 1476.

Prostate Cancer 2008 Continued from page 13

Predictors of outcomesPrognostic markers in early-stage dis-

ease, beyond Gleason grade, primarytumor, regional node, metastasis stage,and serum PSA predictive of outcomein men with prostate cancer, have beenthe focus of a number of studies inrecent years. Diabetes, a leading causeof death in the United States, is associ-ated with decreased prostate cancerincidence.19 However, obesity, a risk fac-tor for diabetes, is associated withgreater prostate cancer mortality.Therefore, to clarify the relationshipbetween diabetes and prostate canceroutcomes, Smith and colleaguesassessed this relationship using datafrom the Radiation Therapy OncologyGroup protocol 92-02.20 This protocolwas a randomized trial of 1554 mentreated with radiation therapy andeither short-term (4 months) or long-term (28 months) adjuvant goserelin forlocally advanced prostate cancer. Theauthors utilized proportional hazardmodels to evaluate the relationshipbetween prevalent diabetes and all-cause mortality, prostate cancer mortal-ity, and nonprostate cancer mortalitywith standard covariates. Diabetes wasassociated with greater all-cause mortal-ity and nonprostate cancer mortalitybut not prostate cancer mortality inboth a univariate analysis and whencontrolling for covariates. Conversely,weight was associated with greaterprostate cancer mortality but not all-cause or nonprostate cancer mortality.

In patients with metastatic prostatecancer, PSA has been used as a marker

of response in clinical trials. A recentanalysis of data from S9346 and S9916,which involved treatment of metastaticprostate cancer, revealed that PSA pro-gression is a predictor of overall sur-vival.21 The 1015 patients enrolled inS9346 received continuous androgendeprivation, while the 573 patientsfrom S9916 were treated with docetaxeland prednisone or mitoxantrone andprednisone. The investigators reportedthat a PSA progression defined as anincrease of ≥25% over baseline or nadirwith an absolute increase of at least 2ng/mL to 5 ng/mL is a strong predictor ofoverall survival in metastatic hormone-sensitive and-resistant prostate cancer.

ConclusionsIn 2008, there were significant

advances in the understanding of themolecular biology of prostate cancer aswell as the management of disease. Achallenge to interpreting earlier datahas been the lack of standard criteriafor the end points of many trials. Thepublication of the recommendations ofthe Prostate Cancer Clinical TrialsWorking Group provides standards ofevaluation in prostate cancer trials.22

Utilizing these recommendations fortrial design and end point assessment,future trials based on recent datashould continue to result in significantad vances in the prevention and man-agement of prostate cancer.

References1. Thompson IM, Goodman PJ, Tangen CM, et

al. The influence of finasteride on the develop-ment of prostate cancer. N Engl J Med. 2003;

349:215-224.2. Pinsky P, Parnes H, Ford L. Estimating rates of

true high-grade disease in the prostate cancer pre-vention trial. Cancer Prev Res. 2008;1:182-186.

3. Redman MW, Tangen CM, Goodman PJ, et al.Finasteride does not increase the risk of high-grade prostate cancer: a bias-adjusted modelingapproach. Cancer Prev Res. 2008;1:174-181.

4. Lucia MS, Darke AK, Goodman PJ, et al.Pathologic characteristics of cancers detected inthe Prostate Cancer Prevention Trial: implica-tions for prostate cancer detection and chemo-prevention. Cancer Prev Res. 2008;1:167-173.

5. Kramer BS, Hagerty KL, Justman S, et al. Use of5-alpha reductase inhibitors for prostate cancerchemoprevention: American Society of ClinicalOncology-American Urological Association2008 clinical practice guideline. February 24,2009 www.asco.org/guidelines/5ari. AccessedMarch 5, 2009.

6. Lippman SM, Klein EA, Goodman PJ, et al.Effect of selenium and vitamin E on risk ofprostate cancer and other cancers: the Seleniumand Vitamin E Cancer Prevention Trial(SELECT). JAMA. 2009;301:39-51.

7. Zheng SL, Sun J, Wiklund F, et al. Cumulativeassociation of five genetic variants with prostatecancer. N Engl J Med. 2008;358:910-919.

8. Lu-Yao GL, Albertsenn PC, Moore DF, et al.Survival following primary androgen deprivationtherapy among men with localized prostate can-cer. JAMA. 2008;300:173-181.

9. Alibhai SM, Duong-Hua M, Sutradar R, et al.Impact of androgen deprivation therapy onbone, cardiovascular, and endocrine outcomes: apropensity-matched analysis of 20,000 patients.J Clin Oncol. 2008;26(suppl 20):Abstract 5012.

10. Wilt TJ, MacDonald R, Rutks I, et al. Systematicreview: comparative effectiveness and harms oftreatments for clinically localized prostate can-cer. Ann Intern Med. 2008;18:435-448.

11. Trock BJ, Han M, Freedland SJ, et al. Prostatecancer-specific survival following salvage radio-therapy vs observation in men with biochemicalrecurrence after radical prostatectomy. JAMA.2008;299:2760-2769.

12. Figg WD, Aragon-Ching JB, Steinberg SM, etal. Randomized phase III trial of thalidomide orplacebo for non-metastatic PSA recurrent pros -tate cancer treated with intermittent therapy. JClin Oncol. 2008;26(suppl 20):Abstract 5016.

13. Attard G, Reid AHM, Yap TA, et al. Phase Iclinical trial of a selective inhibitor of CYP17,abiraterone acetate, confirms that castration-resistant prostrate cancer commonly remains hor-

mone driven. J Clin Oncol. 2008;26:4563-4571.14. Ryan C, Smith MR, Rosenberg JE, et al. Impact

of prior ketoconazole therapy on response pro-portion to abiraterone acetate, a 17-alphahydroxylase C17,20-lyase inhibitor in castrationresistant prostate cancer. J Clin Oncol. 2008;26(suppl 20):Abstract 5018.

15. Reid AH, Attard G, Molife R, et al. SelectiveCYP17 inhibition with abiraterone acetate(AA) results in a high response rate (RR) in cas-tration-resistant prostate cancer (CRPC) con-firming the continued importance of targetingandrogen receptor (AR) signaling. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=54&abstractID=20623. Accessed March 5, 2009.

16. Danila DC, Rathkopf DE, Morris MJ, et al.Abiraterone acetate and prednisone in patientswith progressive metastatic castration resistantprostate cancer after failure of docetaxel-basedchemotherapy. J Clin Oncol. 2008;26(suppl 20):Abstract 5019.

17. Sartor AO, Petrylak DP, Witjes JA, et al.Satraplatin in patients with advanced hormone-refractory prostate cancer: overall survival resultsfrom the phase III satraplatin and prednisoneagainst refractory cancer (SPARC) trial. J ClinOncol. 2008;26(suppl 20):Abstract 5003.

18. Ning YM, Arlen PM, Gulley JL, et al. Phase IItrial of thalidomide, bevacizumab, and docetaxelin patients with metastatic castration-refractoryprostate cancer. J Clin Oncol. 2008;26(suppl 20):Abstract 5000.

19. Kasper JS, Giovannucci E. A meta-analysis ofdiabetes mellitus and the risk of prostate cancer.Cancer Epidemiol Biomarkers Prev. 2006;15:2056-2062.

20. Smith MR, Bae K, Efstathiou JA, et al.Diabetes and mortality in men with locallyadvanced prostate cancer: RTOG 92-02. J ClinOncol. 2008;26:4333-4339.

21. Hussain MH, Goldman B, Tangen CM, et al.Use of prostate-specific antigen progression(PSA-P) to predict overall survival (OS) inpatients (pts) with metastatic prostate cancer(PC): data from S9346 and S9916. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=55&abstractID=32059. Accessed March 5, 2009.

22. Scher HI, Halabi S, Tannock I, et al. Design andend points of clinical trials for patients with pro-gressive prostate cancer and castrate levels oftestosterone: recommendations of the ProstateCancer Clinical Trials Working Group. J ClinOncol. 2008;26:1148-1159.

http://www.asco.org/guidelines/5ari

http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=54&abstractID=20623

http://www.asco.org/ASCO/Abstracts

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Scientific Developments inthe Management ofMyelodysplastic Syndromes

Sandra E. Kurtin, RN, MS, AOCN, ANPSandra E. Kurtin, RN, MS, AOCN, ANP, Arizona Cancer Center, University of Arizona, Tucson

Several key scientific events withinthe past decade have shaped thecurrent strategy for management

of myelodysplastic syndromes (MDS).The majority of these have occurred inthe past 5 years. An improved under-standing of this heterogeneous group ofmyeloid stem-cell malignancies, includ-ing insights into key elements of themalignant clone, the bone marrowmicroenvironment, and the variabilityin disease trajectory, have been key toclinical advances.

A revised World Health Organization(WHO) classification system has beenrecently published incorporating thisnew information.1 Hematopathologistsand clinicians must develop the abilityto translate data obtained using olderdefinitions into current clinical trialsthat will be based on the revisednomenclature. The rate of scientific dis-covery creates a number of challenges toclinical application of the findings,including transition of practice pat-terns, education of the clinician and thepatient, safety, and financial or reim-bursement obstacles.

Core therapiesThe establishment of an epidemi -

ological data reporting system specificto MDS in the United States has vali-dated similar trends in incidence andage to those in the more establisheddata from European sites.2,3 These dataprovide a critical resource for analysisof therapies for MDS and confirm that

the highest incidence is in individualsmore than 70 years of age. There is anexpected increase in incidence as thepopulation ages.

To date, allogeneic stem-cell trans-plants are the only potentially curativetherapy for MDS. This is not an optionfor the majority of MDS patients, how-ever, based on age, comorbid condi-tions, and donor availability. Therefore,treatment strategies that are feasible inthe older population will be the core of

MDS therapy. Improved quality of life,limited toxicity, reduced need for hospi-talization, and affordability will be criti-cal to successful therapies. Oncology cli-nicians will need a basic understandingof treating the older adult with cancer.

The term myelodysplastic syndromeswas first used in 1982 by John Bennett,MD, and colleagues, who differentiatedMDS from acute myeloid leukemia.4The clinical application of scientific

advances in the diagnosis, risk stratifica-tion, and treatment of MDS since thedisease was recognized as a unique enti-ty have been concentrated in the past 5years. Three active agents—azacitidine,decitabine, and lenalidomide—are cur-rently approved by the US Food andDrug Administration (FDA) in theUnited States as well as many othercountries for the treatment of MDS.Direct clinical comparison of theseagents is limited as each of these drugs

has only recently been approved for usein the setting of monotherapy and broadinclusion criteria (all risk groups).

Based on key clinical trials and ongo-ing investigation, the first treatmentguidelines for MDS were developed bythe National Comprehensive CancerNetwork in 2004. They have beenrevised a number of times each yearsince then, consistent with the relative-ly new understanding of key aspects ofthis disease and strategies for treatment.In addition, definitions of response,desired primary end points (survival vsresponse), and evolving recommenda-tions for risk-adapted treatment selec-tion based on prognostics and individ-ual patient profiles continue to evolve.A comparative trial using azacitidineand decitabine, which are bothdemethylating agents, is planned for2009. Development of novel agentswith unique therapeutic targets is ongo-ing (Table 1). Key clinical trials forFDA-approved therapies for MDS willbe highlighted in this review with dis-cussion of the implications for clinicalpractice and patient care.

Risk-adapted therapy for MDSHarris and colleagues1 in the revised

WHO classification for MDS state that“classification is the language of medi-cine: disease must be described,defined, and named before it can bediagnosed, treated, and studied.”Understanding the pathobiology ofMDS has allowed identification oftherapeutic targets and refinement oftreatment strategies, including theconcept of risk-adapted therapy. Theheterogeneous nature of the diseaseentities described within the MDSnomenclature presents a challenge forhematopathologists and clinicians.

The integration of the Interna tionalPrognostic Scoring System (IPSS) and,more recently, the World HealthPrognostic Scoring System (WPSS)have guided the selection of therapybased on projected disease trajectoryand the risk of leukemic transformation.The accepted classification for clinicalmanagement uses two primary cate-gories: low to intermediate-1 risk orintermediate-2 to high-risk diseasebased on blasts percentage, cytogeneticprofile, and number of cytopenias.Several studies have proposed addition-al adverse risk factors, including throm-bocytopenia, transfusion burden, lacticdehydrogenase, and performance sta-

“Treatment strategies that are feasible inthe older population will be the core ofMDS therapy.”

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Table 1. Novel Agents and Targeted Therapies for the Treatment of MDS

Mechanism of action Therapeutic compound Application

Immunosuppression ATG, cyclosporine Low-risk hypocellular disease

Immune modulation Thalidomide, lenalidomide Low to intermediate-1 risk, in particular del(5q)In combination with demethylating agents

Inhibitors of angiogenesis Bevacizumab, lenalidomide, thalidomide, arsenic trioxide

Variable applications

DNA hypomethylation Azacitidine, decitabine All risk categories

Inhibition of histone deactylation

Valproic acid, depsipeptide, MS275 In combination with demethylating agents orpurine analogs

Oncogene deactivation Farnesyl transferase inhibitors: tipifarnib, lonafarnib

In combination with demethylating agents orpurine analogs

Enzyme and kinase inhibition

TLK199, Src family kinase inhibitors,p38 MAPK inhibitor

In clinical trials for variable populations

Purine analogs Clofarabine, cytarabine Combinations for high-risk MDS in the elderly

Monoclonal antibodies Gemtuzumab ozogamicin High-risk disease in the elderly

Thrombopoiesis-stimulating hormone

Romiplostim Treatment-associated thrombocytopenia in allrisk categories


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tus.5-9 Continued review is certain as animproved understanding of the pathobi-ology of this disease and resulting clini-cal implications are realized.

Lower risk MDS is accepted as achronic myeloid malignancy with anemphasis on improved hematopoiesis,including transfusion independence,improved quality of life, and extendedoverall survival (OS). Treatment untildisease progression or unacceptable tox-icity is now an accepted paradigm,emphasizing the need to refine support-ive care strategies.10,11

In addition, trials using the im -munomodulatory agent lenalidomidefor low-intermediate risk MDS haveelucidated a difference in mechanism ofaction for selected patient subsets.Analysis of the data from the threelenalidomide trials in MDS suggeststhat lenalidomide has a different mech-anism of action in patients with or with-out chromosome 5q deletion, a possibledirect cytotoxic effect on the malignant

clone with del(5q) and effect on themicroenvironment in patients withoutthe deletion of chromosome 5q.12-14

Cytogenetic re sponses have been shownto correlate with improved survival inpatients with chromosome 5q deletion.A follow-up evaluation of six patientsparticipating in the MDS-001 trial indi-cated the response to lenalidomide to bedurable with sustained transfusion inde-pendence up to 6.5 years and providedevidence of sustained cytogeneticremissions in some patients.14

Higher risk disease presents a particu-lar challenge in the older population, inwhom the focus of treatment is on sur-vival, suppression of the leukemicclone, and management of disease andtreatment toxicities. A fundamentalprinciple of active therapy for any stageof MDS is that sustained treatment for aminimum of 3 to 4 months is necessaryto effectively evaluate efficacy, and thedepth of response may continue toimprove up to 6 to 9 months after initi-ating therapy.15 The challenge is inaggressively managing potential toxici-ties during the initial therapy to mini-mize gaps in treatment or unnecessarydiscontinuation of therapy.16 Data sup-porting the potential to improve OS inthis disease, even in patients with high-risk features, reinforce the need to refineclinical strategies for supportive care.

Chromosome 7 abnormalities are anunfavorable risk factor in MDS. Animportant study by Mufti and col-leagues17 indicated a survival benefitwith standard-dose azacitidine in high-risk MDS, including chromosome 7abnormalities (-7/del[7q]). For the 57patients with -7/del(7q) alone or aspart of a complex karyotype, the hazard

ratio (HR) for risk of death was 0.33(95% confidence interval, 0.16-0.68),indicating that azacitidine reduced therisk of death by 67% in these patients.OS was significantly longer in the aza -citidine group than in the convention-al care response group (13.1 months vs4.6 months).

Fenaux and colleagues studied 358patients with intermediate-2 or high-risk MDS.18 The primary end point wasOS in patients treated with azacitidine75 mg/m2 per day on days 1 through 7for 28 days compared with convention-al chemotherapy (cytarabine [ARA-C]/daunorubicin 7 + 3, or low-doseARA-C). The patients treated withazacitidine had a significant improve-ment in OS compared with conven-tional care (P = .0001, HR = 0.58).Median survival was improved, fromapproximately 15 months on conven-tional care to 24.4 months with azacit -idine treatment. Approximately 52%of patients treated with azacitidine

were alive at 2 years compared with26% of patients who received conven-tional care. Considering the originalsurvival data from the IPSS and WPSSwith median survival of 1.2 years forintermediate-2 and 4 months for high-risk disease, this provides hope topatients with MDS. This is the firsttrial in MDS to document a survivaladvantage for active therapies.

Wijermans and colleagues reportedresults from a phase 3 trial using low-dose decitabine versus best supportivecare for 223 patients with high-riskMDS.19 Decitabine was administered ata dose of 15 mg/m2 intravenously over 4hours every 8 hours for 3 consecutivedays (n = 119) versus base supportivecare (n = 114). In a population ofpatients with intermediate-2 or high-risk MDS (93%), many of whom hadpoor cytogenetic risk profiles (46%),the median OS was not significantlylonger with the decitabine group (10.1months vs 8.5 months). It is importantto note that patients who did achieve acomplete response received a maximumof eight cycles, and the median numberof cycles in this high-risk group wasthree. Given the recent shift towardtreatment until progression and theexpectation of a minimum of 4 to 6months of therapy before achieving aresponse, these disappointing data maybe a reflection of clinical trial design. Itunderscores the challenge of integratingrapidly changing primary end pointsinto a meaningful clinical trial and theimportance of continued enrollment ofpatients in clinical trials.

Supportive care Supportive care strategies have also

been refined and are recognized asessential components of the overalltreatment strategy, including quality oflife. The goals of therapy have shiftedfrom supportive care alone to aggres-sive management of cytopenias, in -cluding achievement of transfusionindependence, iron chelation therapy,and development of new cytokines forthe treatment of thrombocytopenia.Myelosuppression is the most commondose-limiting toxicity associated withactive therapies, and thus strategies tominimize cytopenias may allow pa -tients to maintain active therapy.

Iron overload is associated withincreased morbidity and mortality inpatients with MDS, and iron chelationtherapy has been shown to improveOS.5,8 Sanz and colleagues studied 2994patients with primary MDS. The major-ity of these patients (78) had low-inter-mediate-1 risk disease.5 The study endpoints were OS and leukemia-free sur-vival (LFS). Results of the study showedthat red blood cell (RBC) transfusion-dependency (OS–HR = 7.20, P <.001;LFS–HR = 2.9, P <.001) and iron over-load (OS–HR = 2.11, P <.001; LFS–HR= 1.57, P <.001) have prognostic valueindependent of the IPSS score. Thisstudy is thought to confirm the validityof adding RBC transfusion dependencyto the revised WHO prognostic scoringsystem. It also supports transfusiondependence as a valid indicator for ini-tiation of active therapies. Patients withMDS should be screened using a serumferritin at the time of diagnosis withcontinued monitoring of these values.Ferritin levels >1000 have been shownto be associated with adverse outcomes.

Myelosuppression is the most com-mon treatment-related toxicity in ther-apeutic regimens for MDS. Thrombocy -topenia is a particular challenge becauseof the increased risk of bleeding in a pri-marily elderly population.

Romiplostim, a thrombomimeticagent, was used in combination with

azacitidine and compared with azaciti-dine and placebo. In patients receivingromiplostim, the platelet count beforeeach course of therapy and the plateletnadir were higher than the counts forpatients in the placebo group. In addi-tion, the group receiving the romi-plostim required fewer platelet transfu-sions, and the incidence of grade 3bleeding events was lower.20 The addi-tion of this type of agent to active ther-apies for MDS, which require severalmonths for maximum response whileinducing significant myelosuppression,can provide the supportive care neces-sary to maintain therapy long enoughto achieve response.

SummaryThe robust pace of scientific discov-

eries relative to understanding thepathobiology of MDS and the develop-ment and clinical application of thera-pies based on this understanding pro-vides great hope for patients andclinicians. Several key concepts foreffective treatment of MDS have beenidentified (Table 2). There are stillmany questions unanswered and a needto continue refinement of the diagnos-tic and risk stratification for this disease.New agents will be necessary to providecontinued treatment options. Thisunderscores the benefit of clinical trialparticipation in diseases with limitedavailable treatment options and evolv-ing scientific discoveries. MDS is one ofmany diagnoses with a rapidly changingtreatment paradigm based on scientificadvances and clinical managementstrategies. The goals of therapy inpatients with MDS are to improvequality of life, minimize toxicity, im -prove hematopoiesis, reduce cytopenias,achieve transfusion independence, andprolong survival. These outcomes havenow been realized in several of the stud-ies discussed. Consideration of theunique needs of the elderly patient arecritical to achieve optimal clinical man-

“The goals of therapy have shifted fromsupportive care alone to aggressivemanagement of cytopenias.”

Table 2. Key Concepts in the Treatment of MDS

• Myelodysplatic syndromes represent a myeloid stem-cell malignancy• Clinical trial end points have shifted from efficacy and safety alone to include

improved overall survival• Complete eradication of the malignant clone is not necessary to prolong survival,

but suppression is associated with transfusion independence, cytogeneticresponse, improved survival, and a reduced risk of leukemic transformation

• Clinical responses often require a minimum of 4 to 6 months of therapy, andprolonged therapy (treating until disease progression or unacceptable toxicity) is likely to become the standard approach

• Concurrent supportive care is essential to optimal therapeutic outcomesincluding iron chelation, transfusion management, cytokine support, andaggressive management of comorbidities; however, supportive care does notaffect the underlying disease

• Treatment-related MDS is associated with a poor prognosis and will requirespecific approaches to treatment that are similar to those used for acutemyeloid leukemia

• MDS is most common in individuals over the age of 70; therefore, treatmentstrategies that are feasible for the older adult will be the core of MDS therapy

6 West Belt, Wayne, NJ 07470 USA 2100 Powell Street, Emeryville, CA 94608 USA

©2009 Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ SS-10-0001-09 3/09 Printed in USA

Guiding Patients Through the First 30 Daysof Therapy—When They Need It Most

• Oncology nurse counselors complement your carethrough periodic outreach to patients and by answeringtheir telephone queries

• Patients receive communications about their therapyand the importance of adherence, tips for stayingactive, and emotional support tools

Please see brief summary of Nexavar Prescribing Informationon the following pages.

A Unique SupportProgram to Help Patientson Nexavar® Therapy

Get Your Patients Connected Today!

For more information, speak to your

Nexavar representative or visit www.NEXAVAR.com

NexConnect Oncology Nurse Counselors—Your Partners in Patient Support

• NexConnect counselors are seasoned oncology nurseswho have extensive training and experience withNexavar therapy

• The 24-hour oncology nurse helpline is available toyour patients 7 days a week

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agement and quality of life; however,advanced age alone should not excludeolder patients from active therapies.

References1. Harris NL, Campo E, Jaffe ES, et al. Intro -

duction to the WHO classification of tumoursof haematopoietic and lymphoid tissues. In:Swerlow S, Campo E, Harris NL, et al, eds.WHO Classification of Tumours of Haematopoieticand Lymphoid Tissues, Vol 4. Geneva, Switzerland:World Health Organization; 2008:14-15.

2. Ma X, Does M, Raza A, Mayne ST. Myelodys -plastic syndromes. Cancer. 2007;109:1536-1542.

3. Germing U, Neukirchen J, Haas R. The epi-demiology of myelodysplastic syndromes. ClinLeukemia. 2008;2:34-38.

4. Bennett JM, Catovsky D, Daniel MT, et al. Pro -posals for the classification of the myelodysplas-tic syndromes. Br J Haematol. 1982;51:189-199.

5. Sanz G, Nomdedeu B, Such E, et al. Inde -pendent impact of iron overload and transfusiondependency on survival and leukemic evolutionin patient with myelodysplastic syndrome. Blood.

2008;112(suppl):Abstract 640.6. Malcovati L, Germing U, Kuendgen A, et al.

Time-dependent prognostic scoring system forpredicting survival and leukemic evolution inmyelodysplastic syndromes. J Clin Oncol. 2007;25:3503-3510.

7. Park MJ, Kim HJ, Kim SH, et al. Is InternationalPrognostic Scoring System (IPSS) still standardin predicting prognosis in patients withmyelodysplastic syndrome? External validationof the WHO Classification-Based PrognosticScoring System (WPSS) and comparison withIPSS. Eur J Haematol. 2008;81:364-373.

8. List AF, Baer MR, Steensma D, et al. Iron chela-tion with deferasirox (Exjade) improves iron bur-den in patients with myelodysplastic syndromes(MDS). Blood. 2008;112(suppl):Abstract 634.

9. Kantarjian KM, O’Brien S, Ravandi F, et al.Development and validation of a new prognosticmodel for myelodysplastic syndrome (MDS) thataccounts for events not considered by theInternational Prognostic Scoring System (IPSS).Blood. 2008;112(suppl):Abstract 635.

10. Kumar A, List AF, Mhaskar R, Djulbegovic B.Efficacy of hypo-methylating agents in thetreatment of myelodysplastic syndromes: a sys-

tematic review and meta-analysis of random-ized controlled trials. Blood. 2008;112(suppl):Abstract 3632.

11. List AF, Fenaux P, Mufti GJ, et al. Effect of azac-itidine (AZA) on overall survival in higher-riskmyelodysplastic syndromes (MDS) withoutcomplete remission. J Clin Oncol. 2008;26(suppl20):Abstract 7006.

12. Sekeres MA, Maciejewski JP, Giagounidis A, etal. Cytopenias correlate with response tolenalidomide in del 5q MDS patients. Leuk Res.2007;31(suppl 1):S37-S38.

13. List A, Dewald G, Bennett J, et al. Lenalidomidein the myelodysplastic syndrome with chromo-some 5q deletion. N Engl J Med. 2006;355:1456-1465.

14. Raza A, Reeves JA, Feldman EJ, et al. Phase 2study of lenalidomide in transfusion-dependent,low- and intermediate-1 risk myelodysplasticsyndromes with karyotypes other than deletion5q. Blood. 2008;111:86-93.

15. Kurtin S, List A. Durable long-term responses inpatients with MDS treated with lenalidomide.Clin Leukemia. 2008. In press.

16. Kurtin S. Clinical advances in the treatment ofmyelodysplastic syndromes: reasons for hope.

Practical Applications. December 2008:1-12.17. Mufti GJ, Fenaux P, Hellstrom-Lindberg E, et al.

Treatment of high-risk MDS patients (pts) with-7/del(7q) with azacitidine (AZA) versus con-ventional care regimens (CCR): effects on over-all survival (OS). J Clin Oncol. 2008;26(suppl20):Abstract 7033.

18. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.Efficacy of azacitidine compared with that ofconventional care regimens in the treatment ofhigher-risk myelodysplastic syndromes: a ran-domized, open-label, phase III study. LancetOncol. 2009; 10:223-232.

19. Wijermans P, Suciu S, Baila L, et al. Low dosedecitabine versus best supportive care in elderlypatients with intermediate or high risk MDS noteligible for intensive chemotherapy: final resultsof the randomized phase III study (06011) of theEORTC leukemia and German MDS studygroups. Blood. 2008;112(suppl):Abstract 226.

20. Kantarjian H, Giles F, Greenberg P, et al. Effectof romiplostim in patients (pts) with low orintermediate risk myelodysplastic syndrome(MDS) receiving azacytidine. Blood. 2008;112(suppl):Abstract 224.

NEXAVAR (sorafenib) tablets, oralInitial U.S. Approval: 2005

BRIEF SUMMARYCONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE1.1 Hepatocellular Carcinoma NEXAVAR is indicated for the treatment of patients with

unresectable hepatocellular carcinoma (HCC).

1.2 Renal Cell Carcinoma NEXAVAR is indicated for the treatment of patients with advancedrenal cell carcinoma (RCC).

4 CONTRAINDICATIONSNEXAVAR is contraindicated in patients with known severe hypersensitivity to sorafenib orany other component of NEXAVAR.

5 WARNINGS AND PRECAUTIONS5.1 Risk of Cardiac Ischemia and/or Infarction In the HCC study, the incidence of

cardiac ischemia/infarction was 2.7% in NEXAVAR patients compared with 1.3% in theplacebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higherin the NEXAVAR group (2.9%) compared with the placebo group (0.4%). Patients withunstable coronary artery disease or recent myocardial infarction were excluded from thisstudy. Temporary or permanent discontinuation of NEXAVAR should be considered inpatients who develop cardiac ischemia and/or infarction.

5.2 Risk of Hemorrhage An increased risk of bleeding may occur following NEXAVARadministration. In the HCC study, an excess of bleeding regardless of causality was not apparentand the rate of bleeding from esophageal varices was 2.4% in NEXAVAR patients and 4% inplacebo patients. Bleeding with a fatal outcome from any site was reported in 2.4% ofNEXAVAR patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causalitywas reported in 15.3% of patients in the NEXAVAR group and 8.2% of patients in the placebogroup. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, inNEXAVAR patients, and 1.3% and 0.2%, respectively, in placebo patients. There was one fatalhemorrhage in each treatment group in RCC Study 1. If any bleeding necessitates medicalintervention, permanent discontinuation of NEXAVAR should be considered.

5.3 Risk of Hypertension Blood pressure should be monitored weekly during the first 6weeks of NEXAVAR therapy and thereafter monitored and treated, if required, in accordancewith standard medical practice. In the HCC study, hypertension was reported in approximately9.4% of NEXAVAR-treated patients and 4.3% of patients in the placebo group. In RCCStudy 1, hypertension was reported in approximately 16.9% of NEXAVAR-treated patientsand 1.8% of patients in the placebo group. Hypertension was usually mild to moderate,occurred early in the course of treatment, and was managed with standard antihypertensivetherapy. In cases of severe or persistent hypertension, despite institution of antihypertensivetherapy, temporary or permanent discontinuation of NEXAVAR should be considered.Permanent discontinuation due to hypertension occurred in 1 of 297 NEXAVAR patientsin the HCC study and 1 of 451 NEXAVAR patients in RCC Study 1.

5.4 Risk of Dermatologic Toxicities Hand-foot skin reaction and rash represent the mostcommon adverse reactions attributed to NEXAVAR. Rash and hand-foot skin reaction areusually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatmentwith NEXAVAR. Management of dermatologic toxicities may include topical therapies forsymptomatic relief, temporary treatment interruption and/or dose modification ofNEXAVAR, or in severe or persistent cases, permanent discontinuation of NEXAVAR.Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 of 297NEXAVAR HCC patients and 3 of 451 NEXAVAR RCC patients.

5.5 Risk of Gastrointestinal Perforation Gastrointestinal perforation is an uncommonadverse reaction and has been reported in less than 1% of patients taking NEXAVAR. Insome cases this was not associated with apparent intra-abdominal tumor. In the event of agastrointestinal perforation, NEXAVAR therapy should be discontinued.

5.6 Warfarin Co-Administration Infrequent bleeding or elevations in the InternationalNormalized Ratio (INR) have been reported in some patients taking warfarin while onNEXAVAR therapy. Patients taking concomitant warfarin should be monitored regularly forchanges in prothrombin time, INR or clinical bleeding episodes.

5.7 Wound Healing Complications No formal studies of the effect of NEXAVAR on woundhealing have been conducted. Temporary interruption of NEXAVAR therapy is recommendedin patients undergoing major surgical procedures. There is limited clinical experienceregarding the timing of reinitiation of NEXAVAR therapy following major surgical intervention.Therefore, the decision to resume NEXAVAR therapy following a major surgical interventionshould be based on clinical judgment of adequate wound healing.

5.8 Interactions with UGT1A1 Substrates Sorafenib can cause increases in plasmaconcentrations of drugs that are substrates of UGT1A1. Caution is recommended whenadministering NEXAVAR with compounds that are metabolized/eliminated predominantlyby the UGT1A1 pathway (e.g. irinotecan) [see Drug Interactions (7.1)**].

5.9 Interaction with Docetaxel Sorafenib can cause increases in plasma concentrations ofdocetaxel. Caution is recommended when NEXAVAR is co-administered with docetaxel [seeDrug Interactions (7.2)**].

5.10 Interaction with Doxorubicin Sorafenib can cause increases in plasma concentrationsof doxorubicin. Caution is recommended when NEXAVAR is co-administered with doxorubicin[see Drug Interactions (7.3)**].

5.11 Pregnancy: Pregnancy Category D Sorafenib may cause fetal harm when administered to a pregnant woman. In rats andrabbits, sorafenib has been shown to be teratogenic and to induce embryo-fetal toxicity(including increased post-implantation loss, resorptions, skeletal retardations, and retardedfetal weight). The effects occurred at doses considerably below the recommended humandose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface areabasis). Adverse intrauterine development effects were seen at doses ≥1.2 mg/m2/day inrats and 3.6 mg/m2/day in rabbits (approximately 0.008 times the AUC seen in cancerpatients at the recommended human dose). A NOAEL (no observed adverse effect level)was not defined for either species, since lower doses were not tested.There are no adequate and well-controlled studies in pregnant women using NEXAVAR.Women of childbearing potential should be advised to avoid becoming pregnant while onNEXAVAR. If this drug is used during pregnancy, or if the patient becomes pregnant whiletaking this drug, the patient should be apprised of the potential hazard to the fetus.

5.12 Hepatic Impairment Hepatic impairment may reduce plasma concentrations ofsorafenib. Comparison of data across studies suggests that sorafenib levels are lower inHCC patients than in non-HCC patients (without hepatic impairment). The AUC ofsorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate(Child-Pugh B) hepatic impairment. The optimal dose in non-HCC patients with hepaticimpairment is not established [see Use in Specific Populations (8.6**) and ClinicalPharmacology (12.3)**].

6 ADVERSE REACTIONS The following risks are discussed in greater detail in the WARNINGSAND PRECAUTIONS section (5):• Cardiac ischemia, infarction [see Warnings and Precautions (5.1)]• Hemorrhage [see Warnings and Precautions (5.2)]• Hypertension [see Warnings and Precautions (5.3)]• Hand-foot skin reaction and rash [see Warnings and Precautions (5.4)]• Gastrointestinal perforation [see Warnings and Precautions (5.5)]• Wound healing complications [see Warnings and Precautions (5.7)]• Teratogenicity and embryofetal toxicity [see Warnings and Precautions (5.11)]

The data described in sections 6.1 and 6.2 reflect exposure to NEXAVAR in 748 patientswho participated in placebo controlled studies in hepatocellular carcinoma (N=297) oradvanced renal cell carcinoma (N=451). The most common adverse reactions (≥20%), which were considered to be related toNEXAVAR, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.Because clinical trials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of a drug cannot be directly compared to rates in theclinical trials of another drug and may not reflect the rates observed in practice.

6.1 Adverse Reactions in HCC Study Table 2 shows the percentage of HCC patientsexperiencing adverse reactions that were reported in at least 10% of patients and at ahigher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactionswere reported in 39% of patients receiving NEXAVAR compared to 24% of patients receivingplacebo. CTCAE Grade 4 adverse reactions were reported in 6% of patients receivingNEXAVAR compared to 8% of patients receiving placebo.

Table 2 Adverse Reactions Reported in at Least 10% of Patients and at a HigherRate in NEXAVAR Arm than the Placebo Arm – HCC Study

NEXAVAR PlaceboN=297 N=302

Adverse Reaction All Grade Grade All Grade GradeNCI- CTCAE v3 Grades 3 4 Grades 3 4Category/Term % % % % % %

Any Adverse Reaction 98 39 6 96 24 8

Constitutional symptoms

Fatigue 46 9 1 45 12 2

Weight loss 30 2 0 10 1 0


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Adverse Reaction All Grade Grade All Grade GradeNCI- CTCAE v3 Grades 3 4 Grades 3 4Category/Term % % % % % %

Dermatology/skin

Rash/desquamation 19 1 0 14 0 0

Pruritus 14 <1 0 11 <1 0

Hand-foot skin reaction 21 8 0 3 <1 0

Dry skin 10 0 0 6 0 0

Alopecia 14 0 0 2 0 0

Gastrointestinal

Diarrhea 55 10 <1 25 2 0

Anorexia 29 3 0 18 3 <1

Nausea 24 1 0 20 3 0

Vomiting 15 2 0 11 2 0

Constipation 14 0 0 10 0 0

Hepatobiliary/ pancreas

Liver dysfunction 11 2 1 8 2 1

Pain

Pain, abdomen 31 9 0 26 5 1

Hypertension was reported in 9% of patients treated with NEXAVAR and 4% of those treatedwith placebo. CTCAE Grade 3 hypertension was reported in 4% of NEXAVAR treatedpatients and 1% of placebo treated patients. No patients were reported with CTCAE Grade4 reactions in either treatment group. Hemorrhage/bleeding was reported in 18% of those receiving NEXAVAR and 20% of placebopatients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo group(CTCAE Grade 3 - 3% NEXAVAR and 5% placebo and CTCAE Grade 4 - 2% NEXAVAR and 4%placebo). Bleeding from esophageal varices was reported in 2.4% in NEXAVAR treatedpatients and 4% of placebo treated patients.Renal failure was reported in <1% of patients treated with NEXAVAR and 3% of placebotreated patients.The rate of adverse reactions (including those associated with progressive disease) resultingin permanent discontinuation was similar in both the NEXAVAR and placebo groups (32%of NEXAVAR patients and 35% of placebo patients).

Laboratory Abnormalities The following laboratory abnormalities were observed inHCC patients: Hypophosphatemia was a common laboratory finding, observed in 35% of NEXAVAR-treatedpatients compared to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2mg/dL) occurred in 11% of NEXAVAR-treated patients and 2% of patients in the placebogroup; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in theplacebo group. The etiology of hypophosphatemia associated with NEXAVAR is not known.

Elevated lipase was observed in 40% of patients treated with NEXAVAR compared to 37%of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% ofpatients in each group. Elevated amylase was observed in 34% of patients treated withNEXAVAR compared to 29% of patients in the placebo group. CTCAE Grade 3 or 4 amylaseelevations were reported in 2% of patients in each group. Many of the lipase and amylaseelevations were transient, and in the majority of cases NEXAVAR treatment was notinterrupted. Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients(CTCAE Grade 2).

Elevations in liver function tests were comparable between the 2 arms of the study.Hypoalbuminemia was observed in 59% of NEXAVAR-treated patients and 47% of placebopatients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group.

INR elevations were observed in 42% of NEXAVAR-treated patients and 34% of placebopatients; CTCAE Grade 3 INR elevations were reported in 4% of NEXAVAR-treated patientsand 2% of placebo patients; there was no CTCAE Grade 4 INR elevation in either group.

Lymphopenia was observed in 47% of NEXAVAR-treated patients and 42% of placebo patients. Thrombocytopenia was observed in 46% of NEXAVAR-treated patients and 41% of placebopatients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of NEXAVAR-treatedpatients and less than 1% of placebo patients.

6.2 Adverse Reactions in RCC Study 1 Table 3 shows the percentage of RCC patientsexperiencing adverse reactions that were reported in at least 10% of patients and at ahigher rate in the NEXAVAR arm than the placebo arm. CTCAE Grade 3 adverse reactionswere reported in 31% of patients receiving NEXAVAR compared to 22% of patients receivingplacebo. CTCAE Grade 4 adverse reactions were reported in 7% of patients receivingNEXAVAR compared to 6% of patients receiving placebo.

Table 3: Adverse Reactions Reported in at Least 10% of Patients and at a HigherRate in NEXAVAR Arm than the Placebo Arm – RCC Study 1


Adverse Reactions All Grade Grade All Grade Grade NCI- CTCAE v3 Grades 3 4 Grades 3 4Category/Term % % % % % %

Any Adverse Reactions 95 31 7 86 22 6

Cardiovascular, General

Hypertension 17 3 <1 2 <1 0

Constitutional symptoms

Fatigue 37 5 <1 28 3 <1

Weight loss 10 <1 0 6 0 0

Dermatology/skinRash/desquamation 40 <1 0 16 <1 0

Hand-foot skin reaction 30 6 0 7 0 0

Alopecia 27 <1 0 3 0 0

Pruritus 19 <1 0 6 0 0

Dry skin 11 0 0 4 0 0

Gastrointestinal symptoms

Diarrhea 43 2 0 13 <1 0

Nausea 23 <1 0 19 <1 0

Anorexia 16 <1 0 13 1 0

Vomiting 16 <1 0 12 1 0

Constipation 15 <1 0 11 <1 0

Hemorrhage/bleeding

Hemorrhage – all sites 15 2 0 8 1 <1

NeurologyNeuropathy-sensory 13 <1 0 6 <1 0

Pain Pain, abdomen 11 2 0 9 2 0

Pain, joint 10 2 0 6 <1 0

Pain, headache 10 <1 0 6 <1 0

Pulmonary

Dyspnea 14 3 <1 12 2 <1

The rate of adverse reactions (including those associated with progressive disease) resultingin permanent discontinuation was similar in both the NEXAVAR and placebo groups (10%of NEXAVAR patients and 8% of placebo patients).

Laboratory Abnormalities The following laboratory abnormalities were observed inRCC patients in Study 1: Hypophosphatemia was a common laboratory finding, observed in 45% of NEXAVAR-treated patients compared to 11% of placebo patients. CTCAE Grade 3 hypophosphatemia(1–2 mg/dL) occurred in 13% of NEXAVAR-treated patients and 3% of patients in theplacebo group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL)reported in either NEXAVAR or placebo patients. The etiology of hypophosphatemiaassociated with NEXAVAR is not known. Elevated lipase was observed in 41% of patients treated with NEXAVAR compared to 30%of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% ofpatients in the NEXAVAR group compared to 7% of patients in the placebo group. Elevatedamylase was observed in 30% of patients treated with NEXAVAR compared to 23% ofpatients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1%of patients in the NEXAVAR group compared to 3% of patients in the placebo group. Manyof the lipase and amylase elevations were transient, and in the majority of cases NEXAVARtreatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 NEXAVAR-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAEGrade 2) in the placebo group.

metastatic RCC. Agents that have beenFDA approved as well as others thathave been investigated in clinical trialshave shown improved survival and aremore tolerable than the traditionalimmunologic agents used to treat thisdisease. Although more tolerable, theside effects of these newer agents areunique and still require monitoring. Asmore experience is gained with thesetherapies, clinicians may be better ableto select therapies based on uniquecharacteristics of the patient.

References1. National Comprehensive Cancer Network. Clini -

cal Practice Guidelines in Oncology: Kidney Cancer.2006. www.nccn.org/professionals/physician_gls/PDF/kidney.pdf. Accessed March 5, 2007.

2. Cohen HT, McGovern FJ. Renal-cell carcino-ma. N Engl J Med. 2005;353:2477-2490.

3. Motzer RJ, Hutson TE, Tomczak P, et al. Suni -tinib versus interferon alfa in metastatic renal cellcarcinoma. N Engl J Med. 2007;356: 115-124.

4. Escudier B, Eisen T, Stadler WM, et al. Sorafenibin advanced renal cell carcinoma. N Engl J Med.2007;356:125-134.

5. Hudes G, Carducci M, Tomczak P, et al.Temsirolimus, interferon-alfa, or both for ad -vanced renal cell carcinoma. N Engl J Med.2007;356:2271-2281.

6. Escudier BJ, Ravaud A, Negrier S. Update onAVOREN trial in metastatic renal cell carcinoma(mRCC): efficacy and safety in subgroups of pa -tients (pts) and pharmacokinetic (PK) analysis. JClin Oncol. 2008;26(suppl 20):Abstract 5025.

7. Escudier B, Pluzanska A, Koralewski P, et al.Bevacizumab plus interferon alfa-2a for treat-ment of metastatic renal cell carcinoma: a ran-domized, double-blind, placebo-controlled trial.Lancet. 2007;370:2103-2111.

8. Stadler WM. Genitourinary cancer (testes, kid-ney, and bladder). 2008 ASCO Annual MeetingSummaries. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Annual+Meeting+Summaries?&vmview=summ_detail_view&confID=55&summaryID=11. Accessed November 15, 2008.

9. Melichar B, Koralewski P, Ravaud A, et al. First-line bevacizumab combined with reduced doseinterferon-alpha 2a is active in patients withmetastatic renal cell carcinoma. Ann Oncol.2008;19:1470-1476.

10. Motzer RJ, Escudier B, Oudard B, et al. Efficacyof everolimus in advanced renal cell carcinoma:a double-blind, randomized, placebo-controlledphase III trial. Lancet. 2008;372:449-456.

11. Parsa VK, Heilbrun L, Smith D, et al. Safety andefficacy of sorafenib therapy in patients: metasta-tic renal cell carcinoma with impaired renalfunction. 2008 ASCO Genitourinary Sym -posium. Abstract 365. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/ Abstracts?&vmview=abst_detail_view&confID=54&abstract ID=20420. Accessed November 15, 2008.

12. Hariharan S, Szcylik C, Porta C, et al. Sunitinibin metastatic renal cell carcinoma (mRCC)patients (pts) with brain metastases (mets): datafrom an expanded access trial. J Clin Oncol.2008;26(suppl 20):Abstract 5094.

13. Bukowski RM, Stadler WM, Figlin RA, et al.Safety and efficacy of sorafenib in elderlypatients (pts) ≥ 65 years: a subset analysis fromthe advanced renal cell carcinoma sorafenib(ARCCS) expanded access program in NorthAmerica. J Clin Oncol. 2008;26(suppl 20):Abstract 5045.

Renal Cell Carcinoma Continued from page 9

http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Annual+Meeting+Summaries?&vmview=summ_detail_view&confID=55&summayrID=11

http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf

http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf



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COMMENTARY

A NURSE’S PERSPECTIVEChanges, Choices, and ChallengesGary Shelton, MSN, ARNP, AOCNNew York University Cancer Institute, New York

Arelatively rare cancer, renal cell carcinoma (RCC) is often diagnosed at late stages or pro-gresses after primary therapy. The majority of RCC patients seen in a busy medical oncolo-gy office are of these categories. The therapeutic options for the stage IV population have

changed and are expanding as a result of several clinical trials.These changes are welcome for both seasoned and newer nurses, providing choices that are

improving outcomes and allow for greater optimism when speaking with patients about treatmentoptions. Nurses at an advanced level will take an active role in discussing treatment options withpatients. All nurses, however, can benefit from knowing and an ticipating the adverse events expect-ed or likely to occur with these therapies. Many events may have been underreported in clinical tri-

als, as they seem to occur more oftenin clinical practice.

There is growing evidence thatsunitinib, sorafenib, and temsirolimuscan have an effect on thyroid func-tion. Thus, baseline laboratory evalu-ation should include thyroid evalua-tion with follow-up monitoring ofthyroid-stimulating hormone duringtherapy. As with other treatment con-siderations, the use of targeted thera-pies should include the investigationsof body system functions and comor-bid conditions. Age alone, should notnegate their use.

Whatever their level in practice orexperience, nurses “own” the man-agement of side effects. It is ourresponsibility to address and incorpo-rate into a plan of care strategies thatallow for quality of life for patientswhile they go through their varioustreatment modalities. There shouldbe few surprises.

Understanding the possible sideeffects provides a framework for dis-cussion. This understanding can alsofacilitate the development of assess-ment tools and management guide-lines. It is the responsibility of nursesto accept the challenges of managingside effects: know what they are,know when they will occur, knowwhat evidence there is on treatmentstrategies.

Research is being conducted onprophylactic and ongoing treatmentof anticipated toxicities with targetedtherapies. For example, Lacoutureand colleagues at Northwestern Uni -versity, Chicago, have published rec-ommendations on skin care issues.1

This information will allow a morethorough treatment plan, whenimplementing new therapies foradvanced renal cancer. Otherresearch is ongoing. Nurses will takean active part in bringing the evi-dence to the bedside.

Reference1. Lacouture ME, Wu S, Robert C, et al. Evolving

strategies for the management of hand-footskin reactions with multitargeted kinaseinhibitors sorafenib and sunitinib. Oncologist.2008;13: 1001-1011.

14. Telli ML, Wittles RM, Fisher GA, Srinivas S. Cardiotoxicity associ-ated with the cancer therapeutic agent sunitinib malate. 2008ASCO Genitourinary Symposium. Abstract 351. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=54&abstractID=20439. Accessed Novem -ber 15, 2008.

15. Chu DT, Lacouture ME, Fillos T, Wu S. Risk of sorafenib-inducedhand-foot reaction in patients with renal cell carcinoma and non-renal cell malignancy. 2008 ASCO Genitourinary Sympo sium.Abstract 377. www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=54&abstractID= 20097. Accessed November 15, 2008.

16. Billemont B, Barete S, Meric JB, et al. Skin toxicity of sunitinib:prospective analysis in patients (pts) with metastatic renal cell carci-noma (mRCC). J Clin Oncol. 2008;26(suppl 20): Abstract 16146.

17. deSouza PL, Radulovic S, Beck J, et al. Characterization of hyper-glycemia, hypercholesterolemia, and hyperlipidemia in patients withadvanced renal cell carcinoma treated with temsirolimus or interfer-on alfa. J Clin Oncol. 2008; 26(suppl 20):Abstract 5116.

18. Clement P, Wolter P, Stefan C, et al. Thyroid dys function in patients(pts) with metastatic renal cell carcinoma (RCC) treated withsorafenib. J Clin Oncol. 2008;26(suppl 20): Abstract 16145.

19. Vakkalanka BK, Elson P, Wood L, et al. Long-term toxicity of tyro-sine kinase inhibitors (TKIs) in patients with metastatic clear cellrenal cell carcinoma (RCC). J Clin Oncol. 2008;26(suppl 20):Abstract 16045.

Lymphopenia was observed in 23% of NEXAVAR-treated patients and 13% of placebopatients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of NEXAVAR-treatedpatients and 7% of placebo patients. Neutropenia was observed in 18% of NEXAVAR-treatedpatients and 10% of placebo patients. CTCAE Grade 3 or 4 neutropenia was reported in 5%of NEXAVAR-treated patients and 2% of placebo patients.Anemia was observed in 44% of NEXAVAR-treated patients and 49% of placebo patients.CTCAE Grade 3 or 4 anemia was reported in 2% of NEXAVAR-treated patients and 4% ofplacebo patients.Thrombocytopenia was observed in 12% of NEXAVAR-treated patients and 5% of placebopatients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of NEXAVAR-treatedpatients and 0% of placebo patients.

6.3 Additional Data from Multiple Clinical Trials The following additional drug-relatedadverse reactions and laboratory abnormalities were reported from clinical trials ofNEXAVAR as monotherapy (very common 10% or greater, common 1 to less than 10%,uncommon 0.1% to less than 1%): Cardiovascular: Uncommon: hypertensive crisis*, myocardial ischemia and/or infarction*,congestive heart failure*Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushingUncommon: folliculitis, eczema, erythema multiforme, keratoacanthomas/squamous cellcancer of the skinDigestive: Very common: increased lipase, increased amylase Common: mucositis, stomatitis(including dry mouth and glossodynia), dyspepsia, dysphagia Uncommon: pancreatitis,gastrointestinal reflux, gastritis, gastrointestinal perforations*Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitisshould not be made solely on the basis of abnormal laboratory valuesGeneral Disorders: Very common: hemorrhage (including gastrointestinal* & respiratorytract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth,bone, and tumor pain) Common: decreased appetite, influenza-like illness, pyrexiaUncommon: infectionHematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia,thrombocytopenia Uncommon: INR abnormalHypersensitivity: Uncommon: hypersensitivity reactions (including skin reactions andurticaria)Metabolic and Nutritional: Very common: hypophosphatemia Common: transientincreases in transaminases Uncommon: dehydration, hyponatremia, transient increases inalkaline phosphatase, increased bilirubin (including jaundice), hypothyroidism, cholecystitis,cholangitis Musculoskeletal: Common: arthralgia, myalgiaNervous System and Psychiatric: Common: depression Uncommon: tinnitus,reversible posterior leukoencephalopathy*Renal and Genitourinary: Common: renal failureReproductive: Common: erectile dysfunction Uncommon: gynecomastiaRespiratory: Common: hoarseness Uncommon: rhinorrhea*adverse reactions may have a life-threatening or fatal outcome. In addition, the following medically significant adverse reactions were uncommon duringclinical trials of NEXAVAR: transient ischemic attack, arrhythmia, thromboembolism,acute renal failure. For these adverse reactions, the causal relationship to NEXAVAR hasnot been established. ** See specific section in full prescribing information.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.11)].

8.3 Nursing Mothers It is not known whether sorafenib is excreted in human milk. Becausemany drugs are excreted in human milk and because of the potential for seriousadverse reactions in nursing infants from NEXAVAR, a decision should be madewhether to discontinue nursing or to discontinue the drug, taking into account theimportance of the drug to the mother. Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio wasapproximately 5:1.

8.4 Pediatric Use The safety and effectiveness of NEXAVAR in pediatric patients have notbeen studied.Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening ofthe femoral growth plate at daily sorafenib doses ≥ 600 mg/m2 (approximately 0.3times the AUC at the recommended human dose), hypocellularity of the bone marrowadjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at therecommended human dose), and alterations of the dentin composition at 600mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.

8.5 Geriatric Use In total, 59% of HCC patients treated with NEXAVAR were age 65 years orolder, and 19% were 75 and older. In total, 32% of RCC patients treated with NEXAVARwere age 65 years or older, and 4% were 75 and older. No differences in safety or efficacywere observed between older and younger patients, and other reported clinical experiencehas not identified differences in responses between the elderly and younger patients, butgreater sensitivity of some older individuals cannot be ruled out.

8.6 Patients with Hepatic Impairment In vitro and in vivo data indicate that sorafenib isprimarily metabolized by the liver. Comparison of data across studies suggests thatpatients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment havesorafenib AUCs that may be 23- 65% lower than subjects with normal hepatic function.Systemic exposure and safety data were comparable in HCC patients with Child-Pugh Aand B hepatic impairment. NEXAVAR has not been studied in patients with Child-Pugh C hepaticimpairment [see Warnings and Precautions (5.12) and Clinical Pharmacology (12.3)].

8.7 Patients with Renal Impairment NEXAVAR has not been studied in patients undergoingdialysis. No dosage adjustment is necessary when administering NEXAVAR to patients withmild, moderate or severe renal impairment not undergoing dialysis [see ClinicalPharmacology (12.3)].Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

Manufactured by: Bayer HealthCare AG, Leverkusen, Germany

Manufactured for: Bayer HealthCare Pharmaceuticals Inc.,Wayne, NJ 07470

Onyx Pharmaceuticals, Inc.,2100 Powell Street, Emeryville, CA 94608

Distributed and marketed by: Bayer HealthCare Pharmaceuticals Inc.,Wayne, NJ 07470

Marketed by: Onyx Pharmaceuticals, Inc.,2100 Powell Street, Emeryville, CA 94608

80771372BS, R.2 Revised: 10/2008 14244©2008 Bayer HealthCare Pharmaceuticals Inc. Printed in U.S.A.




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The terms stomatitis and oralmucositis (OM) are used inter-changeably in the literature.

Although the clinical appearance maybe the same for both, the actual process-es are different. OM is the inflammationof the oral mucosa, ranging from ery-thema to ulcerations caused either byradiation and/or chemotherapy (CT).1Broader in scope, stomatitis refers to anyinflammatory condition of oral tissues(mucosa, dentition, and periodontium)and infections of oral tissues (gingivitis,glossitis). Hence, the defining featuresof stomatitis encompass OM.2,3

OM is one of the challenging symp-toms facing oncology clinicians inpractice today, but there is no rapidturnover of information. During theNational Comprehensive Cancer Net -work (NCCN) 2008 Annual Confer -ence on Clinical Practice Guidelinesand Quality Cancer Care, OM emergedas a topic of interest. Affecting at least400,000 cancer patients annually, OMis a debilitating side effect, complicatedby its dependence on type and dosing ofCT regimen and irradiation of the headand neck.4 Comments by MarkSchattner, MD, a member of theNCCN Task Force on Prevention andManagement of Mucositis in CancerCare, highlighted the major implica-tions of OM. He cited six potentialissues: nutritional problems, systemicinfections, increased morbidity, in -

creased emergency department visitswith longer hospitalization stays,increased medical costs, and possibledose reductions with its corollarydiminished response.5

Discussions continue to surround pre-vention, anticipation, management,and patient education. This articlereviews the current research regardingthese areas, along with documentationstrategies. Selected current clinical tri-als are reviewed, and the barriers thatoncology clinicians face in deliveringcare are discussed.

Prevention strategiesDental evaluation. The first step in

prevention of OM includes a completeoral health examination by a dentistfamiliar with the oral side effects of anti-cancer treatments. The dentist canidentify and treat teeth at risk for

infection or decay to avoid problemsduring and after radiation and CT. Inan attempt to prevent OM, fluoridetreatments also should be initiated bythe dental provider. Concurrently withthe dental examination, patientsshould be instructed to use a soft-bris-tled toothbrush and dental floss toremove plaque and debris. Additionalpreventive techniques cited in the lit-erature include smoking cessation,avoiding alcohol, and good nutrition.6-9

The best place to begin patient educa-tion would be in the dental office,closely followed by a visit to the oncol-ogy interdisciplinary team.

Fluoride products. Although not eval-uated in clinical trials side by side, topi-cal fluorides frequently are used toinduce fluoride incorporation intotooth enamel and dentin. Topical fluo-rides can be in the form of gels, rinses,vacuum-formed vinyl splints filled withfluoride gels, and varnishes. Any of thesetreatments will reduce oral bacteria.10

Calcium and phosphate rinses. Calci umand phosphate ions are crucial in main-taining the oral health of patients whoare receiving oncology treatments.11 Atthe 2008 Oncology Nursing SocietyAdvance Practice Conference, Haasand Mercedes presented data from alarge multisite, open-label, observation-al registry on use of a supersaturated cal-cium and phosphate oral rinse (Capha -sol) in radiation and chemo therapy

settings.12 The registry investigated thedosing of and compliance with therinse, the satisfaction levels of physi-cians and patients, and monitoringtreatment delays. Secondary objectivesassessed were OM frequency, duration,and severity according to the NationalCancer Institute (NCI) common toxic-ity scales. The rinse was begun at theinitiation of treatment with high-doseradiation and CT agents having highrisk of causing OM. The trial of 218patients from 26 sites consisted of 140patients who received CT alone and 78patients who received chemotherapy incombination with radiation (CT/RT).

Overall, patients rinsed with the solu-tion at least once a day (96% patients),an average of four times a day amongCT patients, and an average of at leastfive times a day among CT/RT patients.Twelve patients stopped using the oral

rinse, nine for reasons unrelated to therinse, two for their experience with badtaste, and one for nausea induced byswishing with the rinse.

Global physician and patient satisfac-tion rates were high within the CTgroup (75% excellent ratings by physi-cians and 80% very satisfied ratings bythe patients) and the CT/RT group(81%, 82%, respectively). Of the CTpatients, 93% experienced clinical NCIgrade 0-1 OM, as compared with 54% of

the CT/RT patients. The majority ofCT patients experienced none-to-mildfunctional OM (97%), as comparedwith 48% by CT/RT patients. CT/RTpatients experienced more grade 3 dys-phagia and pain (23%, 14%, respec-tively), as compared with CT patients(1%, 1%, respectively). No groupsreached grade 4 in regard to dysphagiaand pain. The researchers concludedthat the use of this electrolyte solutionwas beneficial to patients.

Palifermin. Studies of palifermin inhematologic cancers have shown thisagent beneficial in treating OM,13,14

and its use in solid tumors is now beingdiscussed.17 At the American Societyfor Therapeutic Radiology and On -cology (ASTRO) 2008 conference, Leand colleagues presented their findingsusing palifermin in patients with local-ly advanced head and neck cancertreated with chemoradiotherapy.15 Thisphase 3, multinational, randomized,double-blind, placebo-controlled studyenrolled 188 patients to either intra-venous (IV) palifermin or placebo 3days before the initiation of concurrentcisplatin and radiation and once aweek thereafter for 7 weeks.

The incidence of World HealthOrganization (WHO) grade 3/4recombinant human keratinocytegrowth factor was significantly lower inthe group given IV palifermin (54% vs69%, P = .041). Median time to onsetof severe OM was 47 days; duration ofsevere OM was 5 days; and develop-ment of grade 2 or higher xerostomiawas 67% among patients given palifer-min (placebo onset time 35 days, dura-tion 26 days, and 80% of patients devel-

oped xerostomia). The researchers con-cluded that palifermin was effective inreducing severe OM.

Another clinical trial presented atthe ASTRO conference in 2008 wasconducted by Lee and colleagues, whoinvestigated palifermin in head andneck cancer patients receiving radio-therapy with or without CT.16 In thisphase 2 study, 113 patients from sixinstitutions were divided into threegroups, each of which was receiving

radiation therapy with conventionalfractionation. The researchers foundthat palifermin, administered as a spraytwice a day, showed significant reduc-tion in the incidence of severe OMusing the Radiation Therapy OncologyGroup (RTOG) scale (63% paliferminvs 34% control, P = .0227).

Glutamine. Glutamine is a nonpre-scription supplement.17 In early studies,oral glutamine was found to protect ani-mals from the toxic effects of abdominalradiation and methotrexate-inducedCT. Although not regulated by the USFood and Drug Administra tion (FDA),many medical and radiation oncolo-gists, oncology nurses, and dieticianscontinue to prescribe the supplement toprevent OM.

An investigational oral glutaminesuspension shows promising results. Ina randomized, placebo-controlled clin-ical trial, Peterson and associates eval-uated 326 breast cancer patientsreceiving anthracycline-based CT.18

Compared with placebo, the suspen-sion significantly reduced the inci-dence of grade 3 OM using the WHOgrading scale (1.2% suspension vs 6.7%placebo; P = .005). This trial alsorevealed a lower-than-expected OMrate when crossing over from cycle 1during which patients received the sus-pension to cycle 2 when patientsreceived placebo. The carryover effectwas significant (P = .027).

Benzydamine HCl. Despite severalclinical trials, benzydamine HCl isapproved only for use in Europe. Ben -zydamine is a nonsteroidal drug, withanalgesic, anesthetic, antiinflammato-ry, and antimicrobial properties.19

Oral Mucositis: The ChallengingIssues Facing Oncology CliniciansMarilyn L. Haas, PhD, ANP-CNurse Practitioner, Mountain Radiation Oncology, Asheville, North Carolina

“The best place to begin patienteducation would be in the dental office,closely followed by a visit to the oncologyinterdisciplinary team.”

“Affecting at least 400,000 cancer patientsannually, OM is a debilitating side effect.”


SUPPORTIVE CA

RE

Studies have shown benefit in prevent-ing OM when patients used benzy-damine while receiving moderate dosesof radiation (50 Gy).3,20

Previous studies provide evidencedemonstrating the effectiveness of ben-zydamine, but a recent study byPutwatana and colleagues from MahidolUniversity, Bangkok, Thailand, report-ed less efficacy when compared withglycerin payayor (a Thai-preparedherbal product).21 Sixty patients wererandomized to two treatment arms andgiven either glycerin payayor drippedinto the mouth or benzydamine used asa mouth rinse. Comparisons were per-formed in relationship to onset of OM,pain, severity, xerostomia, treatmentdelays, patient satisfaction, and bodyweight. Significantly higher patient sat-isfaction and body weight were seen inthe payayor group. The researchers con-cluded that payayor prevented orrelieved radiation-induced OM betterthan benzydamine based on satisfactionand body weight.

Anticipated side effectsErythematous OM generally begins

to appear 7 to 10 days after initiation ofhigh-dose cancer therapy.22 Oncologyclinicians, whether in CT or radiationsettings, should be alert to potentialCT agents or radiotherapy with a highrisk of causing OM in patients.Increased toxicity can be ex pected inpatients when receiving combinedchemoradiation. Knowledge of whento expect the physical signs of OM willbe important in assessments, patienteducation, and intervention strategies.

Chemotherapy. Depending on thetherapeutic agent, CT-induced OM isdose dependent; the severity of whichdepends on treatment schedule. Pos -sible offending agents would includeantimetabolites, anthracyclines, andtaxanes.23 Generally, patients can expectCT-induced OM to begin 4 to 5 daysafter treatment and for it to last at least1 week but no longer than 3 weeks.24

Radiation therapy. With standarddaily radiation treatment of 2.0 Gy,mucosal changes occur within the firstweek.25 Factors that influence thedegree and severity of OM are radiationsource, cumulative dose, dose intensity,and volume of irradiated mucosa. OMbecomes visible within 2 to 3 weeksafter starting radiation in head andneck cancer patients. OM can intensi-fy with induction or concurrent CT, aswell as ongoing use of tobacco, inges-tion of alcohol, and poor nutritionalstatus. All of these factors can slowmucosal recovery.

ManagementAt the 2008 ASTRO annual meet-

ing, Xu and colleagues quantifiedhealthcare personnel time spent inmanaging OM.26 Experienced physi-cians and registered nurses (n = 101),working in radiation oncology withhead and neck cancer patients, respond-

ed to a Web-based survey. Physiciansreported spending 7.2 hours per patientduring radiation therapy, while nursesspent considerably more time, 12.1hours total during the course of radia-tion treatments. The researchers con-cluded that estimates of time spent car-ing for patients who developed OM wassubstantial and more emphasis on pre-vention strategies should be a priorityfor healthcare professionals.

Practices for managing OM have notchanged in recent years. Normal saline(1 teaspoon of table salt added to 32ounces of water) remains one of themainstays of therapy. Experts agree thatnormal saline (either refrigerated orroom temperature) provides oral com-fort.22,27,28 If patients begin to developthick, ropey secretions, sodium bicar-bonate (1-2 teaspoons per quart of nor-mal saline) can be added to help removesecretions, sooth the mucosa, and nor-malize pH of the oral cavity.25 Today,the use of hydrogen peroxide rinses arediscouraged in the presence of OMbecause of the damage to fibroblasts andkeratinocytes that can cause delay inwound healing.29,30

Topical anesthetics also relieve OMpain; however, they neither protect theintegrity nor hasten the recovery of theoral mucosa. Unfortunately, there is nostandardization between prepared mix-tures. Coating agents (antacids) are fre-quently added to 2% viscous lidocaine,diphenhydramine solution, or dyclo-nine rinses. The proportions and ingre-dients can differ between providers andinstitutions. When topical anestheticsbecome ineffective, systemic analgesicsshould be prescribed. Short-acting nar-cotics are the initial choice, followed byextended-release, long-acting narcotics.The implementation of the WHO stepapproach to pain management is pre-ferred; however, most OM patients will

require starting with narcotics ratherthan nonsteroidal agents.

Once healed from acute OM,patients may experience other long-lasting problems: dry mouth, tastechanges, and dental caries. The health-care team can assist patients in main-taining oral health after treatment.Products that can alleviate dry mouth,help with taste changes, and preventfuture dental caries can be purchasedover-the-counter (Table 1). In general,clinicians should follow and monitorpatients closely after completing thera-py to ensure pain is controlled, healingcontinues, and education about thelong-term effects of cancer therapieshas begun.

Patient educationThe close working relationships that

oncology healthcare professionals formwith their patients enable them to fulfillimportant roles as educators. These pro-fessionals should inform patients aboutexpected side effects and their timingand also offer supportive care measures.After review of the patient’s history andinitial patient assessment, the educa-tional plan should be inclusive of reliefmeasures for oral discomfort, dentalhygiene needs, and any nutritionalissues (loss of weight, hypogeusia, dys-phagia). After each treatment visit, aclinician should examine for presence ofOM and other oral problems to furthereducate about prevention or manage-ment of complications (oral candidiasis,bleeding, acute xerostomia).

DocumentationIn their third revision, the NCI has

developed an assessment documenta-tion tool for OM. Their scale, CommonTerminology Criteria for AdverseEvents, separates OM into clinical andfunctional ratings.31 This update distin-

guishes between the functional abilitiesand the clinical assessment of OM.Clinical grades 1 and 2 are less severe(erythema to noncontiguous patches ofpseudomembranous reactions) thanhigher grades 3 and 4, which representconfluent pseudomembranous reactionsto deep ulcerations or possibly necrosis.Functional grades rate the patients’ abil-ity to eat a normal diet and swallow andhydrate and whether the disease hasbecome life-threatening (grades 0-5).

Other available assessment instru-ments are the WHO Oral ToxicityScale, the Oral Assessment Guide, theRTOG and European Organization forResearch and Treatment of CancerScale, the McDibbs Mouth Assessment,and the Oral Mucositis AssessmentScale. These tools differ from eachother in content and ratings of OM. Forcontinuity between assessments, clini-cians should select one tool to achieveconsistency at their institution.

Clinical trialsClinical trials provide an excellent

opportunity for patients who face OMas a result of their therapy to enroll in astudy that could prevent or managetheir side effects. Whether at clinicalrounds, interdisciplinary tumor boards,or one-on-one interactions with pa -tients, oncology team members canencourage patients to participate inclinical studies.

Today, more patients are searchingonline for supportive care studies andare becoming more knowledgeableabout potential beneficial research.MedLine Plus, a service of the USNational Library of Medicine and theNational Institutes of Health, has anexcellent patient tutorial aboutenrolling in clinical trials (www.nlm.nih.gov/medlineplus/tutorials/cancerclinicaltrials/htm/index.htm). A siteproduced by the National Library ofMedicine (www.clinicaltrials.gov) pro-vides a database of current clinicalresearch studies for patients, familymembers, and the public. The NCIClinical Trials Resources and PhysicianData Query (PDQ) (www.cancer.gov/clinicaltrials) also offers searches, resultsof clinical trials, and educational mate-rials for patients.

Cochrane Reviews are intended toassist oncology providers in clinical deci-sion making and developing an evi-dence-based approach to managing OM.Worthington and colleagues discussedtheir findings on the effectiveness ofprophylactic agents for OM in cancerpatients.32 Of 565 reviewed studies, 288were excluded because of lack of infor-mation on OM. Of the remaining stud-ies, only 89 had pertinent preventioninformation on a total of 7523 random-ized patients. The researchers evaluated33 interventions (Table 2).32 Althoughthe strength of the evidence was vari-able, several of the interventions werefound to have benefit in preventing orreducing OM. Furthermore, the re -

Table 1. Nonprescription Products for Oral Care

Side effects Available products

Dry mouth Oasis rinse, spray

Orajel gel, spray, toothpaste

OraMoist time-released dry mouth discsBiotène rinse, spray, toothpaste, gum, liquid moisturizerThayers Natural Remedies spray, lozenges

Salivart spray

BetaCell rinse

MedOral spray

Moi-Stir moisturizer

GC Dry Mouth Gel

Rain dry mouth spray

Glycerin (mix ¼ tsp in 8 oz of water, swish)

Taste changes Zinc (18 mg-45 mg)

Dental caries (prevention) Mouthwashes: Perox-A-Mint (contains no alcohol),Biotène antibacterialFluoride toothpastes: Biotène, Gel-Kam, PreviDent

http://www.nlm.nih.gov/medlineplus/tutorials/cancerclinicaltrials/htm/index.htm

http://www.clinicaltrials.gov

http://www.cancer.gov/clinicaltrials

http://www.cancer.gov/clinicaltrials

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SUPPORTIVE CA

RE

searchers identified the need for betterwell-designed studies that would enrollsufficient numbers to analyze by sub-groups (type of disease and/or CT agents).

Another Cochrane Review focusedon treatment of OM in the setting ofCT and radiation therapy.33 Clarksonand colleagues found four agents thatimprove symptoms of OM, one agentthat eradicates OM, and several agentsthat are not effective (Table 3).33

Additionally, patient-controlled analge-sia pumps were compared with continu-ous infusion pumps, and no statisticaldifference was found in controllingpatients’ OM pain.

Barriers to careThe lack of standardized protocols

from institution to institution compli-cates the management of OM. Whileguidelines generally should includeatraumatically cleansing the oralmucosa (soft-bristled toothbrush, fluo-ride toothpaste, and nonastringentmouthwash), lubricating lips and oraltissues, and relieving pain and inflam-mation, healthcare providers andpatients still follow different protocols.Implementing a stepped approachwould be preferred. Begin with bothbland rinsing for cleansing and a super-saturated electrolyte oral rinse. Go on totopical anesthestics and mucosal coat-ing agents when OM begins to becomepainful. Proceed to pain-relieving nar-cotics when appropriate. Oncology cli-nicians can develop evidence-basedprotocols for patients and the interdisci-plinary team by utilizing resources fromthe Oncology Nursing Society PuttingEvidence into Practice card, ManagingOral Mucositis.34

Aside from the lack of treatment stan-dardization, patient compliance/adher-ence with dental care can be an issue atthe beginning of, during, or after thera-py. Adherence to a regular oral regimenhas shown to impact duration and sever-ity of OM.3,35 Historically, patients withhead and neck cancer typically consumealcohol and use tobacco products. Headand neck cancer patients are frequentlymen, have lower socioeconomic status,and are less health conscious.36 Whenpatients are not compliant with per-forming oral care three to four times aday every 1 to 4 hours and at bedtime, itcan complicate therapy and impedehealing. After therapy is complete andOM begins to heal, dental aftercare rec-ommendations may not be followedconsistently. Oncology nurses shouldtake responsibility for ensuring that fol-low-up appointments with dentists arearranged, fluoride trays are utilized daily,and high intake of sugars are avoided.

Documenting various stages of OMcan be complicated. Numerous tools areavailable, which makes it difficult tocompare institutional outcomes tothose in the literature or at other insti-tutions. Each member of the oncologyhealthcare team may want to use afamiliar instrument, but providers mustreach an agreement and be consistent indocumentation.

ConclusionsOM is a direct effect of cytotoxic

agents and/or ionizing radiation andrepresents a challenge for oncology careproviders. The treatment side effects(pain, odynodysphagia, dysgeusia, dehy-dration, and possibly malnutrition)interfere with the patient’s quality of

life, can have significant morbidity, maydemand treatment delays, can increasetherapeutic expenses, and add addition-al time to patient care. Several steps canbe taken prophylactically to reduce OMseverity, manage the symptoms usingnonpharmaceutical and pharmaceuticalapproaches, and offer patient teachingand support.

References1. Sonis ST. Mucositis as a biological process: a new

hypothesis for the development of chemothera-py-induced stomatotoxicity. Oral Oncol. 1998;34:39-43.

2. Sonis ST, Elting LS, Keefe D, et al. Perspectiveson cancer therapy-induced mucosal injury:pathogenesis, measurement, epidemiology, andconsequences for patients. Cancer. 2004;100(suppl 9):1995-2025.

3. Rubenstein EB, Peterson DE, Schuber M, et al.Clinical practice guidelines for the preventionand treatment of cancer therapy-induced oraland gastrointestinal mucositis. Cancer. 2004;100(suppl 9):2026-2046.

4. Meraw SJ, Reeve CM. Dental considerationsand treatment of the oncology patient receivingradiation therapy. J Am Dent Assoc. 1998;129:201-205.

5. Susman E. NCCN annual conference: increasedfocus on control of mucositis. Oncol Times.2008;30:6-7.

6. Shieh SH, Wang ST, Tsai ST, Tseng CC. Mouthcare for nasopharyngeal cancer patients undergo-ing radiotherapy. Oral Oncol. 1997;33:36-41.

7. Rugg T, Saunders MT, Dische S. Smoking andmucosal reactions to radiotherapy. Br J Radiol.1990;63:554-556.

8. Greenberg MS, Cohen SG, McKitrick JC,Cassileth PA. The oral flora as a source of sep-ticemia in patients with acute leukemia. OralSurg Oral Med Oral Pathol. 1982;53:32-36.

9. Sonis S, Kunz A. Impact of improved dentalservices on the frequency of oral complicationsof cancer therapy for patients with non-head-and-neck malignancies. Oral Surg Oral Med OralPathol. 1988;65:19-22.

10. American Dental Association Council onScientific Affairs. Professionally applied topicalfluoride: evidence-based clinical recommenda-tions. J Dent Educ. 2007;71:393-402.

11. Papas AS, Clark RE, Martuscelli G, et al. Aprospective, randomized trial for the preventionof mucositis in patients undergoing hematopoi-etic stem cell transplantation. Bone MarrowTransplant. 2003;31:705-712.

12. Haas M, Mercedes T. Improving quality of life in

head/neck chemoradiation patients when usinga supersaturated electrolyte oral rinse. OncolNurs Forum. 2008;35:977.

13. Spielberger R, Stiff P, Bensinger W, et al.Palifermin for oral mucositis after intensive ther-apy for hematologic cancers. N Engl J Med. 2004;351:2590-2598.

14. Radtke ML, Kolesar JM. Palifermin (Kepivance)for the treatment of oral mucositis in patientswith hematologic malignancies requiringhematopoietic stem cell support. J Oncol PharmPract. 2005;11:121-125.

15. Le Q, Kim C, Schneider G, et al. Paliferminreduces severe oral mucositis in subjects withlocally advanced head and neck cancer under-going chemoradiotherapy. Int J Radiat OncolBiology Physics. 2008;72: S32-S33.

16. Lee S, Wu H, Song Y, et al. The therapeuticeffect of recombinant human epidermal growthfactor (rhEGF) on mucositis in patients withhead and neck cancer undergoing radiotherapywith or without chemotherapy: a double-blindplacebo-controlled prospective phase II multi-institutional clinical trial. Int J Radiat OncolBiology Physics. 2008;72:S32.

17. Anderson PM, Schroeder G, Skubitz KM. Oralglutamine reduces the duration and severity ofstomatitis after cytotoxic cancer chemotherapy.Cancer. 1998;83:1433-1439.

18. Peterson DE, Jones JB, Petit RG 2nd.Randomized, placebo-controlled trial of saforisfor prevention and treatment of oral mucositis inbreast cancer patients receiving anthracycline-based chemotherapy. Cancer. 2007;109:322-331.

19. Quane PA, Graham GG, Ziegler JB. Pharma -cology of benzydamine. Inflammopharma cology.1998;6:95-107.

20. Epstein JB, Silverman S Jr, Paggiarino DA, et al.Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: results from a multicen-ter, randomized, double-blind, placebo-con-trolled clinical trial. Cancer. 2001;92:875-885.

21. Putwatana P, Sanmanowong P, OonprasertpongL, et al. Relief of radiation-induced oral mucosi-tis in head and neck cancer. Cancer Nurs. 2009;32:82-87.

22. National Cancer Institute. Oral complications ofchemotherapy and head/neck radiation (PDQ)Health Professional Version. November 2008.www.cancer.gov/cancertopics/pdq/supportivecare/oralcomplications/HealthProfessional/page6. Accessed January 24, 2009.

23. Scully C, Epstein J, Sonis S. Oral mucositis: achallenging complication of radiotherapy, che -motherapy, and radiochemotherapy: part 1,pathogenesis and prophylaxis of mucositis. HeadNeck. 2003;25:1057-1070.

24. Kostler W, Hejna M, Wenzel C, Zielinski CC.Oral mucositis complicating chemotherapy and/or radiotherapy: options for prevention andtreatment. CA Cancer J Clin. 2001;51:290-315.

25. Khan A, Smith B. Useful tools for radiationoncology. In: Haffty B, Wilson LD, eds.Handbook of Radiation Oncology: Basic Principlesand Clinical Protocols. Sudbury, MA: Jones andBartlett; 2009:173-204.

26. Xu X, Barron R, Mautner B, et al. Burden ofmucositis management on radiation oncologyfacility staff treating head and neck cancerpatients. Int J Radiat Oncol Biology Physics. 2008;72:S413-S414.

27. Keefe DM, Schubert MM, Elting LS, et al.Updated clinical practice guidelines for the pre-vention and treatment of mucositis. Cancer.2007;109:820-831.

28. Bensinger W, Schuber M, Ang KK, et al. NCCNTask Force Report: prevention and managementof mucositis in cancer care. J Natl Compr CancNetw. 2008;6(suppl 1):1-23.

29. Oral Complications of Cancer Therapies: Diagnosis,Prevention, and Treatment. NIH ConsensusStatement. 1989;7:1-11.

30. Tombes MB, Gallucci B. The effects of hydrogenperoxide rinses on the normal oral mucosa. NursRes. 1993;42:332-337.

31. Cancer Therapy Evaluation Program, NationalInstitutes of Health, National Cancer Institute.Common Terminology Criteria for Adverse Events.Version 3.0. Bethesda, MD; 2003.

32. Worthington H, Clarson J, Eden T. Interventionsfor preventing oral mucositis for patients withcancer receiving treatment. Cochrane DatabaseSyst Rev. 2007;(2):CD000978.

33. Clarkson J, Worthington H, Eden T. Inter -ventions for treating oral mucositis for patientswith cancer receiving treatment. CochraneDatabase Syst Rev. 2007;(2):CD001973.

34. Harris DJ, Eilers JG, Cashavelly BJ, et al. PuttingEvidence into Practice: Mucositis. Pittsburgh, PA:Oncology Nursing Society; 2006.

35. Specht L. Oral complications in the head andneck radiation patient. Introduction and scope ofthe problem. Support Care Cancer. 2002;10:36-39.

36. McGuire DB, Correa ME, Johnson J, WienandtsP. The role of basic oral care and good clinicalpractice principles in the management of oralmucositis. Support Care Cancer. 2006;14:541-547.

Table 2. Interventions for Preventing Oral Mucositis in Patients Receiving Cancer Treatment

Possible interventions reviewed

Interventions with

> 1 meta-analysis

showing benefit

Intervention with 1 study showing benefit

Acyclovir, allopurinol mouth rinse, aloe vera, antibiotic pastille orpaste, benzydamine, beta carotene, calcium phosphate, chamomile,Chinese medicine, chlorhexidine, etoposide, folinic acid, glutamine,granulocyte-macrophage colony-stimulating factor, histamine gel,honey, hydrolytic enzymes, ice chips, iseganan, keratinocyte growthfactors, misonidazole, piolcarpine, pentoxifylline, povidone, pred-nisone, propantheline bromide anticholinergics, prostaglandin,sucralfate, systemic antibiotic clarithromycin, traumeel, zinc sulphate

Amifostine (RR = 0.95),Chinese medicine (RR =0.44), hydrolyticenzymes (RR = 0.52),ice chips (RR = 0.64)

Benzydamine, calciumphosphate, etoposidebolus, honey, iseganan,oral care, zinc sulphate

RR indicates risk ratio (calculated using random-effects models).Source: Reference 32.

Table 3. Interventions for Treating Oral Mucositis for Patients Receiving Cancer Care

Interventions showing

improvement benefit

Intervention showing

eradicating benefit Interventions showing no benefit

Allopurinol (RR = 3.33), granulocyte-macrophage colony-stimulating factor (RR = 4.23), immunoglobulin (RR = 1.81),human placental extract (RR = 4.50)

Allopurinol (RR = 19.0) Benzydamine HCl, sucralfate, tetrachlorodecaoxide, chlorhexidine and “magic” (lidocainesolution, diphenhydramine hydrochloride, andaluminum hydroxide suspension)

RR indicates risk ratio (calculated using random-effects models). Source: Reference 33.

http://www.cancer.gov/cancertopics/pdq/supportivecare/oralcomplications/HealthProfessional/page

1 Mouridsen HT et al. Treatment of anthracycline extravasation with savene (dexrazoxane).

Results from two prospective clinical multicentre studies. Ann Oncol 2007; 18:546-550.

2 Totect® package insert.

© 2009 TopoTarget USA. All rights reserved. TOT0077/02-09

Totect and its logo mark are registered trademarks of TopoTarget USA, Inc., Rockaway, NJ, USA.

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http://www.totect.com

Totect® – Brief prescribing information Please

refer to the package insert for full prescribing in-

formation. Each Totect carton contains 10 vials of

Totect® (dexrazoxane for injection) 500 mg and 10

vials of 50 mL diluent. Indication: Treatment of

extravasation resulting from IV anthracycline che-

motherapy. Dosage and administration: Admin-

istration of Totect should begin as soon as possible

and within 6 hours following the anthracycline ex-

travasation. Totect should be given as an intravenous

(IV) infusion once daily for 3 consecutive days. The

dose of Totect is based on the patient’s body surface

area: day one, 1000 mg/m2; day two, 1000 mg/m2;

day three, 500 mg/m2. For patients with a body sur-

face area of > 2 m2, a dose of 2000 mg should be

given on days 1 and 2, and a dose of 1000 mg should

be given on day 3. The Totect dose should be reduced

50% for patients with creatinine clearance values

of <40 mL/minute. Cooling procedures such as ice

packs should be removed from the affected area at

least 15 minutes prior to Totect administration. To-

tect (dexrazoxane for injection) must be reconstitut-

ed with diluent, supplied in the carton. The patient’s

Totect dose is diluted in 0.9% 1000 mL NaCl prior to

administration. Contraindications: None known.

Warnings: Pregnancy Category D. Dexrazoxane was

toxic to pregnant rats at doses of 2 mg/kg (1/80 the

human dose on a mg/m2 basis) and embryotoxic

and teratogenic at 8 mg/kg when given daily during

the period of organogenesis. Teratogenic effects in

the rat included imperforate anus, microphthalmia,

and anophthalmia. In offspring allowed to develop

to maturity, fertility was impaired in the male and

female rats treated in utero during organogenesis at

8 mg/kg. In rabbits, doses of 5 mg/kg daily during

the period of organogenesis caused maternal toxicity

and doses of 20 mg/kg were embryotoxic and terato-

genic. Teratogenic effects in the rabbit included sev-

eral skeletal malformations such as short tail, rib and

thoracic malformations, and soft tissue variations in-

cluding subcutaneous, eye and cardiac hemorrhagic

areas, as well as agenesis of the gallbladder and of

the intermediate lobe of the lung. There is no ad-

equate information about the use of Totect in preg-

nant women. If this drug is used during pregnancy,

or if the patient becomes pregnant while taking this

drug, the patient should be apprised of the potential

hazard to the fetus. Precautions: Totect is a cyto-

toxic drug. When administered to patients receiving

anthracycline-containing cytotoxic therapy, additive

cytotoxicity may occur. Treatment with Totect is as-

sociated with leukopenia, neutropenia, and throm-

bocytopenia. Reversible elevations of liver enzymes

may occur. Blood counts and liver enzymes should

be monitored. Greater exposure to dexrazoxane may

occur in patients with compromised renal function.

The Totect dose should be reduced by 50% in pa-

tients with creatinine clearance values <40 mL/min.

Dimethyl sulfoxide (DMSO) should not be used in pa-

tients who are receiving dexrazoxane to treat anthra-

cycline-induced extravasation. Women who have the

potential to become pregnant should be advised that

Totect might cause fetal harm. There are no known

drug interactions. No carcinogenicity studies have

been done with Totect in animals. The carcinogenic

potential of dexrazoxane has not been investigated.

Long term dosing with razoxane (the racemic mix-

ture of dexrazoxane, ICRF-187, and its enantiomer

ICRF-186) is associated with the development of ma-

lignancies in rats and possibly in mice. Dexrazoxane

was not mutagenic to bacteria in vitro (Ames assay),

but caused significant chromosomal aberrations in

mammalian cells in vitro. It also increased the forma-

tion of micronucleated polychromatic erythrocytes in

mice. Dexrazoxane is mutagenic and clastogenic. The

possible adverse effects of Totect on the fertility of

humans and experimental animals, male or female,

have not been adequately studied. Testicular atrophy

was seen with dexrazoxane administration at doses

as low as 30 mg/kg weekly for 6 weeks in rats (about

1/5 the human dose on a mg/m2 basis) and as low

as 20 mg/kg weekly for 13 weeks in dogs. The effect

of dexrazoxane on labor and delivery in humans has

not been studied. It is not known whether dexrazox-

ane or its metabolites are excreted in human milk.

Because many drugs are excreted in human milk and

because of the potential for serious adverse reac-

tions in nursing infants from dexrazoxane, a decision

should be made whether to discontinue nursing or

to discontinue the drug, taking into account the im-

portance of the drug to the mother. The safety and

effectiveness of Totect in pediatric patients have not

been established. No differences in safety or efficacy

were observed between older and younger patients,

and other reported clinical experience has not iden-

tified differences in responses between the elderly

and younger patients, but greater sensitivity of some

older patients has been observed. This drug is known

to be substantially excreted by the kidney, and the

risk of toxic reactions to this drug may be greater in

patients with impaired renal function. Because el-

derly patients are more likely to have decreased renal

function, care should be taken in dose selection, and

it may be useful to monitor renal function. Adverse

reactions: Adverse reactions of nausea/vomiting,

diarrhea, stomatitis, bone marrow suppression (neu-

tropenia, thrombocytopenia), altered liver function

(increased AST/ALT), and infusion site burning have

been observed. These adverse reactions have been

reversible.

Rx only

Totect® is a registered trademark of

TopoTarget A/S

US Patent No. 6,727,253B2

NDC 38423-110-01

Manufactured by:

Ben Venue Laboratories, Inc.

Bedford, OH 44146

Hameln Pharmaceuticals GmbH

31789 Hameln

Germany

Manufactured for:

TopoTarget A/SSymbion

Science Park

Fruebjergvej 3

DK-2 100 Copenhagen

Denmark

Marketed by:

TopoTarget USA Inc.

100 Enterprise Drive

Rockaway, New Jersey

07866

(866) 478-8274

Answers for Cancer.

www.totect.com

TOT0077/02-09

©2009 TopoTarget USA

http://www.totect.com


SUPP

ORT

IVE

CAR

E

Can you come? I think I have anextravasation.” I have had thesecalls throughout my career and

seen the concerned look on the faces ofthe nurse, patient, and family. TheOncology Nursing Society (ONS) andthe Infusion Nurses Society have bothcreated guidelines for the prevention,assessment, and treatment of infiltra-tion and extravasation. Nurses involvedin infusion therapy in the oncology set-ting are generally familiar with theseguidelines. No matter how careful thenurse and the preventive measuresundertaken, however, the potential forinfiltration and extravasation exists.Dexrazoxane for injection is a relativelynew treatment for anthracyclineextravasations, packaged in an emer-gency toolkit,1 which has been added tothe new 2009 ONS guidelines.

What is extravasation?Extravasation refers to the escape of a

chemotherapy drug into the extravascu-lar space, either by leakage from a vesselor by direct infiltration. The overallincidence of extravasation injuries fromvesicant chemotherapy administrationhas been reported to range from 1% toapproximately 6%. Local symptoms (eg,pain, erythema, swelling) are usual, butit is difficult to differentiate these symp-toms as a flare reaction or a vesicant

extravasation. Extravasation can beextremely debilitating and disablingand requires immediate attention. If theextravasation is significant, necrosismay occur. A lesion can heal slowly, ornot at all, and possibly result in a long-term or permanent disability. Increasingawareness of the complications of extra -vasation and improved infusion tech-niques among the healthcare communi-ty may lead to a lower incidence.

The Infusion Nurses Society stan-dards define infiltration and extravasa-tion as2:

• Infiltration—inadvertent adminis-tration of nonvesicant medicationof solution into the surroundingtissue

• Extravasation—inadvertent ad -

ministration of vesicant medication orsolution into the surrounding tissue.

Extravasation injuries have beendescribed frequently in the oncology lit-erature, and education on how to pre-vent and treat cancer chemotherapyextravasation is common among oncol-ogy staff. It is important to note, how-ever, that injury can also occur in thenononcology setting. Reports of signif-icant patient morbidity have beenrelated to extravasation of a variety ofvasoconstrictive substances and hyper-osmolar and/or concentrated elec-trolyte solutions, such as potassiumchloride, parenteral nutrition, sodiumbicarbonate, norepinephrine, andphenytoin.2

In a review of systemic infusionchemotherapeutic agents, extravasa-tions were reported in 0.1% to 6.5% ofcases.2 Extravasation may or may notlead to tissue injury, and the potentialfor tissue injury is related to the vesi-cant/irritant properties of the solution(eg, cytotoxicity, pH, and osmolality),concentration of the drug, volumeextravasated, and the affected tissue/anatomical structure location. The clas-sification of nonvesicant, irritant, orvesicant is based on the drug’s potentialto cause local tissue injury (Table 1).

The potential for chemotherapeuticdrugs to cause tissue damage can be clas-

sified further according to whether theagents bind to the nucleic acids inDNA. For example, vinca alkaloids orepipodophylotoxins do not bind toDNA, allowing these agents to bemetabolized and more easily neutral-ized. The degree of tissue damage will bedetermined by the ability of the patientto clear the agent metabolically, whichdepends on the concentration and vol-ume. In general, extravasations of thesedrugs can be mildly to moderatelypainful, tend to remain localized, andimprove over time. Conversely, anthra-cyclines bind to the nucleic acids inDNA. Upon initial absorption intolocal tissue cells, direct cell death andendocytolysis is induced. The releasedcellular contents allow surrounding cells

to uptake the anthracycline, leading toprogressive tissue destruction through acycle of cellular destruction and sur-rounding cell drug uptake. Therefore,anthracyclines can remain in the sur-rounding tissue for months.2-5

Table 2 lists some of the agents com-monly used for chemotherapy. As men-tioned previously, chemotherapy agentsare categorized into three categories:vesicants, irritants, and nonvesicants.In addition, these agents can be classi-fied according to their DNA- or non-DNA–binding properties. Nonneo -plastic solutions are listed as irritants,but these solutions have vesicant poten-tial depending on their chemical prop-erties, concentration, and volume ofextravasation. Vesicants or irritantsmanifest as local signs and symptoms,but these agents may cause local tissuedeath or necrosis while irritants do not.

Location of the access device, drugconcentration, and amount of vesicantleaking into the local area play factorsin the severity of the extravasation.5,6

Functional muscle damage andchanges can occur within a few hours,and nerve damage can take place with-in 24 hours.7 Anthracyclines, mech -lorethamine, and vinca alkaloids usual-ly cause immediate pain. Pain fromother agents (eg, mitomycin C) maynot become apparent until a few daysor a week later. Other examples ofproblematic agents are oxaliplatin(reported to have vesicant properties),cisplatin (vesicant potential if greaterthan 20 mL of 0.5 mg/mL concentra-tion extravasates), and mitroxantrone.

Prevention of extravasationPrevention of extravasation is

always the goal. Peripheral intravenous(IV) catheters should be established insmooth pliable veins, preferably in theforearm, taking care to avoid areas of

flexion or apparent injury, small fragileveins, areas of altered venous return,and lower extremities. After thevenous access is established peripheral-ly or centrally, blood return and paten-cy should be verified before and duringadministration.

Signs and symptoms of extravasation

Little or no blood return from the IVdevice being used for chemotherapy isone possible indication of infiltra-tion/extravasation. Others are if the IVfluid rate decreases or stops completely,or a pump alarm sounds, indicating anocclusion. These signs should be takenseriously, and the peripheral or centralchemotherapy-infusion site should bechecked for symptoms. Swelling at thesite is a very common symptom and usu-ally the first to be observed. Other signsand symptoms of a vesicant extravasa-tion are redness and discomfort. How -ever, not all patients experience symp-toms, and loss of blood return may bethe only indication.

In the case of central venous access,further evaluation using radiographswith dye studies may be indicated todetermine line placement and integritybefore further use. Upon determinationof an extravasation, the infusion shouldbe discontinued, and the catheter dis-connected. Aspiration of residual solu-tion at the site should be attempted, theperipheral IV or port needle should beremoved, the symptoms assessed, thephysician or advanced practice nursenotified, and appropriate managementmeasures initiated.5 Blistering, ulcera-tion, and tissue necrosis may appearquickly or within a few days to a weekafter the extravasation.5,8 Ultravioletlight and fluorescein may help definenecrotic tissue with doxorubicin extra -vasation.9 Doxorubicin extravasation

Extravasation: Assessment andTreatmentMarianne Bunce-Houston, RN, MS, AOCNS, CRNIOncology Clinical Nurse Specialist, Contra Costa Regional Medical Center, Martinez, California

Table 1. Infiltration and Extravasation Drug Classifications

Classification of nonvesicant, irritant, or vesicant is based on potential to causelocal tissue injury.• Nonvesicant drugs—If extravasated, these drugs will rarely produce tissue

necrosis.• Irritant drugs—These drugs can cause pain at the injection site or along the

vein tract, with or without inflammation. Local tissue injury can occur withlarge amounts of extravasated, concentrated drug solution.

• Vesicant drugs—On inadvertent extravasation, these drugs can cause theformation of blisters, tissue destruction, and necrosis.

Source: Reference 2.

“No matter how careful the nurse andthe preventive measures undertaken,however, the potential for infiltration andextravasation exists.”


SUPPORTIVE CA

RE

tissue injury has been specifically notedto progress slowly, with increasing sever-ity over several weeks but without thetypical healing pattern.10 Early surgerywith debridement followed by skingrafts for significant vesicant extravasa-tion has been recommended to removenecrosis, but can cause permanent dis-figuration.

Treatment of extravasationData on treatment of vesicant anti-

cancer drug extravasations have beenlargely empirically based, have shownan inconsistent frequency in clinicalevents, and have been based mainly onanimal models. Conventional nonphar-macologic and pharmacologic therapieshave had limited efficacy. Nonpharma -cologic therapies include topical cool-ing, saline lavage and suction, hyperbar-ic oxygen, and topical negative pressure.ONS guidelines recommend stoppingthe infusion and applying warm or coldcompresses, depending on the type ofmedication that has escaped into thesubcutaneous tissue.11 For example, coldcompresses or ice packs are appropriatefor anthracycline, whereas heated com-presses are appropriate for plant alka-loids. The application of heat is believedto increase drug distribution throughvasodilation, thereby decreasing theaccumulation of the drug in the local tis-sue. The vasoconstriction associatedwith the application of cold limits thespread of the drug by localizing it.11

Pharmacologic therapies reported inthe literature include the administra-tion/application of growth factors,dimethyl sulfoxide (DMSO), hydrocor-tisone, hyaluronidase, ginkgo bilobaextract, alpha-tocopherol (vitamin E),cimetidine, diphenhydramine, heparin,lidocaine, and N-acetylcysteine. DMSOhas only shown to be effective in a 99%medical grade, which is unavailable inthe United States. Corticosteroids, ini-tially thought to be effective against tis-sue injury by decreasing inflammatoryeffects, have not been shown to be ben-eficial in most circumstances and mayactually be harmful. However, somestudies have reported a benefit in oxali-platin extravasation. Sodium bicarbon-ate was thought to neutralize the agentbut has been shown not to be active andmay, in fact, be a vesicant.4,12-15 Onlytwo compounds have been approved bythe US Food and Drug Administration(FDA) for the treatment of vesicantextravasations. Sodium thiosulfate/me chlorethamine and dexrazoxane.

Dexrazoxane has a unique dualmechanism of action. It inhibits DNAtopoisomerase II, the target of anthracy-cline chemotherapy, and binds to DNAtopoisomerase II at a different step inthe catalytic cycle.16-18 This locks theenzyme in a form that is no longeraffected by the anthracycline. Dexrazox -ane also acts as an iron chelator andminimizes oxidative damage caused byformation of anthracycline–iron com-plexes.19,20 Dexrazoxane is then rap-

idly metabolizedwithin the cell tochelate iron andlimits anthracy-cline-mediatedoxidative injury.

Several clinicaltrials have beenperformed to de -termine the safetyand efficacy ofdexrazoxane. Twointernantional,single-arm, multi-center clinicalstudies were per-formed.21 In theTT01 study, noneof the 19 patientsrequired surgicalintervention norhad serious latecon ditions as aresult of the extra -vasation. In theTT02 study, oneof the 38 patientsrequired surgeryfor re moval of dead tissue. Thirteenpatients were treated for other condi-tions as a result of the extravasation,including pain and atrophy. Theanthracyclines extravasated includedepirubicin, doxorubicin, daunorubicin,and pegylated liposomal doxorubicin.The sites of extravasation included theforearm (63%), hand (21%), antecu-bital area (11%), and central venousaccess device (5%). Patients wereadministered dexrazoxane IV infusionsof 1000 mg/m2 or 500 mg/m2 for 1 to 2hours once daily for 3 days, at 24 and 48hours. Primary efficacy was defined asdebridement surgery not required. Localaspiration of extravasation was recom-mended. Cooling was permitted 15minutes before treatment. No steroid orDMSO treatment was permitted. Thesestudies showed dexrazoxane to have98% overall efficacy in preventingnecrosis that required surgery.21

Dexrazoxane for injection is current-ly the only FDA-approved treatmentspecifically for anthracycline extravasa-tions. Treatment should be initiatedwithin 6 hours of the extravasation andcontinued daily around the same time ofday for a total of 3 days. The product issold in an emergency toolkit that con-tains everything needed for the com-plete 3-day treatment: 10 vials of dexra-zoxane powder (500 mg of dexrazoxanehydrochloride/vial) and 10 vials ofdexrazoxane diluent solution. Uponreconstitution, each vial contains aconcentration of 10 mg/mL dexrazox-ane, which should be infused immedi-ately. Dosage is determined by thepatient’s body surface area. On days 1and 2, the patient should receive 1000mg/m2, and on day 3 a dose of 500mg/m2. The daily dose should notexceed 2000 mg/m2, and the doseshould be reduced by 50% if the creati-nine clearance is less than 40 mL/min.

After the IV catheter is inserted into alarge vein located in the oppositeextremity, the infusion is administeredover 1 to 2 hours. Topical coolingshould be removed at least 15 minutesbefore and during the infusion toenhance perfusion of the affected area.

The most common side effects ofdexrazoxane are neutropenia, thrombo-cytopenia, fever, infusion site pain/phlebitis, and nausea and vomiting.The patient’s complete blood count andliver enzyme levels should be monitoredbecause of the potential for transientliver enzyme increases, neutropenia,and thrombocytopenia.1

ConclusionThe oncology infusion nurse is

responsible for the safe administrationof irritant and vesicant infusates.Prevention of extravasations is alwaysthe goal but is not always possible.Extravasations can be managed by avariety of pharmacologic and nonphar-macologic methods. Clinical trial datasupport the use of some agents but notothers. Anthracycline extravasationshave been particularly difficult to man-age because of the drug’s DNA-bindingcapacity. Dexrazoxane, however, hasbeen shown to be highly effective inpreventing tissue injury due to anthra-cycline extravasation. By following thenational guidelines for safe administra-tion,2,7 nurses will be able to minimizepotential tissue injury related toextravasations.

References1. Totect (dexrazoxane HCl for injection) [package

insert]. TopoTarget A/S, Copenhagen, Denmark.2. Infusion Nurses Society. Infusion nurses standards

of practice. J Infus Nurs. 2006;29(1S):S59-S61.3. Schummer W, Schummer C, Bayer O, et al.

Extravasation injury in the perioperative setting.Anesth Analg. 2005;100:722-727.

4. Ener RA, Meglathery SB, Styler M. Extra -vasation of systemic hemato-oncological thera-

pies. Ann Oncol. 2004;15:858-862.5. Skeel RT, ed. Handbook of Cancer Chemotherapy.

5th ed. New York, NY: Lippincott Williams andWilkins; 1999.

6. Hadaway LC. I.V. infiltration: not just a periph-eral problem. Nursing. 2002;32:36-42.

7. Polovich M, Whitford JM, Olsen M. ONSChemotherapy and Biotherapy Guidelines andRecommendations for Practice. 3rd ed. Pittsburgh,PA: Oncology Nursing Press; 2009.

8. Oncologic emergencies. In: Chisholm-BurnsMA, Wells B, Schwinghammer T, et al. Pharma -cother apy Principles and Practices. New York, NY:McGraw-Hill Companies, Inc; 2008.

9. Wickman R, et al. Vesicant extravasation partII: evidence-based management and continuingcontroversies. Oncol Nurs Forum. 2006;44:1143-1150.

10. Bowers DG Jr, Lynch JB. Adriamycin extravasa-tion. Plast Reconstr Surg. 1978;61:86-92.

11. Polovich M, et al, eds. Catheter placement. JInfus Nurs. 2006;29(1 suppl):S42-S92.

12. Schulmeister L. Totect: a new agent for treatinganthracycline extravasation. Clin J Oncol Nurs.2007;11:387-395.

13. Langer SW, Thougaard AV, Sehested M, JensenPB. Treatment of anthracycline extravasation inmice with dexrazoxane with or without DMSOand hydrocortisone. Cancer Chemother Pharmacol.2006;57:125-128.

14. Bertelli G, Dini D, Forno GB, et al. Hyal -uronidase as an antidote to extravasation ofvinca alkaloids: clinical results. J Cancer Res ClinOncol. 1994;120:505-506.

15. Du Bois A, Fehr MK, Bochtler H, Köchli OR.Clinical course and management of paclitaxelextravasation. Oncology Reports. 1996;3:973-974.

16. Sehested M, Jensen PB. Mapping of DNA topo -isomerase II poisons (etoposide, clerocidin) andcatalytic inhibitors (aclarubicin, ICRF-187) tofour distinct steps in the topoisomerase II catalyt-ic cycle. Biochem Pharmacol. 1996;51:879-886.

17. Jensen PB, Sehested M. DNA topoisomerase IIrescue by catalytic inhibitors: a new strategy toimprove the antitumor selectivity of etoposide.Biochem Pharmacol. 1997;54:755-759.

18. Hasinoff BB. Chemistry of dexrazoxane and ana-logues. Semin Oncol. 1998;25(4 suppl 10):3-9.

19. Andoh T, Ishida R. Catalytic inhibitors of DNAtopoisomerase II. Biochem Biophys Acta. 1998;1400:155-171.

20. Hasinoff BB, Schroeder PE, Patel D. Themetabolites of the cardioprotective drug dexra-zoxane do not protect myocytes from doxoru-bicin-induced cytotoxicity. Mol Pharmacol. 2003;64:670-678.

21. Mouridsen HT, Langer SW, Buter J, et al. Treat -ment of anthracycline extravasation withSavene (dexrazoxane): results from two prospec-tive clinical multicentre studies. Ann Oncol.2007;18:546-550.

DNA-binding agents (vesicants)

Non-DNA–binding agents (vesicants)

Anthracycline agents• Doxorubicinb

• Daunorubicinb

• Epirubicinb

• Idarubicinb

• Mitoxantroneb

Vinca alkaloids

• Vincristineb

• Vinblastineb

• Vindesineb

• Vinorelbineb

Antitumor antibiotics • Mitomycin Cb

• Liposomal doxorubicin • Bleomycin

Taxane agents

• Paclitaxel • Docetaxel

Alkylating agents• Mechlorethamine • Platinum analogs

Other anticancer antibiotics• Dactinomycin • Mitoxantrone

Alkylators

• Amsacrine

Nonneoplastic agents (irritantsa)• Hyperosmotic solutions

(eg, parenteral nutrition) • Concentrated electrolyte solutions

(eg, calcium gluconate) • Agents altering intracellular pH

(eg, sodium bicarbonate)

• Agents inducing severevasoconstriction and ischemia

• Etoposide (VP-16)b

• Oxaliplatinb

• Cisplatinb

aHave vesicant potential depending on their chemical properties, concentration, and volume of extravasation.bHas been shown to evoke extravasation more frequently than the other agents listed.Sources: References 3 and 4.

Table 2. Categories of Chemotherapeutic Agents


BR

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Fortunately, there continues to be agreat deal of ongoing researchrelated to breast cancer; however,

keeping up with the latest data can bechallenging. At recent annual meetingsof the American Society of ClinicalOncology (ASCO), the AmericanSociety for Therapeutic Radiation andOncology (ASTRO), and the OncologyNursing Society (ONS), as well as theASCO Breast Cancer Symposium, ad -vances were presented in various areasof breast cancer research, including riskfactors, diagnostics, new drugs/regi-mens, and quality of life/symptom man-agement issues. Some of these newerstudies are discussed in this article.

Ongoing researchBreast cancer continues to be the

most common cancer (excluding skincancer) in women and the second lead-ing cause of cancer death in this group.Although final numbers are not yetavailable for 2008, it was estimated that182,460 women in the United Stateswould be diagnosed with breast cancerand 40,480 would die of the disease.1 Adisappointing and surprising factrevealed at the ASCO Breast CancerSymposium was that despite the manyadvances in the treatment of metastat-ic breast cancer, there has been no sig-nificant improvement in median sur-vival. A retrospective review done at aNational Cancer Institute comprehen-sive cancer center looked at thedecades 1985-1994 and 1995-2005.Although median overall survival (OS)tended to improve from 2.4 years to 3.1

years, this improvement was not statis-tically significant. No advantage in sur-vival regardless of hormone-receptorstatus was evident.2

A large retrospective review of82,759 patients with breast cancer pre-sented at the ASCO Breast CancerSymposium suggested that contralateralprophylactic mastectomy in womenwho are younger (18-49 years of age)and have early-stage estrogen-receptor–

negative breast cancer appears toimprove breast cancer survival. Olderpatients, those with advanced disease,and those with hormone-receptor–positive cancer did not receive a signifi-cant survival benefit from the surgery.3Although prophylactic mastectomymay not improve survival in thesewomen, they still may choose thisoption to avoid the anxiety of yetanother cancer diagnosis and the mor-bidity and life disruption that accompa-nies such a diagnosis.

An interesting study presented atASCO’s annual meeting revealed thatvitamin D deficiency is common at thetime of diagnosis of breast cancer and isassociated with higher grade tumorsand an increased risk of distant recur-rence and death.4 Thus, testing vita-min D levels in the blood should beconsidered to ensure a healthy range.More research is needed in this area,including a study to evaluate whethervitamin D repletion would make a dif-ference. Vitamin D supplementationshould be done only if levels are low,and patients should be instructed aboutthe dangers of exceeding the recom-mended dose.

Diagnostics and tumor markersThe use of magnetic resonance imag-

ing (MRI) in women with a diagnosis ofbreast cancer remains controversial.One study examined trends in mastec-tomy rates at the Mayo Clinic inRochester, Minnesota, from 2003 to2006. During this time period, theresearchers found that women who had

a preoperative MRI after being diag-nosed with breast cancer were morelikely to undergo a mastectomy thanthose who did not. It also was discov-ered that in the same time period, mas-tectomy rates increased 12% in womenwho did not have a preoperative MRI.No other factors, such as the influenceof MRI findings, role of family history orgenetic testing, and patient or physicianpreference on decision to have an MRI,

were considered.5 Another retrospec-tive review of 577 patient recordsshowed that women who had a pre-treatment MRI had treatment delay andan increased likelihood of mastectomywithout improving outcomes. The timefrom diagnosis to first therapeutic sur-gery averaged 38 days without MRI and57 days with MRI (P = .010). Mas -tectomy was the initial surgical proce-dure in 19.5% of patients who did nothave MRI compared with 27.7% ofthose who did (P = .024).6 In a study of

159 women aged 70 years or older, 5.7%were found to have an occult contralat-eral cancer identified by MRI. This sug-gests that age should not be a deterrentto MRI, but rather this modality shouldbe a prime consideration for diagnosticsin the older population.7

A prospective study evaluatingpositron-emission tomography used toassess axillary lymph nodes in womenhaving sentinel lymph node biopsy(SLNB) showed that the imaging tech-nique was not sufficiently sensitive todetect positive lymph nodes. Its highpositive predictive value in the trial,however, suggests that it could be usedin women with large primary tumors toidentify those in whom an SLNB couldbe omitted prior to therapeutic axillarylymph node dissection.8

Molecular breast imaging (MBI)gained much attention at the ASCOBreast Cancer Symposium. This tech-nique proved better than mammogra-phy in women at high risk for breastcancer who had dense breast tissue.With this imaging device, a radiotraceris administered followed by imagingthat requires approximately 10 minutesper view. Only light compression of thebreast is needed. Among 940 patientsscreened with mammography and MBI,cancers were detected in 10 of 13 whohad MBI compared with three of 13 formammography. The recall rate was7.7% for MBI and 9.4% with mammog-raphy. Currently the molecular imagingmachine is not commercially available.Future research will focus on comparingit with MRI.9

A retrospective review of more than3100 patients showed that those withtriple-negative breast cancer (TN-BC)have a higher risk of developing cere-bral metastases (CM) compared withother types of breast cancer. CMoccurred earlier in those with TN-BCand displayed a trend for poorer out-come. Oncologists might consider rou-tine central nervous system MRI in TN-BC patients.10

The German SUCCESS trial of morethan 1500 node-positive and high-risk

node-negative patients analyzed theperipheral blood for circulating tumorcells (CTCs) before and after adjuvanttaxane-based chemotherapy. The pres-ence of CTCs did not correlate withtumor size, grading, hormonal status, orERBB2 (formerly HER2 or HER2/neu)status of the primary tumor, but with thepresence of lymph node metastases (P =.003). Although the presence of CTCsbefore systemic treatment did not haveprognostic relevance for disease-free sur-vival (DFS) or OS, persistence of CTCsafter chemotherapy was a significantpredictor for both reduced DFS (P =.04) and OS (P = .03). These resultssuggest a potential role for CTC moni-toring in the future. Long-term follow-up is needed as the median follow-uptime in this study was only 12 months.11

TreatmentsSeveral studies have been investigat-

ing the optimal method and durationof radiation therapy to the breast. Inwomen with early-stage breast cancer,partial breast irradiation, using theMammoSite Targeted Radiation Ther -apy System for 1 week, has proved aseffective as standard whole breast radi-ation in preventing recurrence. Theseresults, based on data from 1400women with a median follow-up timeof 36 months, may prompt morewomen, who otherwise were unable orunwilling to undergo 5 to 6 weeks ofstandard radiation therapy, to undergobreast conservation therapy (BCT).Some clinicians, however, may believemore follow-up data are needed before

Recent Advances in Diagnosis and Treatment of Breast CancerCarolyn Weaver, RN, MSN, AOCNClinical Nurse Specialist, Fox Chase Cancer Center, Philadelphia, Pennsylvania

“Vitamin D deficiency is common at the time of diagnosis of breast cancer and is associated with higher gradetumors and an increased risk of distant recurrence and death.”

“Women who had a pretreatment MRIhad treatment delay and an increasedlikelihood of mastectomy withoutimproving outcomes.”


BR

EAST CA

NCER

it becomes standard care.12

A study presented at the ONSAnnual Congress showed the Mam -moSite system to be well tolerated withminimal adverse effects. Overall,patients were satisfied with the treat-ment regimen and cosmetic result.Patients were likely to recommend thistreatment to others. Satisfaction re -mained high at 1 year or longer post-treatment. As expected, the shortertreatment regimen was the determiningfactor in the patients’ selection.13

A study from Canada randomizedmore than 1200 women with node-neg-ative invasive breast cancer to a 3-weekcourse of radiation treatment or thestandard 5 weeks. Results after 10 yearsof follow-up showed that the shorterduration was as effective as the standardcourse. Although the shorter course hasbecome standard of care in Canada, cur-rently, the course remains 5 to 6 weeksin the United States.14

In a 14-year follow-up of more than1800 patients with ductal carcinoma insitu, it was shown there was no value inthe addition of boost radiation therapyin reducing the recurrence of invasiveor noninvasive breast cancers forpatients with this cancer.15

Older women are underrepresentedin clinical trials and, therefore, minimaldata are available for this population.The CALGB/CTSU 49907 study wasdesigned to compare the efficacy ofcapecitabine with standard treatment inbreast cancer patients aged 65 years orolder. Patients (n = 633) were random-ized to receive standard treatment dox-orubicin/cyclophosphamide; cyclophos-phamide, methotrexate, fluorouracil; orcapecitabine. The primary end pointwas relapse-free survival (RFS), definedas locoregional, distant relapse, ordeath. Median follow-up was 2.4 years.Results showed that standard treatmentwas superior to capecitabine for bothRFS and OS, especially in patients withhormone-receptor–negative tumors.16

Women with ERBB2-positive me -tastatic breast cancer that had pro-gressed while on trastuzumab did bene-fit when trastuzumab was used inconjunction with other agents. In arandomized study, 296 heavily pre-treated women with ERBB2-positivemetastatic breast cancer whose cancerprogressed on trastuzumab receivedeither lapatinib alone or in combina-tion with trastuzumab. Results indicat-ed that the combination regimenbrought improvement in progression-free survival (PFS), doubled clinicalbenefit rate, and displayed a trendtoward improved OS as compared withlapatinib alone.17

A study of 736 women with metastat-ic breast cancer who were randomized toreceive docetaxel and bevacizumab ateither 7.5 mg/kg or 15 mg/kg or docetax-el alone showed that both doses of beva-cizumab in combination with docetaxelsignificantly improved PFS and responserate compared with docetaxel alone.18

A prospective study examined out-comes in women with BRCA1/2-asso-ciated breast cancer. They were treat-ed locally with mastectomy versusbreast-conserving surgery and radio-therapy. Fifteen-year rates of con-tralateral breast cancer (CBC) werecomparable with and without radio-therapy, suggesting no detectableincrease in CBC from scatter radiationtherapy. These results are importantfor BRCA1/2 carriers with breast can-cer when considering options.19

Large clinical trialsThe Austrian Breast and Colorectal

Cancer Study Group examined the effi-cacy of ovarian suppression usinggoserelin in combination with anastro-zole or tamoxifen with or without zole-dronic acid in premenopausal women(n = 1800) with hormone-responsivebreast cancer. The addition of zoledron-ic acid (4 mg every 6 months) to adju-vant endocrine therapy significantlyprolonged DFS (by 36%) and RFS (by35%) compared with adjuvant en -docrine therapy alone. There was nosignificant difference in DFS betweentamoxifen and anastrozole. There was anonsignificant trend favoring the zole-dronic acid arm for OS. This large clin-ical trial demonstrates that the antitu-

mor activity of adjuvant zoledronic acidimproves outcomes beyond the effect ofendocrine therapy alone.20

A study of 236 women with locallyadvanced breast cancer who receivedneoadjuvant chemotherapy comparedthe incidence of locoregional recur-rence rate between those undergoingBCT and those receiving mastectomy.Results showed that at a median follow-up time of 58 months, the rate of locore-gional recurrence was low and similar forboth groups: 5% in the BCT group and9% in the mastectomy group (P = .32).Overall 5-year survival rates, however,were 90% in the BCT group and 69% inthe mastectomy group (P = .01).21

Quality of life/symptom management

Many women with breast cancerexperience hot flashes as a result of hor-monal therapies used in treatment orearly menopause due to chemotherapy.Although some medications (eg, ven-lafaxine, gabapentin, and captopril)may help to reduce hot flashes, alterna-tives are being studied. One small (n =47) study randomized patients toreceive venlafaxine or acupuncturetreatments. Results showed that thetwo treatments were equally effectivefor reducing hot flashes, night sweats,and other effects of antiestrogen thera-py. Women in the venlafaxine group

reported a variety of side effects, in -cluding nausea, dry mouth, headache,sleep disturbance, dizziness, vision dis-turbance, increased blood pressure,fatigue, and anxiety, whereas the ac -upuncture group reported no treat-ment-related effects. The acupuncturegroup stated that they had improve-ment in energy, clarity of thought, sex-ual desire, and overall sense of well-being. Women who took venlafaxinehad an increase in the number andintensity of hot flashes within 2 weeksof discontinuing drug therapy, whereaswomen receiving ac upuncture did notbegin to have an increase in the num-ber or severity of hot flashes for 14 or 15weeks after treatment.22

In premenopausal women whodeveloped osteoporotic fractures due tochemotherapy-induced menopause, zo -ledronic acid has been shown toincrease bone mineral density.23

Fertility preservation is anotherimportant area being studied in pre-menopausal women with breast cancer.There is conflicting evidence on the useof gonadotropin-releasing hormone(GnRH) analogs to preserve fertility inwomen undergoing adjuvant chemo -therapy. A study presented at theASCO annual meeting was the firstrandomized clinical trial designed to

evaluate the benefit of GnRH use dur-ing chemotherapy. The results of thissmall study indicated that the use ofGnRH analogs does not appear to pre-serve menstrual status. Follicular-stimu-lating hormone levels in patients inwhom menstruation has returned wasnot significantly different in the GnRHarm versus the control arm.24

Additional information on the latestin breast cancer diagnostics and treat-ment options can be found by access-ing the web sites of ASCO, ASTRO,and ONS.

References1. Jemal A, Siegel R, Ward E, et al. Cancer statis-

tics, 2008. CA Cancer J Clin. 2008;58:71-96.2. Bankhead C. ASCO breast: survival in

metastatic breast cancer static despite newagents. September 2008. www.medpagetoday.com/MeetingCoverage/ASCOBreast/tb/10851.Accessed September 10, 2008.

3. Bankhead C. ASCO breast: survival benefit ofcontralateral prophylactic mastectomy limited.September 2008. www.medpagetoday.com/MeetingCoverage/ASCOBreast/tb/10821.Accessed September 10, 2008.

4. Goodwin PJ, Ennis M, Pritchard KI, et al.Frequency of vitamin D (vit D) deficiency atbreast cancer (BC) diagnosis and associationwith risk of distant recurrence and death in aprospective cohort study of T1-3, N0-1, M0 BC.J Clin Oncol. 2008;26(20 suppl):Abstract 511.

5. Katipamula R, Hoskin TL, Boughey JC, et al.Trends in mastectomy rates at the Mayo ClinicRochester: effect of surgical year and preopera-tive MRI. J Clin Oncol. 2008;26(20 suppl):Abstract 509.

6. Bankhead C. ASCO breast: pretreatment MRIdelays treatment without improving outcomes.

September 2008. www.medpagetoday.com/MeetingCoverage/ASCOBreast/tb/10827.Accessed September 10, 2008.

7. Bernard JR, Vallow LA, DePeri ER, et al.Mammographically occult contralateral breastcarcinoma detected by magnetic resonanceimaging in the elderly. J Clin Oncol. 2008;26(20suppl):Abstract 500.

8. Pritchard KI, Julian J, McCready D, et al. Aprospective study evaluating 18F-Fluo -rodeoxyglucose (18FDG) positron emissiontomography (PET) in the assessment of axillarynodal spread in women undergoing sentinellymph node biopsy (SLNB) for breast cancer.J Clin Oncol. 2008;26(20 suppl):Abstract 533.

9. Bankhead C. ASCO breast: molecular breastimaging tops mammography for dense breasts.September 2008. www.medpagetoday.com/MeetingCoverage/ASCOBreast/tb/10781.Accessed September 16, 2008.

10. Heitz F, Harter P, Traut A, et al. Cerebral metas-tases (CM) in breast cancer (BC) with focus ontriple-negative tumors. J Clin Oncol. 2008;26(20suppl):Abstract 1010.

11. Rack K, Schindlbeck C, Schneeweiss A, et al.Prognostic relevance of circulating tumor cells(CTCs) in peripheral blood of breast cancerpatients before and after adjuvant chemothera-py: The German SUCCESS-Trial. J Clin Oncol.2008;26(20 suppl):Abstract 503.

12. Smith M. ASTRO: partial breast radiationeffective in preventing cancer recurrence.September 2008. www.medpagetoday.com/MeetingCoverage/ASTRO/tb/11001. AccessedSeptember 24, 2008.

13. Powers J, Ricardo A, Shadle K. The MammoSiteRadiation Therapy System experience: thepatient’s perspective. Oncol Nurs Forum. 2008;35(3):Abstract 2619.

14. Smith M. ASTRO: short radiation course afterlumpectomy suggested. September 2008. www.medpagetoday.com/MeetingCoverage/ASTRO/tb/11005. Accessed September 24, 2008.

15. Julian TB, Land SR, Wang Y, et al. Is boost ther-apy necessary in the treatment of DCIS? J ClinOncol. 2008;26(20 suppl):Abstract 537.

16. Muss HB, Berry DL, Cirrincione C, et al.Standard chemotherapy (CMF or AC) versuscapecitabine in early-stage breast cancer (BC)patients aged 65 and older: results ofCALGB/CTSU 49907. J Clin Oncol. 2008;26(20suppl):Abstract 507.

17. O’Shaughnessy J, Blackwell KL, Burstein H, etal. A randomized study of lapatinib alone or incombination with trastuzumab in heavily pre-treated HER2+ metastatic breast cancer pro-gressing on trastuzumab therapy. J Clin Oncol.2008;26(20 suppl):Abstract 1015.

18. Miles D, Chan A, Romieu G, et al. Randomized,double-blind, placebo-controlled, phase III studyof bevacizumab with docetaxel or docetaxel withplacebo as first-line therapy for patients withlocally recurrent or metastatic breast cancer(mBC): AVADO. J Clin Oncol. 2008;26(20suppl):Abstract LBA1011.

19. Pierce LJ, Griffith KA, Buys S, et al. Outcomesfollowing breast conservation versus mastecto-my in BRCA1/2 carriers with early-stage breastcancer. J Clin Oncol. 2008;26(20 suppl):Abstract 536.

20. Gnant M, Mlineritsch B, Schippinger W, et al.Adjuvant ovarian suppression combined withtamoxifen or anastrozole, alone or in combina-tion with zoledronic acid, in premenopausalwomen with hormone-responsive, stage I and IIbreast cancer: first efficacy results fromABCSG-12. J Clin Oncol. 2008;26(20 suppl):Abstract LBA4.

21. Meyers MO, Klauber-Demore N, Ollila DW, etal. Locoregional control in locally advancedbreast cancer using neoadjuvant chemotherapyfollowed by breast conservation. J Clin Oncol.2008;26(20 suppl):Abstract 539.

22. Bankhead C. ASTRO: acupuncture relievesvasomotor symptoms in breast cancer patients.September 2008. www.medpagetoday.com/MeetingCoverage/ASTRO/10990. AccessedSeptember 24, 2008.

23. Shapiro CL, Halabi S, Gibson G, et al. Effect ofzoledronic acid (ZA) on bone mineral density(BMD) in premenopausal women who developovarian failure (OF) due to adjuvant chemother-apy (AdC): first results from CALGB trial 79809.J Clin Oncol. 2008;26(20 suppl):Abstract 512.

24. Ismail-Khan R, Minton S, Cox C, et al. Preserva -tion of ovarian function in young women treatedwith neoadjuvant chemotherapy for breast can-cer: a randomized trial using the GnRH agonist(triptorelin) during chemotherapy. J Clin Oncol.2008;26(20 suppl):Abstract 524.

“Antitumor activity of adjuvant zoledronicacid improves outcomes beyond the effectof endocrine therapy alone.”

http://www.medpagetoday.com/MeetingCoverage/ASCOBreast/tb/10851








http://www.medpagetoday.com/MeetingCoverage/ASTRO/tb/11001





http://www.medpagetoday.com/MeetingCoverage/ASTRO/10990

http://www.medpagetoday.com/MeetingCoverage/ASTRO/10990


MEE

TIN

GSMAY 2009

Meetings3-6 TEL AVIV, ISRAEL12th World Congress on Cancer ofthe Skin [email protected]

13-14 WASHINGTON, DC4th Annual Oncology EconomicsForum: Access to Innovative CancerTherapies in 2009www.conferagroup.com

May 29-June 2ORLANDO, FL2009 ASCO Annual Meetingwww.cancerlearning.com

17-20 MIAMI, FLHOPA 2009: Hematology/OncologyPharmacy Association 5th AnnualConferencewww.hoparx.org

17-20 KOHALA COAST, HI10th International Lung CancerCongresswww.cancerlearning.com

22-26 KOHALA COAST, HI2009 Pan Pacific [email protected]

24-26 MADRID, SPAINVIII Madrid Breast CancerConferencewww.madridbreastcancer2009.com

25-27 ROME, ITALYSupportive Care in CancerMASCC/ISOO 2009 InternationalSymposiumwww.mascc.org

JUNE 2009

RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information.

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan®

(rituximab) is indicated for the treatment of patients with: Relapsed or refractory,low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previouslyuntreated follicular, CD20-positive, B-cell NHL in combination with CVPchemotherapy; Non-progressing (including stable disease), low-grade, CD20-positive B-cell NHL, as a single agent, after first-line CVP chemotherapy;Previously untreated diffuse large B-cell, CD20-positive NHL in combination withCHOP or other anthracycline-based chemotherapy regimens. WARNINGS ANDPRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal,infusion reactions. Severe reactions typically occurred during the first infusion withtime to onset of 30–120 minutes. Rituxan-induced infusion reactions andsequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm,pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction,ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicatepatients with an antihistamine and acetaminophen prior to dosing. Institutemedical management (e.g., glucocorticoids, epinephrine, bronchodilators, oroxygen) for infusion reactions as needed. Depending on the severity of theinfusion reaction and the required interventions, consider resumption of theinfusion at a minimum 50% reduction in rate after symptoms have resolved.Closely monitor the following patients: those with preexisting cardiac orpulmonary conditions, those who experienced prior cardiopulmonary adversereactions, and those with high numbers of circulating malignant cells(≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, AdverseReactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volumefollowed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, orhyperphosphatemia, can occur within 12–24 hours after the first infusion. FatalTLS cases have occurred after administration of Rituxan. A high number ofcirculating malignant cells (≥25,000/mm3) or high tumor burden confers a greaterrisk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk.Correct electrolyte abnormalities, monitor renal function and fluid balance, andadminister supportive care, including dialysis as indicated. [See Boxed Warning.]Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fataloutcome, can occur in patients treated with Rituxan. These reactions includeparaneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis,vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of thesereactions has varied from 1–13 weeks following Rituxan exposure. DiscontinueRituxan in patients who experience a severe mucocutaneous reaction. The safetyof readministration of Rituxan to patients with severe mucocutaneous reactionshas not been determined. [See Boxed Warning, Adverse Reactions.] ProgressiveMultifocal Leukoencephalopathy (PML) JC virus infection resulting in PMLand death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologicmalignancies diagnosed with PML received Rituxan in combination withchemotherapy or as part of a hematopoietic stem cell transplant. The patients withautoimmune diseases had prior or concurrent immunosuppressive therapy. Mostcases of PML were diagnosed within 12 months of their last infusion of Rituxan.Consider the diagnosis of PML in any patient presenting with new-onsetneurologic manifestations. Discontinue Rituxan and consider discontinuation orreduction of any concomitant chemotherapy or immunosuppressive therapy inpatients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis BVirus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminanthepatitis, hepatic failure, and death can occur in patients with hematologicmalignancies treated with Rituxan. The median time to the diagnosis of hepatitiswas approximately 4 months after the initiation of Rituxan and approximately onemonth after the last dose. Screen patients at high risk of HBV infection beforeinitiation of Rituxan. Closely monitor carriers of hepatitis B for clinical andlaboratory signs of active HBV infection for several months following Rituxantherapy. Discontinue Rituxan and any concomitant chemotherapy in patients whodevelop viral hepatitis, and institute appropriate treatment including antiviraltherapy. Insufficient data exist regarding the safety of resuming Rituxan in patientswho develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.]Other Viral Infections The following additional serious viral infections, eithernew, reactivated, or exacerbated, have been identified in clinical studies orpostmarketing reports. The majority of patients received Rituxan in combinationwith chemotherapy or as part of a hematopoietic stem cell transplant. These viralinfections included cytomegalovirus, herpes simplex virus, parvovirus B19,varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viralinfections occurred as late as one year following discontinuation of Rituxan andhave resulted in death. [See Adverse Reactions.] Cardiovascular Discontinueinfusions for serious or life-threatening cardiac arrhythmias. Perform cardiacmonitoring during and after all infusions of Rituxan for patients who developclinically significant arrhythmias or who have a history of arrhythmia or angina.[See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occurafter Rituxan administration in patients with hematologic malignancies. Renaltoxicity has occurred in patients with high numbers of circulating malignant cells(≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome andin patients with NHL administered concomitant cisplatin therapy during clinicaltrials. The combination of cisplatin and Rituxan is not an approved treatmentregimen. Use extreme caution if this non-approved combination is used in clinicaltrials and monitor closely for signs of renal failure. Consider discontinuation ofRituxan for patients with a rising serum creatinine or oliguria. Bowel Obstructionand Perforation Abdominal pain, bowel obstruction and perforation, in some

WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME(TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVEMULTIFOCAL LEUKOENCEPHALOPATHY (PML)Infusion Reactions: Rituxan administration can result in serious,including fatal infusion reactions. Deaths within 24 hours of Rituxaninfusion have occurred. Approximately 80% of fatal infusion reactionsoccurred in association with the first infusion. Carefully monitorpatients during infusions. Discontinue Rituxan infusion and providemedical treatment for Grade 3 or 4 infusion reactions [see Warningsand Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS):Acute renal failure requiring dialysis with instances of fatal outcomecan occur in the setting of TLS following treatment of non-Hodgkin’slymphoma (NHL) patients with Rituxan [see Warnings and Precautions,Adverse Reactions]. Severe Mucocutaneous Reactions: Severe,including fatal, mucocutaneous reactions can occur in patientsreceiving Rituxan [see Warnings and Precautions, Adverse Reactions].Progressive Multifocal Leukoencephalopathy (PML): JC virus infectionresulting in PML and death can occur in patients receiving Rituxan [seeWarnings and Precautions, Adverse Reactions].

cases leading to death, can occur in patients receiving Rituxan in combinationwith chemotherapy. In postmarketing reports, the mean time to documentedgastrointestinal perforation was 6 (range 1–77) days in patients with NHL.Perform a thorough diagnostic evaluation and institute appropriate treatment forcomplaints of abdominal pain, especially early in the course of Rituxan therapy.[See Adverse Reactions.] Immunization The safety of immunization with live viralvaccines following Rituxan therapy has not been studied and vaccination with livevirus vaccines is not recommended. For NHL patients, the benefits of primary orbooster vaccinations should be weighted against the risks of delay in initiation ofRituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20-positive B lymphocytes (malignant and non-malignant), obtain complete bloodcounts (CBC) and platelet counts at regular intervals during Rituxan therapy andmore frequently in patients who develop cytopenias [see Adverse Reactions]. Theduration of cytopenias caused by Rituxan can extend months beyond thetreatment period. ADVERSE REACTIONS The most common adverse reactions ofRituxan (incidence ≥25%) observed in patients with NHL are infusion reactions,fever, chills, infection, asthenia, and lymphopenia. The most important seriousadverse reactions of Rituxan are infusion reactions, tumor lysis syndrome,mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML,other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstructionand perforation. Clinical Trials Experience Non-Hodgkin’s LymphomaBecause clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directly comparedto rates in the clinical trials of another drug and may not reflect the rates observedin practice. The data described below reflect exposure to Rituxan in 1606patients, with exposures ranging from a single infusion up to 6–8 months. Rituxanwas studied in both single-agent and active-controlled trials (n = 356 and n =1250). These data were obtained in adults with low-grade, follicular, or DLBCLNHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion,given as a single agent weekly for up to 8 doses, in combination withchemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses.Infusion Reactions In the majority of patients with NHL, infusion reactionsconsisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension,headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, orhypertension occurred during the first Rituxan infusion. Infusion reactions typicallyoccurred within 30 to 120 minutes of beginning the first infusion and resolvedwith slowing or interruption of the Rituxan infusion and with supportive care(diphenhydramine, acetaminophen, and intravenous saline). The incidence ofinfusion reactions was highest during the first infusion (77%) and decreased witheach subsequent infusion. [See Boxed Warning, Warnings and Precautions.]Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis,occurred in less than 5% of patients with NHL in the single-arm studies. Theoverall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%,and fungal 1%). [See Warnings and Precautions.] In randomized, controlledstudies where Rituxan was administered following chemotherapy for thetreatment of follicular or low-grade NHL, the rate of infection was higher amongpatients who received Rituxan. In diffuse large B-cell lymphoma patients, viralinfections occurred more frequently in those who received Rituxan. Cytopeniasand hypogammaglobulinemia In patients with NHL receiving rituximabmonotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% ofpatients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%),anemia (3%), and thrombocytopenia (2%). The median duration of lymphopeniawas 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116days). A single occurrence of transient aplastic anemia (pure red cell aplasia) andtwo occurrences of hemolytic anemia following Rituxan therapy occurred duringthe single-arm studies. In studies of monotherapy, Rituxan-induced B-celldepletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgGserum levels occurred in 14% of these patients. Single-Agent Rituxan Adversereactions in Table 1 occurred in 356 patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL treated in single-arm studies ofRituxan administered as a single agent. Most patients received Rituxan 375 mg/m2

weekly for 4 doses.Table 1Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, Low-Grade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

aAdverse reactions observed up to 12 months following Rituxan.

bAdverse reactions graded for severity by

NCI-CTC criteria.

In these single-arm Rituxan studies, bronchiolitis obliterans occurred during andup to 6 months after Rituxan infusion. Rituxan in Combination WithChemotherapy Adverse reactions information below is based on 1250 patientswho received Rituxan in combination with chemotherapy or followingchemotherapy. Rituxan in Combination With Chemotherapy for Low-GradeNHL In Study 4, patients in the R-CVP arm experienced a higher incidence ofinfusional toxicity and neutropenia compared to patients in the CVP arm. Thefollowing adverse reactions occurred more frequently (≥5%) in patients receivingR-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing(14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs.3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactionswere reported more frequently (≥5%) in patients receiving Rituxan following CVPcompared to patients who received no further therapy: fatigue (39% vs. 14%),anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections(19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs.7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain(11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction thatoccurred more frequently (≥2%) in the Rituxan arm compared with those whoreceived no further therapy (4% vs. 1%). Rituxan in Combination With

All Grades (%) Grade 3 and 4 (%)

Any Adverse Events 99 57Body as a Whole 86 10

Fever 53 1Chills 33 3Infection 31 4Asthenia 26 1Headache 19 1Abdominal Pain 14 1Pain 12 1Back Pain 10 1Throat Irritation 9 0Flushing 5 0

Heme and Lymphatic System 67 48Lymphopenia 48 40Leukopenia 14 4Neutropenia 14 6Thrombocytopenia 12 2Anemia 8 3

Skin and Appendages 44 2Night Sweats 15 1Rash 15 1Pruritus 14 1Urticaria 8 1

All Grades (%) Grade 3 and 4 (%)

Respiratory System 38 4Increased Cough 13 1Rhinitis 12 1Bronchospasm 8 1Dyspnea 7 1Sinusitis 6 0

Metabolic and Nutritional Disorders 38 3

Angioedema 11 1Hyperglycemia 9 1Peripheral Edema 8 0LDH Increase 7 0

Digestive System 37 2Nausea 23 1Diarrhea 10 1Vomiting 10 1

Nervous System 32 1Dizziness 10 1Anxiety 5 1

Musculoskeletal System 26 3Myalgia 10 1Arthralgia 10 1

Cardiovascular System 25 3Hypotension 10 1Hypertension 6 1

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions,regardless of severity, were reported more frequently (≥5%) in patients age ≥60years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lungdisorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%).Detailed safety data collection in these studies was primarily limited to Grade 3and 4 adverse reactions and serious adverse reactions. In Study 7, a review ofcardiac toxicity determined that supraventricular arrhythmias or tachycardiaaccounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs.1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred morefrequently among patients in the R-CHOP arm compared with those in the CHOParm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia(Study 8). Immunogenicity As with all therapeutic proteins, there is a potentialfor immunogenicity. The observed incidence of antibody (including neutralizingantibody) positivity in an assay is highly dependent on several factors includingassay sensitivity and specificity, assay methodology, sample handling, timing ofsample collection, concomitant medications, and underlying disease. For thesereasons, comparison of the incidence of antibodies to Rituxan with the incidenceof antibodies to other products may be misleading. Using an ELISA assay, anti-human anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patientswith low-grade or follicular NHL receiving single-agent Rituxan. Three of the fourpatients had an objective clinical response. The clinical relevance of HACAformation in rituximab treated patients is unclear. Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use ofRituxan in hematologic malignancies. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not always possible to reliablyestimate their frequency or establish a causal relationship to drug exposure.Decisions to include these reactions in labeling are typically based on one or moreof the following factors: (1) seriousness of the reaction, (2) frequency of reporting,or (3) strength of causal connection to Rituxan. Hematologic: prolongedpancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscositysyndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure.Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis,lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocalleukoencephalopathy (PML), increase in fatal infections in HIV-associatedlymphoma, and a reported increased incidence of Grade 3 and 4 infections inpatients with previously treated lymphoma without known HIV infection.Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneousreactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatalbronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUGINTERACTIONS Formal drug interaction studies have not been performed withRituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There areno adequate and well-controlled studies of rituximab in pregnant women.Postmarketing data indicate that B-cell lymphocytopenia generally lasting lessthan six months can occur in infants exposed to rituximab in-utero. Rituximab wasdetected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’slymphoma is a serious condition that requires treatment. Rituximab should beused during pregnancy only if the potential benefit to the mother justifies thepotential risk to the fetus. Reproduction studies in cynomolgus monkeys atmaternal exposures similar to human therapeutic exposures showed no evidenceof teratogenic effects. However, B-cell lymphoid tissue was reduced in theoffspring of treated dams. The B-cell counts returned to normal levels, andimmunologic function was restored within 6 months of birth. Nursing Mothers Itis not known whether Rituxan is secreted into human milk. However, Rituxan issecreted in the milk of lactating cynomolgus monkeys, and IgG is excreted inhuman milk. Published data suggest that antibodies in breast milk do not enterthe neonatal and infant circulations in substantial amounts. The unknown risks tothe infant from oral ingestion of Rituxan should be weighed against the knownbenefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxanin pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received Rituxan in combination with chemotherapy.Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 orgreater. No overall differences in effectiveness were observed between thesepatients and younger patients. Cardiac adverse reactions, mostly supraventriculararrhythmias, occurred more frequently among elderly patients. Serious pulmonaryadverse reactions were also more common among the elderly, includingpneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’sLymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive,B-cell NHL did not include sufficient numbers of patients aged 65 and over todetermine whether they respond differently from younger subjects.OVERDOSAGE There has been no experience with overdosage in human clinicaltrials. Single doses of up to 500 mg/m2 have been given in dose-escalationclinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis,Impairment of Fertility No long term animal studies have been performed toestablish the carcinogenic or mutagenic potential of Rituxan or to determinepotential effects on fertility in males or females. PATIENT COUNSELINGINFORMATION Patients should be provided the Rituxan Medication Guide andprovided an opportunity to read prior to each treatment session. Because cautionshould be exercised in administering Rituxan to patients with active infections, it isimportant that the patient’s overall health be assessed at each visit and anyquestions resulting from the patient’s reading of the Medication Guide bediscussed. Rituxan is detectable in serum for up to six months followingcompletion of therapy. Individuals of childbearing potential should use effectivecontraception during treatment and for 12 months after Rituxan therapy.

Revised 9/2008 (4835505)

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©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008


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You help patients reach their treatment goalsRITUXAN is a proven path for many patients battling non-Hodgkin’s lymphoma (NHL),but they can’t complete the journey alone.

Oncology nurses are central members of a cancer care team—working together to achieve improved outcomes. Your guidance and leadership help patients reach their treatment goals. We recognize your commitment and support your continued efforts with innovative patient-education materials and services.

RITUXAN is indicated for the treatment of patients with:

• Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent

• Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy

• Non-progressing (including stable disease), low-grade, CD20-positive,B-cell NHL, as a single agent, after first-line CVP chemotherapy

• Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

Reference: 1. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

Please see brief summary of prescribing information on adjacent page.

Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion.

BOXED WARNINGS and Additional Important Safety Information

The most important serious adverse reactions of RITUXAN are fatal infusionreactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions,progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation withfulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, andbowel obstruction and perforation. The most common adverse reactions of RITUXAN(incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills,infection, asthenia, and lymphopenia.1

Leading patients towardimproved outcomes

To learn more, ask a RITUXAN representative or visit

www.rituxan.com/lymphoma

PROVE N. POWE R FU L.

©2008 Genentech, Inc., and Biogen Idec Inc. All rights reserved. 9231900 April 2008

http://www.rituxan.com/lymphoma

may 2009 vol. 2 no. 3

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