incorporating antibodies into treatment strategies …...exceptional responders, and a brief review...

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BREAST CANCER SURGERYMD Anderson Cancer Center Feasibility Trial for Eliminating Breast Cancer Surgery in Exceptional RespondersHenry M. Kuerer, MD, PhD, FACS

ACUTE LYMPHOBLASTIC LEUKEMIAIncorporating Antibodies into Treatment Strategies for Acute Lymphocytic LeukemiaNicholas J. Short, MD, and Elias Jabbour, MD

BREAST CANCEROmitting Radiation in Older Breast Cancer PatientsJennifer K. Plichta, MD, and Kevin S. Hughes, MD

LYMPHOMA Are New Treatment Options Shifting How and When We Treat Waldenström Macroglobulinemia?Morie A. Gertz, MD, MACP

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

A Peer-Reviewed Resource

for Oncology Education

ajho

www.AJHO.com ISSN 1939-6163 (print) ISSN 2334-0274 (online)

Volume 12 Number 5 5.16

LUNG CANCER CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

A Look at the Near Future of Lung Cancer Treatment

AUGUST 4-6, 2016Hyatt Regency Huntington BeachHuntington Beach, CA

Lung CancerCONGRESS®

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The International Lung Cancer Congress® provides current, practical information on the management of lung cancer, as well as a look at the novel agents and strategies that will shape the future of lung cancer therapy. Leading international and national faculty will address critical topics in lung cancer staging, personalized therapy, and the latest clinical data impacting the treatment of lung cancer. Cutting-edge lectures, panel discussions, multidisciplinary tumor boards, and interactive question-and-answer sessions will provide a unique opportunity for participants to engage with faculty as they share their perspectives and personal experiences on the clinical challenges and ongoing controversies in lung cancer management. The meeting also includes a recurring session that highlights clinical research activity of cooperative groups in the United States, Europe, and Asia.Physicians’ Education Resource®, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.Physicians’ Education Resource®, LLC designates this live activity for a maximum of 22.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Physicians’ Education Resource®, LLC is approved by the California Board of Registered Nursing, Provider #16669 for 22.0 Contact Hours. This activity is supported by educational grants from AstraZeneca, Celgene, Lilly, Merck, and Pfizer. For further information concerning Lilly grant funding visit www.lillygrantoffice.com. PER® complies with the Physician Payments Sunshine Act as part of the Affordable Care Act. Accordingly, we may be required to collect information on transfers of value provided to any covered recipient under the Act.

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Table of Contents

BREAST CANCER SURGERY

MD Anderson Cancer Center Feasibility Trial for Eliminating Breast Cancer Surgery in Exceptional RespondersHenry M. Kuerer, MD, PhD, FACSGiven our understanding of breast cancer subtypes and better imaging modalities available to us, it is our obligation to test the hypothesis that surgery can be safely eliminated in patients with documented patho-logic responses, which is a practice that has been utilized in other solid organ malignancies.

ACUTE LYMPHOBLASTIC LEUKEMIA

Incorporating Antibodies into Treatment Strategies for Acute Lymphoblastic LeukemiaNicholas J. Short, MD, and Elias Jabbour, MDFuture studies involving the combination of monoclonal antibodies with chemotherapy, and possibly with each other, could lead to less reliance on intensive cytotoxic chemotherapy.

BREAST CANCER

Omitting Radiation in Older Breast Cancer PatientsJennifer K. Plichta, MD, and Kevin S. Hughes, MDIn the current era of cost containment, the actual benefit of each therapy must be weighed carefully. Women over age 70, with clinical stage 1, ER+ breast cancers, have a much greater risk to their lives and well-being from other causes. Is it time to reconsider radiation therapy in this subset population?

LYMPHOMA

Are New Treatment Options Shifting How and When We Treat Waldenström Macroglobulinemia?Morie A. Gertz, MD, MACPActive clinical trials for Waldenström macroglobulinemia are investigating treatment combinations including rituximab-bendamustine-ibrutinib, rituximab-ibrutinib, and lenalidomide-ibrutinib, which will further improve the outcomes for these patients.

CME

CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLCLUNG CANCER

A Look at the Near Future of Lung Cancer TreatmentBenjamin Levy, MD, Assistant Professor, Icahn School of Medicine, Mt Sinai Hospital informs physi-cians about the recent advances, as well as anticipated advances, in the field of lung cancer treatment.

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Patrick I. Borgen, MDChairman, Department of Surgery Maimonides Medical CenterDirector, Brooklyn Breast Cancer ProgramBrooklyn, NY

Julie R. Brahmer, MDAssociate Professor, Oncology Johns Hopkins University School of

MedicineSidney Kimmel Comprehensive Cancer

CenterBaltimore, MD

J. Michael Dixon, MD, OBEProfessor of Surgery and Consultant

SurgeonClinical Director, Breakthrough Research

UnitEdinburgh Breast UnitEdinburgh, UK

David R. Gandara, MDProfessor of MedicineDirector, Thoracic Oncology ProgramSenior Advisor to the DirectorDivision of Hematology/OncologyUC Davis Comprehensive Cancer CenterSacramento, CA

Andre Goy, MD, MSChairman and DirectorChief of LymphomaDirector, Clinical and Translational Cancer ResearchJohn Theurer Cancer Center at Hackensack University Medical CenterHackensack, NJ

Omid Hamid, MDChief, Translational Research and ImmunotherapyDirector, Melanoma TherapeuticsThe Angeles Clinic and Research InstituteLos Angeles, CA

Roy S. Herbst, MD, PhDEnsign Professor of Medicine (Medical

Oncology)Professor of PharmacologyChief of Medical OncologyAssociate Director for Translational ResearchYale Cancer CenterYale School of Medicine New Haven, CT

Thomas J. Lynch, Jr, MDCEO and ChairmanMassachusetts General Physicians

OrganizationMassachusetts General HospitalBoston, MA

Maurie Markman, MDPresident, Medicine and ScienceNational Director, Medical OncologyCancer Treatment Centers of AmericaPhiladelphia, PA

John L. Marshall, MDChief, Hematology and Oncology Director, Otto J. Ruesch Center for the

Cure of Gastrointestinal CancersLombardi Comprehensive Cancer CenterGeorgetown University Medical CenterWashington, DC

Hyman B. Muss, MDProfessor of OncologyUniversity of North CarolinaDirector of Geriatric OncologyLineberger Comprehensive Cancer CenterChapel Hill, NC

Joyce A. O’Shaughnessy, MDCo-Director, Breast Cancer ResearchBaylor Charles A. Sammons Cancer

Center Texas Oncology The US Oncology NetworkDallas, TX

Daniel P. Petrylak, MDProfessor of Medicine (Medical Oncology) and of UrologyCo-Director, Signal Transduction Research

ProgramYale Cancer Center and Smilow Cancer

HospitalNew Haven, CT

Heather A. Wakelee, MDAssociate Professor, Medicine (Oncology)Stanford University Medical CenterStanford, CA

Jeffrey S. Weber, MD, PhDSenior Member and DirectorDonald A. Adam Comprehensive Melanoma Research CenterMoffitt Cancer CenterTampa, FL

PER® Executive Board/AJHO Editorial Board

VOL. 12, NO. 5 THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY® 3

We are living in exciting times in our understanding of the biology of cancer. Each day brings new research, new

insight, new gains, and new opportunities to face the disease. One of the overarching goals of this publication, The

American Journal of Hematology/Oncology®, is to disseminate the research that informs clinicians as they deliver care to

patients. We strive to be the vehicle to transmit that data through review manuscripts, medical meetings coverage, and

original research.

We know that there are inequities in care, in access, and in outcomes. We also know that much of the progress that

has been made has not reached all patients. What can we do better to ensure that all patients benefit from what we

know is working? We can democratize knowledge—and make the information as widely available as possible.

I would encourage the readers of The American Journal of Hematology/Oncology to consider sharing their insights,

research, and knowledge with our audience. It is only through the sharing of this knowledge that progress can be made.

Looking towards the current issue, we explore topics about monoclonal antibodies in acute lymphoblastic leukemia,

the use of radiation therapy in older women with breast cancer, the potential for eliminating breast cancer surgery in

exceptional responders, and a brief review of therapies for Waldenström’s macroglobulinemia.

In “Incorporating Antibodies into Treatment Strategies for Acute Lymphoblastic Leukemia,” Nicholas J. Short, MD,

and Elias Jabbour, MD, explore the role monoclonal antibodies may hold in improving the outcomes of patients with

acute lymphoblastic leukemia (ALL). The addition of rituximab to cytotoxic chemotherapy has been shown to improve

overall survival in younger patients, and next-generation anti-CD20 antibodies also show promise in the management

of ALL.

Is it time to reconsider the use of radiation therapy in older breast cancer patients? That’s the question asked by

Jennifer K. Plichta, MD, and Kevin S. Hughes in their manuscript, “Omitting Radiation in Older Breast Cancer Pa-

tients.” There is now increasing interest in identifying patients who may avoid the cost, morbidity, and inconvenience

of radiation after breast-conserving surgery without compromising their ultimate outcome. Plichta and Hughes

write that the cost of medicine must be contained, and the actual benefit of each therapy must be weighed carefully

against cost. They note that radiation for women aged 70 and above with clinical stage 1, ER+ cancers is expensive

and has minimal benefit.

“These women have much greater risk to their lives and well-being from other causes, with 94% of women who

died in CALGB 9343 dying of something other than breast cancer. It is time to consider whether healthcare dollars are

better spent on other more deadly aspects of their health rather than on radiation,” according to the authors.

Along similar lines, Henry M. Kuerer, MD, PhD, of the MD Anderson Cancer Network, proposes undertaking a

feasibility study that suggests that the ultimate breast-conserving therapy might exclude the need for surgery, especially

for patients who respond to neoadjuvant chemotherapy, both at the primary site and lymph nodes. He writes that with

our understanding of breast cancer subtypes and response with better imaging, it becomes our obligation to test the

hypothesis that surgery can be safely eliminated among patients with documented pathologic responses, a practice that

has been utilized in other solid organ malignancies.

Our understanding of Waldenström macroglobulinemia has grown significantly in the last few years, writes Morie

Gertz, MD. The introduction of new agents for the treatment of Waldenström macroglobulinemia has had a dramatic

impact on survivorship in this disease. Earlier diagnosis has led to a reduced frequency of hyperviscosity. Currently

active clinical trials include rituximab-bendamustine-ibrutinib, rituximab-ibrutinib, and lenalidomide-ibrutinib, which

will further improve the outcomes for these patients.

Michael J. Hennessy, Sr

Chairman and Chief Executive Officer

Chairman’s Letter

The content of this publication is for general information purposes only. The reader is encouraged to confirm the information presented with other sources. American Journal of Hema-tology/Oncology makes no representations or warranties of any kind about the completeness, accuracy, timeliness, reliability, or suitability of any of the information, including content or advertisements, contained in this publication and expressly disclaims liability for any errors and omissions that may be presented in this publication. American Journal of Hematology/Oncology reserves the right to alter or correct any error or omission in the information it provides in this publication, without any obligations. American Journal of Hematology/Oncology further disclaims any and all liability for any direct, indirect, consequential, special, exemplary, or other damages arising from the use or misuse of any material or information presented in this publication. The views expressed in this publication are those of the authors and do not necessarily reflect the opinion or policy of American Journal of Hematology/Oncology.

4 www.ajho.com MAY 2016

EDITORIAL STAFF

The May issue of AJHO highlights how progress in one type of malignancy can inform another. This is especially important in rarer cancers, so called “orphan diseases,” where the body of literature and number of patients available for trials are quite low and limits the generation of definitive recommendations and the development of new drugs. The update on acute lymphocytic leukemia (ALL) by Drs Short and Jabbour highlights the developments and current base of evidence with newer therapies, in particular, the importance of targeting CD20 with rituximab. Further emphasis on the importance of this target comes from the development and approval of other anti-CD20 antibodies. This was initially witnessed by the sweeping change in the management of B-cell malignancies, starting with B-cell lymphomas, extending to chronic and acute B-cell leukemias. More recently, as described by Dr Gertz in an accompanying review on Waldenström macroglobulinemia (WM), rituximab is now being used as a part of combination therapy effectively for this disease, long marked by its inexorable progression and refractoriness to thera-py. Other examples of drugs imported for use in WM from other B-cell-derived malignancies include bendamustine, approved for CLL and relapsed lymphoma, the Bruton tyrosine kinase inhibitor ibru-tinib for mantle cell lymphoma and CLL, as well as bortezomib and lenalidomide approved for multiple myeloma. In fact, the approval of ibrutinib for WM would not have been possible without the infor-mation from other diseases, as the basis for its accelerated approval for WM was a phase II trial with only 63 patients. Ibrutinib is the only FDA approved drug specifically for WM (even though as pointed out in the WM review, many other standards exist), so it is likely that additional drug approvals for this disease will emanate from other cancers of similar lineage.

This brings us back to the review of new active drugs for ALL—oth-er CD20 antibodies such as ofatumumab, the anti-CD19 bispecific T-cell engager blinatumomab, and the anti-CD22 antibody-drug con-jugate inotuzumab ozogamicin. All these antigens are also expressed on WM. This along with drugs tested successfully for more common B-cell malignancies may hold promise for WM and also be relevant across a spectrum of these related diseases. Hopefully, these examples will be repeated for other orphan cancers—this will require the con-tinuation of robust drug development in general with cross-commu-nication across expertise in other cancers, dedication to continued innovation with smaller and smarter trials for rarer malignancies and special pathways through the FDA.

CORPORATE OFFICERS Chairman and CEOMichael J. Hennessy, Sr

Vice Chairman Jack Lepping

President Mike Hennessy, Jr

Chief Operating Officer and Chief Financial Officer Neil Glasser, CPA/CFE

Executive Vice President and General Manager John Maglione

Vice President, Digital Media Jung Kim

Chief Creative Officer Jeff Brown

Human Resource Director Shari Lundenberg

Debu Tripathy, MD Editor-in-Chief

From the Editor Editor-in-ChiefDebu Tripathy, MD

Professor and Chair Department of Breast Medical Oncology The University of Texas MD Anderson Cancer Center Houston, TX

Associate EditorJason J. Luke, MD, FACP

Assistant Professor of MedicineUniversity of ChicagoChicago, IL

Managing EditorHoward Whitman [email protected] Art Director Nicole Martino

Editorial OfficesPhysicians’ Education Resource®, LLC666 Plainsboro Road, Ste 356Plainsboro, NJ 08536(609) 378-3701

PresidentPhil Talamo, CHCP

Medical DirectorMichael Perlmutter, PharmD, MS

· BREAST CANCER ·


MD Anderson Cancer Center Feasibility Trial for Eliminating Breast Cancer Surgery in Exceptional Responders

Henry M. Kuerer, MD, PhD, FACS

IntroductionWe have reached a pivotal time in the management of breast cancer, as there have been marked improvements in our systemic therapies resulting in complete pathologic responses (pCR) in the breast and lymph nodes, as much as 50% of the time.1,2 We are at a crossroad similar to the time, 30 to 40 years ago, when investigators were discussing the potential of breast-conserving therapy (BCT) and beginning randomized landmark clinical trials internationally, testing the hypothesis that conserving the breast, with or without the use of radiotherapy, was not inferior to the standard at that time, radical mastectomy. In this regard, it is interesting to note that these trials began before modern

breast imaging and routine screening mammography. We have now known for decades that some patients will have a dramatic response to neoadjuvant chemotherapy, both at the primary site and lymph nodes, which suggests that the ultimate BCT might exclude the need for surgery at all.3,4

Taken together, with our understanding of breast cancer sub-types and response with better and better imaging, it becomes our obligation to test the hypothesis that surgery can be safe-ly eliminated among patients with documented pathologic re-sponses, a practice that has been utilized in other solid organ malignancies. The rationale for avoidance of breast and nodal surgery can be simply stated as: patients would prefer to not have surgery at all if their breast cancer can be safely and effectively treated without it. Although surgical techniques have improved substantially in the last two decades, surgery still can have an ad-verse personal impact with respect to physical, psychosocial, and sexual well-being, as well as other well-described complications.5-7

Inability of Breast Imaging to Predict pCRThe main obstacle and challenge, with the elimination of breast cancer surgery among exceptional responders with neoadjuvant systemic therapy, is that current imaging is not accurate to pre-dict pCR without surgery. The concept of proceeding directly to radiotherapy without surgery among patients with a good clinical response is not new.1 Prior studies attempting to deliver radiotherapy among complete clinical responders without breast surgery resulted in unacceptably high local regional recurrence rates.8-15

The other major issues with these studies—besides utilizing selection based on clinical response—were limited use of breast imaging for selection of patients, and they were also prior to our basic understanding of subtype response, best available system-ic regimens, and, certainly, optimized modern breast imaging. It is also interesting to note that, on average, a breast imaging radiologic complete response occurs in about 20% of patients with the triple-negative and HER2 phenotype receiving preoper-ative systemic therapy, yet about 50% of patients will be found to have a pCR.1 Evaluation of documented nodal metastases and response to therapy are also very poor, with negative predictive values between 29% and 81%.1 Therefore, in order to also elimi-

Abstract

Patients with triple-negative and HER2-amplified breast

cancers routinely have complete eradication of disease in

up to 50 to 60% of patients in the breast and lymph nodes

after effective neoadjuvant chemotherapy. We have

reached a critical crossroad in the discussions, which be-

gan 30 to 40 years ago, regarding the potential safety of

breast-conserving surgery compared with radical mas-

tectomy, randomized clinical trials that began without

modern-day breast imaging, and routine screening mam-

mography. Although imaging has markedly improved, it

remains ineffective in predicting which patients will have

a complete pathologic response. It is our hypothesis that

we can accurately identify patients who would be eli-

gible for clinical trials to avoid surgery, and just follow

with standard radiotherapy utilizing state-of-the-art im-

age–guided, extensive vacuum-assisted core biopsy fol-

lowing neoadjuvant therapy by correlating final surgical

pathology. If this feasibility study proves accurate, trials

will shortly commence to test the safety of eliminating

surgery in exceptional responders.

Key words: triple-negative breast cancer, HER2-ampli-

fied breast cancer, radical mastectomy, breast-conserv-

ing surgery, breast imaging, pathologic responses, radio-

therapy, vacuum-assisted biopsy

· BREAST CANCER ·


nate axillary surgery, it might be best to begin with patients who do not have documented or clinically detectable nodal disease based on physical examination, and at the minimum, an ultra-sound evaluation.

MD Anderson Protocol 2014-1039: Pilot Study for Identification of Breast Cancer Patients for Potential Avoidance of SurgeryBy collaborating with breast radiologists and integrating im-age-directed extensive vacuum-assisted biopsy following neoadju-vant therapy, it is our hypothesis that we can accurately identify patients with a pCR without residual ductal carcinoma in situ or invasive breast cancer. This is currently being tested in MD Anderson Cancer Center protocol PA 2014-1039.16 Patients on this study have triple-negative or HER2 positive breast cancer receiving standard neoadjuvant chemotherapy. This group of pa-tients was selected as they are the most likely to have a dramatic response with eradication of disease. Furthermore, patients with a pCR are also known, not only to have an increased overall and disease-free survival, but specifically, very low local regional recurrence rates.17

In our latest evaluation, the 5-year local regional recurrence rates were significantly less than those without a pCR, and, in fact, was only 2.6% and 1.4% among patients with HER2-posi-tive and triple-negative disease, respectively.17 Patients are eligible for this study if they present with cancers less than 5 cm, have a partial or complete imaging response, and vacuum-assisted biopsy (VAB) is performed with a 9G device with a minimum sampling of six cores. The trial has specific endpoints related to a comparison of VAB versus fine-needle aspiration and a com-bination compared with final surgical pathology excision histol-ogy. If this proves to be an accurate and safe methodology, the sometimes overwhelming physical and emotional side effects of breast cancer treatments would likely be dramatically improved. Patients would much prefer going home with a bandage than a surgical procedure on their breasts. Accrual to this study has been brisk, and with over half of the patients accrued, the pre-liminary results of this study have been so promising, that it is our expectation that we will begin accrual on a definitive trial later this year to eliminate surgery among exceptional responders with triple-negative and HER2-positive disease with documented complete pCR by VAB. This will be followed by standard whole breast radiotherapy. Internationally, several groups, multi-center organizations, and cooperative groups, have commenced or are planning similar studies.18,19

ConclusionThe past half-century has witnessed remarkable clinical advance-ments and increased survival based on clinical trials for patients with breast cancer. It can be expected that there will be continued improvements in breast cancer systemic agents that will continue to yield higher and higher pathologic complete responses. There-fore, it is intuitive to consider whether or not surgery is necessary

among these types of patients. The physical and psychological morbidity of surgery, particularly among patients with a diagno-sis of invasive breast cancer, is tremendous. The opportunity to potentially increase patients’ quality of life, without impacting their long-term health, is our obligation, and this necessitates designing trials to advance the field.

Affiliation: Henry M. Kuerer, MD, PhD, FACS, is from the Uni-versity of Texas MD Anderson Cancer Center, Houston, TX.Disclosures: None.Address correspondence to: Henry M. Kuerer, MD, PhD, FACS, MD Anderson Cancer Network, Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1400 Pressler St., Unit 1434, Houston, TX 77004. Phone: 713-745-5043; Fax: 713-792-4689. E-mail: [email protected]: Portions of this manuscript were presented at the 33rd Annual Miami Breast Cancer Conference March 10-13, 2016. This project was supported by the PH and Fay Etta Robinson Distinguished Professorship in Research endowment (HMK) and the National Institutes of Health (NIH) Cancer Cen-ter Support Grant (CA16672).

REFERENCES1. van la Parra RF, Kuerer HM. Selective elimination of breast cancer surgery in exceptional responders: historical perspective and current trials. Breast Cancer Res. 2016;18(1):28. doi: 10.1186/s13058-016-0684-6.2. Boughey JC, McCall LM, Ballman KV, et al. Tumor biology correlates with rates of breast-conserving surgery and pathologic complete response after neoadjuvant chemotherapy for breast cancer: findings from the ACOSOG Z1071 (Alliance) Prospec-tive Multicenter Clinical Trial. Ann Surg. 2014;260(4):608-614; discussion 614-606. doi: 10.1097/SLA.0000000000000924.3. Kuerer HM, Newman LA, Fornage BD, et al. Role of axillary lymph node dissection after tumor downstaging with induction chemotherapy for locally advanced breast cancer. Ann Surg Oncol. 1998;5(8):673-680. 4. Kuerer HM, Newman LA, Smith TL, et al. Clinical course of breast cancer patients with complete pathologic primary tumor and axillary lymph node response to doxorubicin-based neoadju-vant chemotherapy. J Clin Oncol. 1999;17(2):460-469.5. Al-Hilli Z, Thomsen KM, Habermann EB, Jakub JW, Boughey JC. Reoperation for Complications after Lumpectomy and Mastectomy for Breast Cancer from the 2012 National Surgical Quality Improvement Program (ACS-NSQIP). Ann Surg Oncol. 2015;22 Suppl 3:S459-469. doi: 10.1245/s10434-015-4741-7.6. Losken A, Pinell-White X, Hodges M, Egro FM. Evaluating outcomes after correction of the breast conservation therapy de-formity. Ann Plast Surg. 2015;74 Suppl 4:S209-213. doi: 10.1097/SAP.0000000000000443.7. Cano SJ, Klassen AF, Scott AM, Cordeiro PG, Pusic AL.

BREAST CANCER CLINICAL TRIAL ADVANCES


The BREAST-Q: further validation in independent clinical samples. Plast Reconstr Surg. 2012;129(2):293-302. doi: 10.1097/PRS.0b013e31823aec6b.8. Daveau C, Savignoni A, Abrous-Anane S, et al. Is radiotherapy an option for early breast cancers with complete clinical response after neoadjuvant chemotherapy? Int J Radiat Oncol Biol Phys. 2011;79(5):1452-1459. doi: 10.1016/j.ijrobp.2010.01.003.9. De Lena M, Varini M, Zucali R, et al. Multimodal treatment for locally advanced breast cancer. Result of chemotherapy-ra-diotherapy versus chemotherapy-surgery. Cancer Clin Trials. 1981;4(3):229-236.10. Ellis P, Smith I, Ashley S, et al. Clinical prognostic and predic-tive factors for primary chemotherapy in operable breast cancer. J Clin Oncol. 1998;16(1):107-114.11. Mauriac L, MacGrogan G, Avril A, et al. Neoadjuvant che-motherapy for operable breast carcinoma larger than 3 cm: a unicentre randomized trial with a 124-month median follow-up. Institut Bergonie Bordeaux Groupe Sein (IBBGS). Ann Oncol. 1999;10(1):47-52.12. Perloff M, Lesnick GJ, Korzun A, et al. Combination che-motherapy with mastectomy or radiotherapy for stage III breast carcinoma: a Cancer and Leukemia Group B study. J Clin Oncol. 1988;6(2):261-269.13. Ring A, Webb A, Ashley S, et al. Is surgery necessary after complete clinical remission following neoadjuvant chemotherapy for early breast cancer? J Clin Oncol. 2003;21(24):4540-4545.

14. Scholl SM, Pierga JY, Asselain B, et al. Breast tumour response to primary chemotherapy predicts local and distant control as well as survival. Eur J Cancer. 1995;31A(12):1969-1975.15. Touboul E, Buffat L, Lefranc JP, et al. Possibility of conser-vative local treatment after combined chemotherapy and preop-erative irradiation for locally advanced noninflammatory breast cancer. Int J Radiat Oncol Biol Phys. 1996;34(5):1019-1028.16. Accuracy of image guided percutaneous sampling compared with surgery to evaluate eradication of breast cancer after preop-erative chemotherapy. National Institute of Health.ClinicalTrials.gov [online], https://clinicaltrials.gov/ct2/show/NCT02455791 (2015).17. Swisher SK, Vila J, Tucker SL, et al. Locoregional control ac-cording to breast cancer subtype and response to neoadjuvant che-motherapy in breast cancer patients undergoing breast-conserv-ing therapy. Ann Surg Oncol. 2016;23(3):749-756. doi: 10.1245/s10434-015-4921-5.18. Heil J, Kummel S, Schaefgen B, et al. Diagnosis of patho-logical complete response to neoadjuvant chemotherapy in breast cancer by minimal invasive biopsy techniques. Br J Cancer. 2015;113(11):1565-1570. doi: 10.1038/bjc.2015.381.19. De Los Santos JF, Cantor A, Amos KD, et al. Magnetic reso-nance imaging as a predictor of pathologic response in patients treated with neoadjuvant systemic treatment for operable breast cancer. Translational Breast Cancer Research Consortium trial 017. Cancer. 2013;119(10):1776-1783. doi: 10.1002/cncr.27995.

· ACUTE LYMPHOBLASTIC LEUKEMIA ·


Incorporating Antibodies into Treatment Strategies for Acute Lymphoblastic Leukemia

Nicholas J. Short, MD, and Elias Jabbour, MD

IntroductionMultiagent cytotoxic chemotherapy is the cornerstone of treat-ment for pediatric and adult patients with acute lymphoblastic leukemia (ALL). For children with ALL, optimized drug com-binations and schedules result in a cure rate of almost 90%.1 Adults with ALL have also seen significant improvements in outcomes with combination chemotherapy, although their cure rate of 40% to 50% is substantially lower than their pediatric counterparts.2,3 Incorporation of novel agents into these highly effective chemotherapy regimens is needed to continue to im-prove survival in these patients. Monoclonal antibodies targeting CD19, CD20, or CD22 on the cell surface of leukemic blasts have shown significant promise in the treatment of ALL, both in the front-line and relapsed settings.4 This review will discuss the clinical activity of these agents in ALL.

Anti-CD20 Antibodies: Rituximab and OfatumumabCD20 expression ≥20% is found on approximately 30% to 40%

of precursor B-cell ALL (B-ALL) leukemia blasts and in near-ly 100% of mature B-ALL.5,6 Historically, CD20 positivity was associated with worse survival in precursor B-ALL,7,8 although this appears to be attenuated by the addition of anti-CD20 an-tibodies to chemotherapy regimens for younger patients with CD20-positive disease. Retrospective studies have reported that the addition of rituximab, a chimeric anti-CD20 antibody im-proves survival in patients with CD20-positive B-ALL who are younger than 60 years compared with historical cohorts.6,9

In one study, the rituximab-containing hyper-CVAD regimen improved the 3-year complete remission (CR) duration from 38% to 70% and 3-year overall survival (OS) from 47% to 75% compared with hyper-CVAD alone.9 These findings have recently been confirmed in a large prospective randomized trial in young-er patients with Philadelphia chromosome (Ph)-negative ALL.10

The addition of rituximab to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) regimen resulted in an improved 2-year event-free survival (EFS) rate (65% vs 52%; P = 0.04) and OS rate (74% vs 63%, P = 0.02) without a significant increase in toxicity. However, the role of rituximab in patients with ALL who are 60 years and older is less clear, as there are limited data and there have been no random-ized studies evaluating anti-CD20 therapy in this population.

In patients with B-ALL, rituximab also has been shown to im-prove outcomes when combined with cytotoxic chemotherapy in several studies.11-14 The addition of rituximab to the hyper-CVAD regimen resulted in a 3-year survival rate of 89% compared with 53% with chemotherapy alone.11 Furthermore, these findings were confirmed by the LMBA02 randomized study where the addition of 4 infusions of rituximab to chemotherapy improved EFS from 60% to 80% (P = .046) and OS from 68% to 84% (P = .024).14

Given the success of incorporating rituximab into standard chemotherapeutic regimens for ALL, there is interest in investi-gating the role of other anti-CD20 antibodies in the treatment of this disease. Ofatumumab is a second-generation anti-CD20 monoclonal antibody that binds to a different epitope than rit-uximab and has increased ability to induce complement-medi-ated lysis, which may allow it to overcome rituximab-resistant disease.15 In the recent interim analysis of 41 patients with

Abstract

Monoclonal antibodies hold significant promise in im-

proving the outcomes of patients with acute lymphoblas-

tic leukemia (ALL). Rituximab has been shown to improve

overall survival in younger patients with CD20-positive

ALL, and next-generation anti-CD20 antibodies may be

able to further improve these outcomes. Antibody-drug

conjugates such as inotuzumab ozogamicin, and the

bi-specific T-cell engager, blinatumomab, represent novel

antibody constructs that have shown significant clinical

activity in ALL. Although most studies have focused on

the use of these agents in the salvage setting, incorpora-

tion of these antibodies into front-line regimens, with the

goal of achieving minimal residual disease negativity, is

also imperative to achieve long-term survival for patients

with this disease.

Key words: acute lymphoblastic leukemia, rituximab,

ofatumumab, inotuzumab ozogamicin, blinatumomab,

Burkitt leukemia, monoclonal antibodies

INCORPORATING ANTIBODIES INTO TREATMENT STRATEGIES FOR ACUTE LYMPHOBLASTIC LEUKEMIA


CD20-positive ALL who received front-line hyper-CVAD chemo-therapy plus ofatumumab, this combination was associated with a minimal residual disease (MRD) negativity rate of 93% and 3-year progression-free survival (PFS) and OS rates of 75% and 67%, respectively.16 These results compare favorably with those historically seen with rituximab and suggest that more potent an-ti-CD20 antibodies may be able to further improve the outcomes of patients with CD20-positive ALL.

Anti-CD22 Antibody-Drug Conjugate: InotuzumabCD22 is expressed in 93% to 98% of precursor B-ALL and uni-versally in Burkitt leukemia.4 Inotuzumab ozogamicin is an im-munoconjugate made up of an anti-CD22 antibody linked to calicheamicin, a potent cytotoxic compound.17 Upon binding to CD22 on leukemic cells, the antibody-drug conjugate is internal-ized and the calicheamicin is released inside the cell, inducing double-stranded DNA breaks. In a phase II trial of inotuzum-ab monotherapy in patients with relapsed or refractory ALL, a weekly schedule of inotuzumab was associated with an overall response rate (ORR) of 59% and a median OS of 9.5 months.18 In a separate multi-center phase II trial in a heavily pretreated cohort of patients with relapsed/refractory ALL, inotuzumab resulted in an remission rate of 66%, with 78% of patients who achieved CR also becoming MRD-negative.19 The median OS was 7.4 months. A randomized trial comparing inotuzumab with physician’s choice of chemotherapy in patients with relapsed ALL in salvage 1 and 2 has completed accrual. Primary end-points included response rates and OS. The objective response rates were 81% and 33%, respectively. Among responders, the MRD-negativity rates were 78% and 28%, respectively. The me-dian response duration was 4.6 versus 3.1 months (P = .02), re-spectively.20 We are awaiting the survival data.

Inotuzumab was also evaluated in both the front-line and salvage settings in combination with a dose-reduced mini–hy-per-CVD regimen.21,22 In recently reported interim results of a phase II study using this combination in 52 patients with re-lapsed/refractory ALL, this regimen resulted in a 77% ORR, with 82% of responders achieving MRD negativity.21 The 2-year PFS and OS rates were 60% and 32%, respectively; in patients treated in salvage 1, the 2-year OS rate was 50%. The survival of patients treated with mini–hyper-CVD plus inotuzumab were su-perior to a historical cohort of patients treated with inotuzumab monotherapy in the salvage setting (median OS: 11 months vs 6 months, respectively; P = .03).

Given the promising results of de-intensified chemotherapy plus inotuzumab in the relapsed setting, this combination was also evaluated in the front-line setting for elderly patients with ALL. Full-intensity chemotherapy is associated with unaccept-ably high rates of toxicity in elderly patients. In one large retro-spective study of older patients receiving hyper-CVAD chemo-therapy, the induction mortality rate was 10% and the death in CR rate was 34%.23 Therefore, less toxic, effective regimens

are especially needed in this patient population. In the most recent update of a study of mini–hyper-CVD plus inotuzumab in older patients with newly diagnosed ALL, 97% of patients achieved CR or CR with inadequate platelet recovery.22 Only one patient (3%) died in the first month of therapy. The 2-year OS was 70%, which compared favorably to the historical 2-year OS rate of 38% in elderly patients treated with full-intensity hyper-CVAD, in part due to lower toxicity with the inotuzumab plus mini–hyper-CVD regimen.

The most serious toxicity associated with inotuzumab is the development of veno-occlusive disease (VOD), the incidence of which is increased in patients with prior allogeneic stem cell transplant (ASCT). In initial studies of inotuzumab monother-apy using a monthly dose of inotuzumab at 1.8 mg/m2, VOD developed in 5 out of 22 patients (23%) with prior history of ASCT, 4 of whom died from VOD.24 However, in subsequent studies using lower doses of inotuzumab (0.5-0.8 mg/m2) weekly, lower post-ASCT rates of 7% have been observed.18 Nevertheless, even at these modified dosing schedules, clinicians should be aware of the VOD risk with inotuzumab, especially in patients with prior ASCT.

Anti-CD19 Bi-Specific T-Cell Engager: BlinatumomabBlinatumomab is a bi-specific T-cell engager antibody against CD3 and CD19 that is designed to direct cytotoxic T cells to CD19-expressing leukemic cells.25 CD19 is nearly universally ex-pressed on the cell surface of both precursor and mature B-ALL leukemic blasts and therefore is a rational target for antibody-di-rected therapy for these diseases.4 In a phase II study of 189 heav-ily pre-treated patients with relapsed/refractory Ph-negative ALL, blinatumomab given as a continuous intravenous infusion for 4 consecutive weeks, on a 6-week cycle, was associated with a CR plus CR with partial hematologic recovery (CRh) rate of 43% and a median response duration and OS of 9 months and 6 months, respectively.26

These promising results have provided the rationale for a phase III randomized trial (TOWER study) of blinatumomab versus investigator’s choice chemotherapy for patients with ALL in first or second relapse. OS was the primary endpoint, and duration of CR, CR, and MRD negativity were secondary end-points. So far, interim analysis shows promising results, as the primary endpoint has been met and final results are pending. A phase II trial combining blinatumomab with hyper-CVAD che-motherapy in the front-line setting is also planned.

Interim results of blinatumomab in patients with Ph-positive ALL suggest that it also has significant clinical activity in this subgroup of patients.27 Forty-five patients with Ph-positive ALL who have relapsed or were refractory to tyrosine kinase inhibi-tor–based therapy were treated with single-agent blinatumomab, which resulted in a CR/CRh rate of 36%. Similar response rates of 35% and 40% were observed in patients with prior ponatinib treatment and known T315I resistance mutation, respectively.

· ACUTE LYMPHOBLASTIC LEUKEMIA ·


Of 16 total responders, the MRD-negativity rate was 88%, and 44% of patients were able to receive ASCT.

In patients who remain MRD-positive after initial therapy or who develop MRD relapse after initial deep remission, blinatum-omab results in a molecular CR rate of approximately 80% and is associated with promising long-term outcomes.28,29 In one study of 116 patients with Ph-negative ALL who remained MRD-posi-tive after initial chemotherapy and subsequently received blina-tumomab, median OS was significantly longer in patients who subsequently achieved MRD negativity compared with those who remained MRD-positive (40 months vs 12 months, respec-tively; P = .001).29 Notably, ASCT did not confer a survival ben-efit for patients who achieved MRD negativity in first remission. These results provide evidence that a strategy of MRD-directed therapy that uses monoclonal antibodies is useful in improving outcomes in ALL.

ConclusionMonoclonal antibodies against CD20, CD22, and CD19 have shown encouraging clinical activity in patients with ALL, both in the front-line and relapsed settings. The addition of rituximab to cytotoxic chemotherapy has been shown to improve OS in younger patients, and next-generation anti-CD20 antibodies also show promise in the management of ALL. Both inotuzumab ozogamicin and blinatumomab are effective monotherapies in the salvage setting. Inotuzumab has also shown significant clin-ical activity when combined with dose-reduced chemotherapy, and the use of blinatumomab in MRD-positive disease suggests that MRD-directed strategies are a viable therapeutic approach in ALL. Future studies will need to address how best to com-bine these monoclonal antibodies with chemotherapy and pos-sibly with each other, with the goal of decreasing our reliance on intensive cytotoxic chemotherapy and ASCT, and ultimately increasing the cure rates of adult ALL to those achieved in the pediatric population.

Affiliations: Nicholas J. Short, MD is from the Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX. Elias Jabbour is from the Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX.Acknowledgement: This research was supported by the MD An-derson Cancer Center Support Grant CA016672.Address correspondence to: Elias Jabbour, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-7305; E-mail: [email protected]

REFERENCES1. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute

lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938-2948. doi: 10.1200/JCO.2014.59.1636. 2. Sive JI, Buck G, Fielding A, et al. Outcomes in older adults with acute lymphoblastic leukaemia (ALL): results from the international MRC UKALL XII/ECOG2993 trial. Br J Haematol. 2012;157(4):463-471. doi: 10.1111/j.1365-2141.2012.09095.x.3. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843-850. doi: 10.1182/blood-2013-09-529008.4. Jabbour E, O’Brien S, Ravandi F, Kantarjian H. Monoclonal antibodies in acute lymphoblastic leukemia. Blood. 2015;125(26):4010-4016. doi: 10.1182/blood-2014-08-596403.5. Raponi S, De Propris MS, Intoppa S, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk Lymphoma. 2011;52(6):1098-1107. doi: 10.3109/10428194.2011.559668.6. Hoelzer D, Gokbuget N. Chemoimmunotherapy in acute lymphoblastic leukemia. Blood Rev. 2012;26(1):25-32. doi: 10.1016/j.blre.2011.08.001.7. Thomas DA, O’Brien S, Jorgensen JL, et al. Prognostic significance of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia. Blood. 2009;113(25):6330-6337. doi: 10.1182/blood-2008-04-151860.8. Maury S, Huguet F, Leguay T, et al. Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. Haematologica. 2010;95(2):324-328. doi: 10.3324/haematol.2009.010306.9. Thomas DA, O’Brien S, Faderl S, et al. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. J Clin Oncol. 2010;28(24):3880-3889. doi: 10.1200/JCO.2009.26.9456.10. Maury S, Chevret S, Thomas X, et al. Addition of rituximab improves the outcome of adult patients with CD20-positive, ph-negative, B-cell precursor acute lymphoblastic leukemia (BCP-ALL): results of the randomized Graall-R 2005 study. Blood. 2015;126(23):1-1.11. Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106(7):1569-1580.12. Hoelzer D, Walewski J, Dohner H, et al. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial. Blood. 2014;124(26):3870-3879. doi: 10.1182/blood-2014-03-563627.13. Rizzieri DA, Johnson JL, Byrd JC, et al. Improved efficacy using rituximab and brief duration, high intensity chemotherapy

INCORPORATING ANTIBODIES INTO TREATMENT STRATEGIES FOR ACUTE LYMPHOBLASTIC LEUKEMIA


with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia group B study 10 002. Br J Haematol. 2014;165(1):102-111. doi: 10.1111/bjh.12736.14. Ribrag V, Koscielny S, Bosq J, et al. Dose-dense chemotherapy and rituximab versus dose-dense chemotherapy alone for HIV-negative adult patients with Burkitt leukaemia/lymphoma: a multicentre phase 3 randomised controlled trial from the intergroup GRAALL-Lysa. Lancet. 2016 (in press).15. Maloney DG. Anti-CD20 antibody therapy for B-cell lymphomas. N Engl J Med. 2012;366(21):2008-2016. doi: 10.1056/NEJMct1114348.16. Sasaki K, Koller PB, Kantarjian HM, et al. Phase II study of the front-line hyper-CVAD in combination with ofatumumab for adult patients (pts) with CD-20 positive acute lymphoblastic leukemia (ALL). Blood. 2015;126(23):1295.17. Yilmaz M, Richard S, Jabbour E. The clinical potential of inotuzumab ozogamicin in relapsed and refractory acute lymphocytic leukemia. Ther Adv Hematol. 2015;6(5):253-261. doi: 10.1177/2040620715596715.18. Kantarjian H, Thomas D, Jorgensen J, et al. Results of inotuzumab ozogamicin, a CD22 monoclonal antibody, in refractory and relapsed acute lymphocytic leukemia. Cancer. 2013;119(15):2728-2736. doi: 10.1002/cncr.28136.19. Advani AS, Stein AS, Kantarjian HM, et al. A phase II study of weekly inotuzumab ozogamicin (InO) in adult patients with CD22-positive acute lymphoblastic leukemia (ALL) in second or later salvage. Blood. 2014;124(21):2255-2255.20. DeAngelo D, Stelljes M, Martinelli G, et al. Efficacy and safety of inotuzumab ozogamicin (INO) vs standard of care (SOC) in salvage 1 or 2 in patients with acute lymphoblastic leukemia (ALL): an ongoing global phase 3 study. Haematologica. 2015;100:S1 abstract #LB2073.21. Sasaki K, Kantarjian HM, O’Brien S, et al. Salvage chemotherapy with inotuzumab ozogamicin (INO) combined with mini-hyper-CVD for adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Blood. 2015;126(23):3721-3721.22. Jabbour E, O’Brien S, Sasaki K, et al. Front-line inotuzumab

ozogamicin in combination with low-intensity chemotherapy (mini-hyper-CVD) for older patients with acute lymphoblastic leukemia (ALL). Blood. 2015;126(23):83-83.23. O’Brien S, Thomas DA, Ravandi F, Faderl S, Pierce S, Kantarjian H. Results of the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen in elderly patients with acute lymphocytic leukemia. Cancer. 2008;113(8):2097-2101. doi: 10.1002/cncr.23819.24. Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13(4):403-411. doi: 10.1016/S1470-2045(11)70386-2.25. Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321(5891):974-977. doi: 10.1126/science.1158545.26. Topp MS, Gokbuget N, Stein AS, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57-66. doi: 10.1016/S1470-2045(14)71170-2.27. Martinelli G, Dombret H, Chevallier P, et al. Complete molecular and hematologic response in adult patients with relapsed/refractory (R/R) Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia (ALL) following treatment with blinatumomab: results from a phase 2 single-arm, multicenter study (ALCANTARA). Blood. 2015;126(23):679-679.28. Topp MS, Gokbuget N, Zugmaier G, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120(26):5185-5187. doi: 10.1182/blood-2012-07-441030.29. Gökbuget N, Dombret H, Bonifacio M, et al. Long-term outcomes after blinatumomab treatment: follow-up of a phase 2 study in patients (Pts) with minimal residual disease (MRD) positive B-cell precursor acute lymphoblastic leukemia (ALL). Blood. 2015;126(23):680-680. doi: http://dx.doi.org/10.1182/blood-2015-06-649111.

· BREAST CANCER ·


Omitting Radiation in Older Breast Cancer Patients

Jennifer K. Plichta, MD, and Kevin S. Hughes, MD

Introduction Breast cancer treatment has evolved concurrently with the ad-vancement of personalized medicine, and as such, many patients are receiving less treatment while still attaining the same rate of cure. Along these lines, there is now increasing interest in identifying patients who may avoid the cost, morbidity, and in-convenience of radiation after breast conserving surgery without compromising their ultimate outcome.

The trend toward lesser treatment has already been employed

in the surgical and medical management of breast cancer. In medical oncology, it was determined early that patients who are negative derive little benefit from anti-estrogen therapy or oophorectomy.1,2 More recently, genomic testing has allowed many patients with low-risk tumors to forego chemotherapy.3 In surgery, it has been clearly demonstrated that many women can undergo lumpectomy (with radiation) instead of mastecto-my,4 and sentinel node biopsy instead of axillary dissection.5,6 In those requiring mastectomy, many can now have their nipple preserved.7 While radiation oncology has examined decreasing breast radiation with hypofractionation techniques8,9 and partial breast irradiation,10 there remains resistance to omitting radia-tion entirely, even in selected cases.

The acceptance of breast conservation in the 1980s is ger-mane to the radiation discussion. The National Surgical Adju-vant Breast and Bowel Project (NSABP) B-06 was designed to study whether breast conservation was equivalent to mastecto-my.4,11 Based on the 1985 analysis, lumpectomy with radiation was deemed an acceptable alternative to mastectomy despite the significant rate of ipsilateral breast tumor recurrence (IBTR) after conservation, because survival was no different than with mastectomy.12 In addition, this study introduced the idea of an acceptable IBTR rate. While survival was the same with or with-out radiation, the IBTR rate with radiation (7.7% at 5 years) was considered acceptable. The IBTR rate without radiation (27.9% at 5 years) was deemed too high. Thus, the validation of lumpec-tomy was based on the tolerance of a moderate amount of IBTR below a given threshold. The Eusoma Guidelines13 suggest that a 1% per year rate of IBTR is acceptable, which translates to 5% at 5 years and 10% at 10 years. Patients and physicians seem to find this threshold acceptable as evidenced by the acceptance of IBTR rates similar to this for women with triple-negative breast cancer,14 young women,15 those with high-grade DCIS,16 and those undergoing preoperative chemotherapy.17 While IBTR rates have continued to improve for many of these subgroups, conservation was still chosen by most physicians and patients even when the reported rates mirrored these thresholds.

Soon after the initial publication of NSABP B-06, the search began for subgroups that might not require radiation after breast-conserving surgery. In the pre-genomic era, characteristics

Abstract

Breast cancer treatment has evolved concurrently with

the advancement of personalized medicine, and as such,

many patients are receiving less treatment while still at-

taining the same rate of cure. Along these lines, there is

increasing interest in identifying patients who may avoid

radiation therapy after breast conserving surgery with-

out compromising outcomes. NSABP B-21 evaluated

women with ER+ tumors 1 cm or less at any age; others

have assessed women with ER+ tumors up to 4 cm but

over age 50; and CALGB 9343 studied women ages 70

and above with ER+, clinical stage 1 breast cancers. All

of these studies randomized patients to radiation versus

no radiation, and most required tamoxifen. In each study,

radiation therapy did not alter survival, although de-

creased rates of recurrence were reported and were least

in older women with smaller cancers. Based on these

and subsequent studies, current guidelines suggest that

most women ages 70 and above with clinical stage 1, ER+

cancers do not require radiation therapy after lumpecto-

my, if they receive standard adjuvant hormonal therapy.

Younger women with low risk tumors by genomic sig-

natures might also be included in a subgroup that may

avoid radiation therapy, and this group is under study.

Radiation oncologists are on the verge of joining breast

surgeons and medical oncologists in decreasing the cost

and morbidity of breast cancer treatment without nega-

tively impacting survival or quality of life.

CONSIDERATIONS FOR MINIMIZING RADIATION THERAPY


chosen were combinations of older age, smaller cancers, and es-trogen-receptor positive (ER+) cancers. NSABP B-21 evaluated women with ER+ tumors 1 cm or less at any age1; Fyles et al, assessed women with ER+ tumors up to 4 cm but over age 50,18 and CALGB 9343 (Cancer and Leukemia Group B, working with ECOG and RTOG) studied women aged 70 and above with ER+, clinical stage 1 breast cancers.19 All of these studies random-ized patients to radiation versus no radiation, and most required tamoxifen use (though NSABP B-21 also had a ‘no tamoxifen’ arm). In each study, survival was not affected, and radiation ther-apy decreased the rate of IBTR, although this benefit was least in older women with smaller cancers. Other trials, such as PRIME 2 (Postoperative Radiotherapy in Minimum-Risk Elderly), have subsequently been published with similar results.20 It is import-ant to note that overall survival was included in the pre-specified analyses of these studies, although information regarding the sta-tistical power to detect differences was not provided for most of them, as the analyses focused on the primary endpoints related to recurrence.

CALGB 934319 accrued 631 eligible patients between July 15, 1994 to February 26, 1999. The median follow-up at the most recent publication was 12 years. Patient and tumor characteris-tics were evenly distributed between the two groups (Table 1). Locoregional recurrence was decreased by the use of radiation, with a 10-year rate of 10% in the tamoxifen alone group and 2% in the tamoxifen plus radiation group. Thus, there was a net 8% benefit from radiation in terms of locoregional recurrence. When axillary recurrences were excluded and only IBTR recur-rences considered, the net benefit decreased to 7%.19

However, no additional benefits were identified. Radiation had no impact on survival, distant disease-free survival, or the ul-timate rate of breast preservation (as many women who who had a recurrence in the breast after tamoxifen alone were still able to salvage their breast with repeat lumpectomy and subsequent radiation at the time of recurrence). Of note, this study was not powered to prove noninferiority with regard to survival.

These results were compelling and changed clinical practice guidelines. The current National Comprehensive Cancer Net-work (NCCN) guidelines state that women aged 70 and above with clinical stage 1 ER+ breast cancers may be treated with or

without radiation.21 This change propagated into most quali-ty measures (eg, Commission on Cancer, American Society of Clinical Oncology Quality Oncology Practice Initiative, and Na-tional Accreditation Program for Breast Cancer), each of whom changed the quality measure requiring radiation after lumpecto-my for all patients to now apply only to women less than 70 years old. Unfortunately, this approach has been slow to disseminate into clinical care.22,23

Some have criticized the CALGB 9343 study, suggesting that while the study is true for many patients, it may not apply to those who are healthy.24,25 These critics may have overlooked the fact that most women in this study lived longer than would have been predicted for a group of women of comparable age, with more than 50% still alive at 12 years median follow-up.19 This study accumulated healthier women, and with a longer life ex-pectancy, than an average group of women that age. Thus, poor health does not appear to explain these results, and these data apply to healthy older women.

Some suggest that while this study may be true for many patients, it may not apply to women with high-grade cancers, high-risk genomic scores, HER2 positive, and possibly other sub-groups.24-26 However, there are no data to support these asser-tions, and yet many older women receive radiation due to these biases. Critics also contend that the 4% IBTR at 5 years and 9%

TABLE 1. Select Patient, Tumor, and Surgical Factors From the CALGB 9343 Trial Comparing Radiation Therapy with Tamoxifen Versus Tamoxifen Alone (Without Radiation)

Radiation Therapy +Tamoxifen N (%)

Tamoxifen N (%)

Total Treated 317 319

Age ≥75 years 176 (56%) 172 (54%)

ER+ 313 (99%) 313 (98%)

Tumor size ≤2 cm 310 (98%) 313 (98%)

No axillary dissection 195 (62%) 200 (63%)

ER indicates estrogen receptor.

TABLE 2. Ipsilateral Breast Tumor Recurrence Rates at 5 Years From the Initial Publications

Ipsilateral Breast Tumor Recurrence Rates at 5 years

Study/Radiation Technique No Radiation Whole Breast Irradiation

CALGB 934219 4% 1%

Partial-Breast Irradiation Whole Breast Irradiation

Accelerated partial-breast irradiation10 4.0% 1.8%

Targeted intraoperative radiotherapy33 3.3% 1.3%

Electron intraoperative radiotherapy34 4.4% 0.4%

· BREAST CANCER ·


IBTR at 10 years in CALGB 9343 are not acceptable.25,26 This criticism is interesting, as many breast cancer clinicians accept a similar rate of IBTR in patients receiving intraoperative or par-tial-breast irradiation (Table 2). The rates of IBTR in high-risk women getting whole breast radiation, in low-risk women not getting radiation, or in low-risk women getting partial breast ra-diation are acceptable, because we are moving away from the con-flation of IBTR, which is accepted and expected in some cases after conservation, with distant recurrence, which is deadly. The acceptance of a finite level of IBTR made breast conservation possible, and a similar recognition is now circulating into the radiation field with the acceptance of conservation without radi-ation, or with less radiation, in select cases.

The outcome of CALGB 9343 was likely a result of the fact that older women tend to have less aggressive cancers that are more responsive to endocrine therapy.27-29 The results likely had less to do with age and more to do with the tumor itself. This has been strongly suggested by others who studied IBTR in younger individuals. For example, in a study of 151 women aged 60 and above with tumors <2 cm, grade 1 or 2, and luminal A subtype, the 10-year rate of IBTR was 1.3% with tamoxifen versus 5% with tamoxifen plus radiation therapy.30

The PRECISION Trial (Profiling Early Breast Cancer for Ra-diotherapy Omission) builds on this work,31 using genomic pro-filing to limit the use of radiation in a subgroup of women that would likely derive little benefit. In this single-arm study, patients who are ER+, PR+, HER2 negative, grade 1 or 2, and low risk by the Prosigna genomic assay, will be eligible for endocrine therapy without radiation. This study will show a finite rate of IBTR, and the investigators hypothesize that this rate will be acceptable (defined as acceptable if the upper limit of the 95% confidence interval for 5-year locoregional recurrence is below 5%).

We are now moving into an era where the cost of medicine must be contained, and the actual benefit of each therapy must be weighed carefully against cost. Radiation for women aged 70 and above with clinical stage 1, ER+ cancers is expensive and has minimal benefit. These women have much greater risk to their lives and well-being from other causes, with 94% of women who died in CALGB 9343 dying of something other than breast can-cer.19 It is time to consider whether healthcare dollars are better spent on other more deadly aspects of their health rather than on radiation.

This will have implications for the financial status of radiation departments. Konski et al recently reported that the change to hypofractionation in breast cancer radiation will cause a per-case marginal reduction in reimbursement of $4,297.32 A similar analysis needs to be done for omitting radiation in older wom-en, where the loss of revenue will be many times that amount, and the financial impact on radiation oncology departments will be profound. Fortunately, this may become more palatable as we move away from fee-for-service models and move towards ac-countable care and value-based medicine.

In summary, most women aged 70 and above with clinical stage 1, ER+ cancers do not need radiation therapy after lumpec-tomy. Furthermore, studies regarding the use of genomic signa-tures in younger women with low-risk tumors might ultimately demonstrate an additional subgroup that may avoid radiation therapy. Radiation oncologists are on the verge of joining breast surgeons and medical oncologists in decreasing the cost and morbidity of breast cancer treatment without negatively impact-ing survival or quality of life.

Affiliations: Jennifer K. Plichta, MD, and Kevin S. Hughes, MD, are from the Department of Surgery, Division of Surgical Oncol-ogy, Massachusetts General Hospital, Boston, MA.Address correspondence to: Kevin S. Hughes, MD, Massachu-setts General Hospital, 55 Fruit Street, Yawkey 7, Boston, MA 02114. Telephone: (617)724-0048, Fax: (617)724-3895,E-mail: [email protected]: Kevin S. Hughes receives Honoraria from Myriad Genetics, Veritas Genetics, and is a founder of and has a finan-cial interest in Hughes Risk Apps, LLC. Dr. Hughes’ interests were reviewed and are managed by Massachusetts General Hos-pital and Partners Health Care in accordance with their conflict of interest policies.

REFERENCES1. Fisher B, Bryant J, Dignam JJ, et al. Tamoxifen, radiation ther-apy, or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol. 2002;20(20):4141-4149. 2. Nomura Y, Tashiro H, Hisamatsu K, Shinozuka K. A ran-domized trial of adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy for operable breast cancer stratified by estrogen receptors. Cancer. 1988;61(11):2168-2175. 3. Sparano JA, Gray RJ, Makower DF, et al. Prospective valida-tion of a 21-gene expression assay in breast cancer. N Engl J Med. 2015;373(21):2005-2014. 4. Fisher B, Anderson S, Bryant J, et al. Twenty-year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med. 2002;347(16):1233-1241. 5. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA. 2011;305(6):569-575. 6. Krag DN, Anderson SJ, Julian TB, et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dis-section in clinically node-negative patients with breast cancer: Overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol. 2010;11(10):927-933. 7. Coopey SB, Tang R, Lei L, et al. Increasing eligibility for nip-ple-sparing mastectomy. Ann Surg Oncol. 2013;20(10):3218-3222.

CONSIDERATIONS FOR MINIMIZING RADIATION THERAPY


8. Haviland JS, Owen JR, Dewar JA, et al. The UK standard-isation of breast radiotherapy (START) trials of radiotherapy hypofractionation for treatment of early breast cancer: 10-year follow-up results of two randomised controlled trials. Lancet On-col. 2013;14(11):1086-1094. 9. Ortholan C, Hannoun-Levi JM, Ferrero JM, Largillier R, Courdi A. Long-term results of adjuvant hypofractionated radio-therapy for breast cancer in elderly patients. Int J Radiat Oncol Biol Phys. 2005;61(1):154-162. 10. Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD. Par-tial breast brachytherapy is associated with inferior effectiveness and increased toxicity compared with whole breast irradiation in older patients. San Antonio Breast Cancer Symposium. 2011;S2-1. 11. Jatoi I, Proschan MA. Randomized trials of breast-conserving therapy versus mastectomy for primary breast cancer: A pooled analysis of updated results. Am J Clin Oncol. 2005;28(3):289-294. 12. Fisher B, Bauer M, Margolese R, et al. Five-year results of a randomized clinical trial comparing total mastectomy and seg-mental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312(11):665-673. 13. Rutgers EJ, EUSOMA Consensus Group. Quality control in the locoregional treatment of breast cancer. Eur J Cancer. 2001;37(4):447-453. 14. Moran MS. Radiation therapy in the locoregional treatment of triple-negative breast cancer. Lancet Oncol. 2015;16(3):e113-22. 15. Bartelink H, Horiot JC, Poortmans PM, et al. Impact of a higher radiation dose on local control and survival in breast-con-serving therapy of early breast cancer: 10-year results of the ran-domized boost versus no boost EORTC 22881-10882 trial. J Clin Oncol. 2007;25(22):3259-3265. 16. Silverstein MJ, Lagios MD. Treatment selection for patients with ductal carcinoma in situ (DCIS) of the breast using the uni-versity of southern California/Van nuys (USC/VNPI) prognos-tic index. Breast J. 2015;21(2):127-132. 17. Mamounas EP, Anderson SJ, Dignam JJ, et al. Predictors of locoregional recurrence after neoadjuvant chemotherapy: Re-sults from combined analysis of national surgical adjuvant breast and bowel project B-18 and B-27. J Clin Oncol. 2012;30(32):3960-3966. 18. Fyles AW, McCready DR, Manchul LA, et al. Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer. N Engl J Med. 2004;351(10):963-970. 19. Hughes KS, Schnaper LA, Bellon JR, et al. Lumpectomy plus tamoxifen with or without irradiation in women age 70 years or older with early breast cancer: Long-term follow-up of CALGB 9343. J Clin Oncol. 2013;31(19):2382-2387. 20. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM, PRIME II investigators. Breast-conserving surgery with or with-out irradiation in women aged 65 years or older with early breast cancer (PRIME II): A randomised controlled trial. Lancet Oncol. 2015;16(3):266-273. 21. Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive

breast cancer version 1.2016, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2016;14(3):324-354.22. McCormick B, Ottesen RA, Hughes ME, et al. Impact of guideline changes on use or omission of radiation in the elderly with early breast cancer: Practice patterns at national comprehen-sive cancer network institutions. J Am Coll Surg. 2014;219(4):796-802. 23. Soulos PR, Yu JB, Roberts KB, et al. Assessing the impact of a cooperative group trial on breast cancer care in the medicare population. J Clin Oncol. 2012;30(14):1601-1607. 24. Kaidar-Person O, Kuten A, Walker GA, Morgan DA. Should radiotherapy be omitted in women age 70 years or older with early breast cancer? J Clin Oncol. 2013;31(36):4569. 25. Tsoutsou PG, Jeanneret Sozzi W, Ozsahin M, Delaloye JF, Bourhis J. Radiotherapy options after breast-conserving sur-gery: How can selection of patients be refined? J Clin Oncol. 2013;31(36):4570-4571. 26. Courdi A, Gerard JP. Radiotherapy for elderly patients with breast cancer. J Clin Oncol. 2013;31(36):4571. 27. Carlson RW, Moench S, Hurria A, et al. NCCN task force report: Breast cancer in the older woman. J Natl Compr Canc Netw. 2008;6 Suppl 4:S1-25; quiz S26-7. 28. Karuturi M, VanderWalde N, Muss H. Approach and management of breast cancer in the elderly. Clin Geriatr Med. 2016;32(1):133-153. 29. Spazzapan S, Crivellari D, Bedard P, et al. Therapeutic man-agement of breast cancer in the elderly. Expert Opin Pharmacother. 2011;12(6):945-960. 30. Liu FF, Shi W, Done SJ, et al. Identification of a low-risk luminal A breast cancer cohort that may not benefit from breast radiotherapy. J Clin Oncol. 2015;33(18):2035-2040. 31. Harris JR. The PRECISION trial (profiling early breast can-cer for radiotherapy omission): A phase II study of breast-con-serving surgery without adjuvant radiotherapy for favorable-risk breast cancer. Available at: https://clinicaltrials.gov/ct2/show/NCT02653755. 2016. 32. Konski A, Yu JB, Freedman G, Harrison LB, Johnstone PA. Radiation oncology practice: Adjusting to a new reimbursement model. J Oncol Pract. 2016;12(5):e576-83. 33. Vaidya JS, Wenz F, Bulsara M, et al. Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiothera-py for breast cancer: 5-year results for local control and over-all survival from the TARGIT-A randomised trial. Lancet. 2014;383(9917):603-613. 34. Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): A randomised controlled equivalence trial. Lancet On-col. 2013;14(13):1269-1277.

· LYMPHOMA ·


Are New Treatment Options Shifting How and When We Treat Waldenström Macroglobulinemia?

Morie A. Gertz, MD, MACP

IntroductionWaldenström macroglobulinemia is defined by the World Health Organization and the International Waldenström’s Working Group as the presence of bone marrow lymphoplas-macytic lymphoma associated with a monoclonal IgM protein of any size. The bone marrow morphology shows both CD38 expressing plasma cells and CD20 expressing lymphoplasmacyt-ic cells. A monoclonal protein is invariably visible on the se-rum protein electrophoresis. Immunofixation identifies an IgM heavy chain. One of the defining syndromes of Waldenström macroglobulinemia is the development of hyperviscosity due to the impact of pentameric IgM on the flow of serum. The most common signs of hyperviscosity are oronasal bleeding or blurred vision secondary to retinal hemorrhage.

IgM monoclonal serum proteins represent 18% of all mono-clonal proteins seen. Since monoclonal gammopathy of unde-termined significance (MGUS) is seen in 3% of adults over the age of 70, 1 adult in 200 will have an IgM monoclonal protein. However, only 1.9% of non-Hodgkin lymphoma are Walden-ström macroglobulinemia, with a median age at diagnosis of 73 and an overall annual age-adjusted incidence of 3.8 per

million. A family history is obtained in 4.3%.1 Waldenström macroglobulinemia is twice as common in men as in women (5.4 vs. 2.7 per million per year) and is more common in whites (4.1 per million per year) than in blacks (1.8 per million per year). A significant annual percentage increase is being seen in patients over the age of 70.2 Age has a profound impact on outcome with median survival of approximately four years for patients age 80 or over compared with an 85% survival at four years for patients under the age of 60.3 The MYD88 mu-tation does not define Waldenström macroglobulinemia, but is observed in 85% to 100% of patients. MYD88 mutations were significantly associated with the presence of 6q deletions. MYD88 is also seen in IgM MGUS, but only rarely seen in diffuse large-cell lymphomas or marginal zone lymphomas and is not seen in multiple myeloma or CLL.4 Approximately 50 % of patients have some aberrancy on conventional cytogenetics and/or fluorescence in situ hybridization (FISH) analysis, with the most common abnormalities being the deletion (del) of the long arm of chromosome 6 (22% to 46%), del13q14 (13% to 15%), trisomy 18 (11% to 23%), trisomy 4 (4% to 12%), and delp53 (4% to 23%). Trisomy 4 is a unique feature and is occa-sionally the only abnormality observed in WM.

Goals of TherapyThe most common question faced by clinicians is determining when is the appropriate time to abandon a regimen for lack of efficacy and change to a second regimen? The answer to this question is driven by the endpoints that led to the initiation of therapy. Waldenström macroglobulinemia does not always need therapy. Patients may be diagnosed with the disorder, but lack sufficient symptoms related to anemia, lymphadenopathy, or constitutional symptoms to warrant intervention. Patients with so-called smoldering Waldenström macroglobulinemia can be monitored without therapeutic intervention, although the rate of progression into overt disease is substantial, and most patients ultimately require therapy. Fludarabine is high-ly active in the treatment of Waldenström macroglobulinemia and has been shown, in a phase III trial, to be superior to chlorambucil in terms of progression-free and overall survival. Moreover, the risk of secondary malignancy with fludarabine

Abstract

The introduction of new agents for the treatment of

Waldenström macroglobulinemia has had a dramatic

impact on survivorship in this disease. Earlier diagno-

sis has led to a reduced frequency of hyperviscosity. The

MYD88 mutation appears to define 90% of patients with

Waldenström macroglobulinemia and helps differentiate

it from other disorders. Bendamustine and rituximab is

a highly active regimen for the treatment of this disease

as is cyclophosphamide, dexamethasone, and rituximab.

Other agents that show high activity include purine nu-

cleoside analogues, bortezomib, carfilzomib, everolimus,

and ibrutinib.

Key words: Waldenström macroglobulinemia; hypervis-

cosity; bendamustine; ibrutinib; proteasome inhibitors;

purine nucleoside analogs

THERAPY OF WALDENSTRÖM’S


is <5%, and transformation into large-cell lymphoma is approximate-ly 10% at eight years.5

The use of dexamethasone-ritux-imab-cyclophosphamide has also been investigated in Waldenström macroglobulinemia in large cohorts. Age has a profound impact on out-come. Patients under the age of 65 have an 80% survival at 100 months compared with <40% in patients over the age of 65. Nearly half of patients with Waldenström macro-globulinemia die of unrelated caus-es, reflecting the indolent nature of this lymphoma. With the dexameth-asone-rituximab-cyclophosphamide regimen, depth of response did not translate into improved survival, and patients achieving a very good partial response (VGPR) or better had the same survival as patients achieving a minor response.6 Given the activity of both cyclophospha-mide and fludarabine, combining them into fludarabine-cyclophos-phamide-rituximab (FCR) shows a very high activity level. The response rate is 80%, VGPR of 32.5%, and an event-free survival of 77 months, independent of stage or prior therapy. Among 40 patients reported, 2 de-veloped MDS and 1 large-cell transformation was seen. The regimen, other than being highly myelosuppressive, is well tol-erated.7 Both cladribine and pentostatin show significant activ-ity in the treatment of Waldenström macroglobulinemia and are alternative purine nucleoside analogs that could be consid-ered.8,9 Single-agent rituximab use is to be discouraged in favor of higher-response-rate combinations.

Proteasome inhibitors, both bortezomib and carfilzomib, have been used in the treatment of Waldenström macroglobu-linemia. Bortezomib combined with rituximab and dexameth-asone resulted in a response rate of 85%. Rituximab was admin-istered in this regimen in cycles 2 and 5 in an effort to reduce the risk of flare, which was seen in only 11%. This regimen, however, given in a 1, 4, 8, 11 schedule, resulted in peripheral neuropathy in 46% of patients. In a large study involving a large cohort of patients treated with bendamustine-dexametha-sone-rituximab, median IgM level reported between cycle 1 and cycle 5 fell from 4000 to approximately 1700, and complete responses were seen in two patients; but time to maximum re-sponse after addition of BDR took as long as one year. With this regimen, overall survival exceeded five years.10 Bortezomib has also been combined with rituximab and cyclophosphamide

and demonstrated responses in 14 of 15 patients, including one complete response.11

The use of carfilzomib has also been investigated in Walden-strömm macroglobulinemia. Carfilzomib administered on days 1, 2, 8, 9 of each cycle with rituximab, and dexamethasone on days 2 and 9 of each cycle were administered to 31 patients. The overall response rate was 87% with 36% ≥VGPR. Median time to response was 2.1 months, and no neuropathy >grade 1 was seen.12

Everolimus shows activity in the treatment of chemothera-py refractory Waldenström macroglobulinemia. Sixty patients with advanced disease achieved an overall response rate of 50% and a clinical benefit rate of 73%. Median time to response was two months. Median progression-free survival was 21 months. Unfortunately, grade 3 or higher toxicities were observed in 67% of patients.13

Autologous stem cell transplantation is active in patients with Waldenström Macroglobulinemia. A review of registry data from Europe covering 158 patients demonstrated partial response (PR) or better in 134 patients, with a median event-free survival of over four years and a median overall survival not reached at eight years.14 The East German Lymphoma Study Group reported a phase III trial of R-CHOP versus R-benda-mustine. Forty-one patients in this cohort had Waldenström macroglobulinemia. Researchers reported that 22 received bendamustine and 19 received R-CHOP. The median progres-

FIGURE 1. Mayo Clinic M-SMART Guidelines for the Treatment of Walden-ström Macroglobulinemia. With permission Mayo Clinic Proceedings.

• IgM MGUS (<10% lymphoplasmacytic infiltration)

• Asymptomatic/smoldering Waldenström macroglobulinemia

• Hemoglobin ≥11g/dL• Platelets ≥120x 109/L

Observation

• Hemoglobin ≥11g/dL or symptomatic

• Platelets ≥120x 109/L• IgM-related neuropathy• WM-associated hemolytic

anemia• Symptomatic

cryoglobulinemia

Single-Agent Rituximab*(1 cycle; no maintenence therapy)*plasmapheres if hyperviscosity

develops with treatment

Bendamustine + Rituximab*(BR)* x 4-6 cycles

No rituximab maintenence therapy

Harvest stem cells ≥70 years and potential autologous stem cell

transplantation candidate in future

• Bulky disease• Profound cytopenias—

- Hemoglogin ≥11g/dL - Platelets ≥120x 109/L

• Constitutional symptoms• Hyperviscosity symptoms

Hyperviscosity symptoms

*Dexamethasone + Rituximab + Cyclophosphamide (DRC)* x 6 cycles is an alternative if the disease burden is low

Plasmapheresis

Yes No

· LYMPHOMA ·


sion-free survival for R-CHOP-treated patients was 36 months versus not reached for R-bendamustine. At analysis, 4 relapses (18%) in the bendamustine group and 11 relapses (58%) in the R-CHOP group were reported. The median progression-free survival was 69.5 months for the bendamustine group and 28.1 months for the R-CHOP group (P = .003).

Ibrutinib, the first-in-class Bruton tyrosine kinase inhib-itor, was administered at a dose of 420 mg for two years to patients with one prior therapy. Median time to response was four weeks. The median IgM fell from 3610 to 1340, and the median hemoglobin rose from 10.5 to 12.6. Overall response rate was 61.9%, VGPR 11.1%, and the median duration of re-sponse has not been reached. Neutropenia was seen in 19%, thrombocytopenia in 14%; other significant side effects includ-ed diarrhea, bleeding, and atrial fibrillation.15 The rate of re-sponse to ibrutinib in patietns with Waldenström macroglobu-linemia was dependent on MYD88 status, with 95% of patients with mutated MYD88 responding to therapy and only 60% of wild type MYD88 responding to therapy. When both MYD88 and CXCR4 were unmutated, the response rate fell to 60% in patients with MYD88.15 When patients were wild type for CXCR4 and MYD88, there were no ibrutinib responses. A sec-ond trial of 31 patients who were rituximab refractory reported a response rate of 84%, with a PR of ≥65%. Adverse events occurred in 94% and two patients with wild type MYD88 pro-gressed on therapy.16 The agent is approved for any line of ther-apy in North America, Europe, and Japan. A recent report indicated a risk of atrial fibrillation of 10.7%.17

SummaryPatients with IgM MGUS or asymptomatic Waldenström mac-roglobulinemia without cytopenias may be safely observed. Patients with bulky disease, constitutional symptoms, hypervis-cosity, or evidence of bone marrow failure can be treated with bendamustine-rituximab, proteosome inhibitor/rituximab,dexa-methasone-rituximab-cyclophosphamide, rituximab-ibrutinib is currently being tested (NCT 02165397). Stem cell transplanta-tion remains an option for younger patients with Waldenström macroglobulinemia (Figure). For relapsed patients, repeating the original therapy if responses are longer than three years, is reasonable. Alternative therapies include purine nucleoside an-alogues, bortezomib, everolimus, carfilzomib, and ibrutinib. Ac-tive clinical trials are investigating various combinations, includ-ing rituximab-bendamustine-ibrutinib, rituximab-ibrutinib, and lenalidomide-ibrutinib, which will further improve the outcomes for these patients.

Address correspondence to: Morie A. Gertz, MD, MACP, Mayo Clinic, 200 First Street, SW, Division of Hematology, Siebens 670, Roland Seidler, Jr Professor and Chair, Department of Medicine, College of Medicine, Mayo Distinguished Clinician, Rochester, MN 55905. E-mail: [email protected]

REFERENCES1. Steingrimsson V, Lund SH, Turesson I, et al. Population-based study on the impact of the familial form of Waldenstrom macro-globulinemia on overall survival. Blood. 2015;125(13):2174-2175. doi 10.1182/blood-2015-01-622068.2. Wang H, Chen Y, Li F, et al. Temporal and geographic vari-ations of Waldenstrom macroglobulinemia incidence: a large population-based study. Cancer. 2012;118(15):3793-3800. doi 10.1002/cncr.26627.3. Castillo JJ, Olszewski AJ, Kanan S, Meid K, Hunter ZR, Treon SP. Overall survival and competing risks of death in patients with Waldenstrom macroglobulinaemia: an analysis of the Surveil-lance, Epidemiology and End Results database. Br J Haematol. 2015;169(1):81-89. doi 10.1111/bjh.13264.4. Jimenez C, Sebastian E, Chillon MC, et al. MYD88 L265P is a marker highly characteristic of, but not restricted to, Walden-strom’s macroglobulinemia. Leukemia. 2013;27(8):1722-1728. doi 10.1038/leu.2013.62.5. Leblond V, Johnson S, Chevret S, et al. Results of a random-ized trial of chlorambucil versus fludarabine for patients with untreated Waldenstrom macroglobulinemia, marginal zone lymphoma, or lymphoplasmacytic lymphoma. J Clin Oncol. 2013;31(3):301-307. doi 10.1200/JCO.2012.44.7920.6. Kastritis E, Gavriatopoulou M, Kyrtsonis MC, et al. Dexa-methasone, rituximab, and cyclophosphamide as primary treat-ment of Waldenstrom macroglobulinemia: final analysis of a phase 2 study. Blood. 2015;126(11):1392-1394. doi 10.1182/blood-2015-05-647420.7. Tedeschi A, Ricci F, Goldaniga MC, et al. Fludarabine, cy-clophosphamide, and rituximab in salvage therapy of Walden-strom’s macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2013;13(2):231-234. doi 10.1016/j.clml.2013.02.011.8. Laszlo D, Andreola G, Rigacci L, et al. Rituximab and sub-cutaneous 2-chloro-2’-deoxyadenosine combination treatment for patients with Waldenstrom macroglobulinemia: clinical and biologic results of a phase II multicenter study. J Clin Oncol. 2010;28(13):2233-2238. doi 10.1200/JCO.2009.23.6315.9. Herth I, Hensel M, Rieger M, et al. Pentostatin, cyclophos-phamide, and rituximab is a safe and effective treatment in pa-tients with Waldenstrom’s macroglobulinemia. Leuk Lymphoma. 2015;56(1):97-102. doi 10.3109/10428194.2014.911869.10. Dimopoulos MA, Garcia-Sanz R, Gavriatopoulou M, et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013;122(19):3276-3282. doi 10.1182/blood-2013-05-503862.11. Leblebjian H, Noonan K, Paba-Prada C, Treon SP, Castillo JJ, Ghobrial IM. Cyclophosphamide, bortezomib, and dexametha-sone combination in waldenstrom macroglobulinemia. Am J He-matol. 2015;90(6):E122-123. doi 10.1002/ajh.23985.

THERAPY OF WALDENSTRÖM’S


12. Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) treatment offers a neuropathy-spar-ing approach for treating Waldenstrom’s macroglobulinemia. Blood. 2014;124(4):503-510. doi 10.1182/blood-2014-03-566273.13. Ghobrial IM, Witzig TE, Gertz M, et al. Long-term results of the phase II trial of the oral mTOR inhibitor everolimus (RAD001) in relapsed or refractory Waldenstrom Macroglobulin-emia. Am J Hematol. 2014;89(3):237-242. doi 10.1002/ajh.23620.14. Kyriakou C, Canals C, Sibon D, et al. High-dose therapy and autologous stem-cell transplantation in Waldenstrom mac-roglobulinemia: the Lymphoma Working Party of the Europe-an Group for Blood and Marrow Transplantation. J Clin Oncol.

2010;28(13):2227-2232. doi 10.1200/JCO.2009.24.4905.15. Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenstrom’s Macroglobulinemia. N Engl J Med. 2015;373(6):584-586. doi 10.1056/NEJMc1506192.16. Dimopoulous MA, Trotman J, Tedeschi A, et al Ibrutinib therapy in Rituximab refractory Patients with Waldenstroms Macroglobulinemia: Initial results from an international mul-ticenter open lael phase 3 substudy (Innovate) Blood. 2015;126 (23) Abstract 2745.17. Gustine JN, Meid K, Dubeau TE, et al. Atrial fibrillation as-sociated with ibrutinib in Waldenstrom macroglobulinemia. Am J Hematol. 2016;91(6):E312-313. doi: 10.1002/ajh.24366.

CME


Dates of certification: May 31, 2016, to May 31, 2017Medium: Print with online posttest, evaluation, and request for credit

The American Journal of Hematology/Oncology® Editorial BoardDebu Tripathy, MDProfessor of Medicine and ChairDepartment of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHouston, TexasDisclosure: Grant/research support from Genentech/Roche, Pfizer, Puma Biotechnology Inc, and Novartis (clinical trial support contracted to the University of Southern California and MD Anderson Cancer Cen-ter); consultant for Eisai, OncoPlex Diagnostics, Merck, and Novartis.

FacultyBenjamin Levy, MDAssistant Professor, Icahn School of MedicineMedical Director, Thoracic Oncology Program, Mount Sinai Health SystemsAssociate Director, Cancer Clinical Trials Office, Mount Sinai HospitalMount Sinai HospitalNew York, NY Disclosure: Consultant: Celgene, AstraZeneca, Lilly, Genentech, Pfizer, Merck; Speaker’s Bureau: Lilly, Genentech.

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OverviewThis activity is designed to inform physicians about the recent ad-vances, as well as anticipated advances, in the field of lung cancer treatment.

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Lung cancer is the second most commonly diagnosed cancer and is the leading cause of cancer-related deaths in the United States. An estimated 224,390 new cases of lung cancer, which is about 14% of all cancer diagnoses, are expected to be diagnosed this year.1 The most common form of lung cancer is non–small cell lung cancer (NS-CLC), and a majority of patients present with a locally advanced or metastatic form of NSCLC at diagnosis. NSCLC is a heterogeneous group of tumors of variable histology, including adenocarcinoma, squamous cell carcinoma, and large-cell carcinoma.2

Treatment of lung cancer has modulated along with the state of cancer science for 2 decades. Recent advances in the field have led to the recognition that different histological subtypes and driv-er mutations determine the biology of these malignancies.2 We now recognize that somatic gene mutations or rearrangements in specific “driver genes” can lead to oncogenic transformation and tumor growth. This recognition stems from the discovery of acti-vating mutations in the epidermal growth factor receptor (EGFR) and rearrangements of the anaplastic large-cell lymphoma kinase (ALK) gene in some advanced NSCLC tumors.3 Following the rec-ognition that oncogenic driver mutations determine the biology of many NSCLC subtypes, the clinical paradigm has shifted to drug development toward targeted and personalized approaches. For instance, we now recognize that presence of EGFR-activating mu-tations in patients with NSCLC can serve as a clinical predictor of their sensitivity and efficacy to EGFR-directed therapy.4 Thus, EGFR mutations and ALK gene rearrangements are successfully be-ing targeted with specific tyrosine kinase inhibitors.5 Personalized treatment approaches with targeted therapies has led to significant improvements in patient outcomes.

While the estimated median overall survival (OS) for patients with advanced/metastatic NSCLC (stage IV) has been 10 to 12 months, in a recently published study, significant survival improve-ment with a median OS of >3 years has been reported for patients with an oncogenic driver undergoing targeted therapy.5 Moreover, data from several clinical trials comparing front-line EGFR tyrosine kinase inhibitor (TKI) treatment with standard platinum chemo-therapy in patients with EGFR-mutated NSCLC have shown that targeted treatment is more effective than standard chemotherapy in patients with these mutations.4

Currently, for EGFR mutations identified prior to frontline therapy, gefitinib, erlotinib, or afatinib monotherapy are Catego-ry 1 recommended EGFR targeted strategies.6 The first TKIs that showed treatment benefits in patients with EGFR mutations were gefitinib and erlotinib; these TKIs are referred to as first-genera-tion EFGR TKIs. Despite an overall response rate of close to 75%, patients eventually develop resistance to first-generation EGFR TKIs.7 About 50% of instances of acquired resistance seen in these patients are due to a secondary T790M mutation in exon 20 of the EGFR gene; however, several other mechanisms of resistance also exist.7 The second- and third-generation EGFR TKIs were de-

signed to provide better inhibition of EGFR and/or to overcome EGFR T790 M. With second-generation EGFR TKIs, afatinib binds irreversibly to the tyrosine kinase of EGFR and is approved as a first-line treatment of advanced NSCLC with activating EGFR mutations. Third-generation EGFR TKIs such as osimertinib are designed to target tumors harboring acquired EGFR T790 M.8,9 In patients with confirmed T790M mutations, treatment with osim-ertinib has shown durable responses10 and is approved for patients with metastatic EGFR T790M mutation–positive tumors.6 Anoth-er third-generation compound that is currently in clinical develop-ment is rociletinib. Similarly, in ALK-positive disease, ALK-targeted monotherapy remains a Category 1 recommended frontline ap-proach (ie, crizotinib followed by ceritinib or alectinib in patients progressing on crizotinib).6 Additionally, multiple new ALK inhib-itors are being developed currently, such as brigatinib (AP26113), entrectinib, and PF-06463922.11,12

Discovery of EGFR mutations and other clinically significant molecular aberrations in NSCLC has also been key to the devel-opment of diagnostic tests to check for these genomic alterations. Advances have also occurred in the diagnostic field to provide less invasive newer techniques such as liquid biopsy as an alternative to tissue-based testing, and for identifying and monitoring patients with these mutations.13 While liquid biopsy is not yet approved, research is ongoing in testing its utility in NSCLC patients. Some of the emerging approaches that use liquid biopsy for tumor geno-typing for NSCLC testing include analyzing techniques that utilize circulating tumor cells, cell-free deoxyribonucleic acid (cfDNA), and exosomes (exoRNA isolation).14 Recently published data vali-dated the utility of plasma genotyping of cfDNA for detection of EGFR and KRAS mutations with the high specificity in patients with advanced NSCLC. Additionally, cfDNA may also be useful in detection of EGFR T790M that may be missed by tissue genotyping due to tumor heterogeneity in resistant disease.15

Additionally, advances in the diagnostic field have also culminat-ed in the development of sophisticated genomic sequencing tech-nology, such as next-generation sequencing (NGS). Also referred to as “massively parallel sequencing,” NGS offers the benefits of high speed and a relatively low cost. Although NGS currently utilizes tumor tissue, it can work with small samples and has the ability to screen the mutational status of different samples such as biopsies, cytological samples, and circulating plasma DNA.16,17

While the use of molecular targeted therapies has improved median OS in a select set of patients with NSCLC whose tumors harbor specific genetic alterations, for a majority of patients with NSCLC, molecular alterations are not yet available to utilize target-ed therapies. Hence, different approaches have been undertaken to stimulate immune response, including therapeutic vaccines and immune checkpoint blockade therapies.18 Among these approach-es, immune checkpoint blockade with nivolumab (PD-1 inhibitor) or pembrolizumab (PD-L1) is currently approved for the treatment

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of advanced lung cancer.6 Additionally, several other checkpoint inhibitors, such as atezolizumab (MPDL3280A), MEDI4736, and ipilimumab are currently at different stages of clinical development for treatment of NSCLC, as well as small-cell lung cancer.19

This is an exciting time in the field of lung cancer treatment with several recent new therapies and several other promising approaches on the horizon, all intended to improve the outcomes of patients.

Benjamin Levy, MD, medical director of Thoracic Medical Oncology for Mount Sinai Health Systems and the associate medical director of the Cancer Clinical Trials Office (CCTO) for Mount Sinai Hospital in New York offered his insights on recent updates and his thoughts on what we might expect to see in the near future in the field of lung cancer treatment.

Moderator: Please summarize how we personalize care for lung can-cer now based on tissue and mutational subtype? Also, are there unmet clinical needs in the field?Dr Levy: We have truly witnessed a seismic paradigm shift in the treatment options for patients with NSCLC. Whereas 10 years ago we were only able to offer patients chemotherapy, we are now able to parse out lung cancer into molecular cohorts that allow for de-livery of genotype-driven therapies. Patients whose tumors harbor mutations such as EGFR mutations and ALK rearrangements are now receiving oral targeted therapies. Other less common, yet ac-tionable, mutations have also been identified, including BRAF, ROS, and RET rearrangements, and more recently, non-receptor tyrosine kinase (NRTK) rearrangements.

Targeted therapies are either approved or are being investigated in clinical trials for many of these genetic alterations. The rapid pace of drug discovery and our expanded knowledge of the genom-ic landscape of lung cancer tumors underscore the importance of next-generation sequencing for patients. Given the availability of existing targeted agents that can be either given as standard of care or are currently being investigated in clinical trials, all patients with NSCLC should have next-generation sequencing performed on their tissue specimens.

Moderator: What is the role of rebiopsy or liquid biopsies for iden-tifying actionable mutations in lung cancer?Dr Levy: Tissue rebiopsies and liquid biopsies (plasma genotyping) now play an integral role for patients who progress on targeted ther-apies. The utility of this approach has been most recently highlight-ed in EGFR-positive patients who have progressed on first- or sec-ond-generation TKIs. Up to two-thirds of these patients develop a secondary mutation in EGFR called T790M. Given the impressive responses and recent approval of a T790M–directed therapy/inhib-itor, osimertinib, it is paramount that these resistant alterations are identified upon progression in order to identify patients eligible for this therapy. This can be done by tissue procurement (rebiopsy) or, more recently, via a simple, minimally invasive blood assay. I foresee in the near future that liquid biopsies or rebiopsies may not just be

restricted to the EGFR-positive patient, as they have already begun to play a role in identifying other genetic cohorts. In addition, liq-uid biopsies may also be considered for treatment-naïve patients in whom there is insufficient material for molecular analysis. At our center, many of our treatment-naïve patients, as well those who have progressed on EGFR TKI therapy, are being considered for plasma genotyping.

Moderator: What do we need to better personalize immuno-therapies?Dr Levy: The emergence and approval of checkpoint inhibitors (PD-1 and PD-L1 agents) has altered the treatment paradigm for patients with advanced-stage lung cancer. These drugs have provid-ed meaningful improvements in survival when compared to sin-gle-agent docetaxel in platinum-refractory patients. Unfortunately, we have yet to define the proper molecular enrichment strategy. While PD-L1 by immunohistochemistry can select patients more likely to respond to these agents, this biomarker has limitations. For one, expression of PD-L1 is heterogeneous within a tumor and varies with the antibody that is utilized. In addition, there are many patients who are PD-L1-negative who still garner meaningful benefits from these drugs. Further refinement of PD-L1 testing is needed, and hopefully, initiatives such as the Blueprint proposal for companion diagnostic comparability will help optimize testing.

In addition, other biomarkers are being evaluated including the mutational load of a tumor as a potential predictor of response to PD-1/PD-L1 blockade. A better understanding of the relationship between certain known driver mutations (EGFR and KRAS) and the efficacy of these drugs is also beginning to unfold. Personaliza-tion of immunotherapeutic approaches will also need to include novel combination strategies with other immunotherapies and che-motherapy. We need to keep in mind that only 20% of patients re-spond to single-agent checkpoint inhibitors, and therefore, further strategies are needed to improve outcomes. One promising strategy currently being evaluated is the combination of hypomethylators and deacetalyters with PD-1 drugs in an effort to exploit epigenetic priming of a tumor to augment checkpoint inhibitor efficacy.

Moderator: What impact will the results from upcoming check-point inhibitor trials, such as CheckMate 227, MYSTIC, and NEPTUNE, have in the treatment of NSCLC?Dr Levy: Now that single-agent checkpoint inhibitors have been cemented as standard-of-care for advanced stage, platinum-refrac-tory patients (second-line), one of the next research initiatives is to understand their efficacy in the treatment-naïve (first-line) setting. CheckMate 227, MYSTIC, and NEPTUNE are each evaluating the optimal strategy of immunotherapies as first-line treatment ei-ther as single-agent or in combination with either chemotherapy or CTLA-4 antibodies. It will be interesting to see if these drugs provide meaningful benefit in survival by moving to the first-line setting and whether any molecular enrichment strategy can be uti-



lized to better predict the efficacy of each strategy. My guess is that there may be a role for these agents in treatment-naïve patients with an optimal enrichment strategy, but I remain skeptical on whether adding these drugs to chemotherapy without selection of the right patients will provide meaningful improvements.

Moderator: What changes in the field of lung cancer can be ex-pected from the PembroPlus that combines pembrolizumab with chemotherapy for treatment of advanced lung cancer?Dr Levy: PembroPlus is a large phase I/II trial evaluating pem-brolizumab in combination with chemotherapy in multiple solid tumors including small cell lung cancer (SCLC). Similar to the first-line studies (NEPTUNE, CheckMate 227), this trial is trying to understand safety, but more importantly, efficacy, by combining pembrolizumab, a PD-1 Ab, with single-agent chemotherapy. Exten-sive-stage SCLC is a disease with many unmet needs and very little improvement in survival over the past 10 years. There is reasonable scientific rationale to exploit these drugs in SCLC, and the hope is that there will be synergy witnessed by combining pembrolizumab with irinotecan in platinum-refractory SCLC.

Moderator: Do you envision vaccines such as CimaVax becoming a promising option for patients with NSCLC in the future? Why or why not?Dr Levy: It remains unclear if CimaVax will make an impact in pa-tients with NSCLC. CimaVax works a little differently than check-point inhibitors in that it is a vaccine against epidermal growth factor, a protein that plays an integral role in cancer cell signaling and survival. The drug was developed in Cuba and has been ad-ministered to over 5000 patients worldwide. Results from a 2008 Journal of Clinical Oncology manuscript did demonstrate a compet-itive survival in stage IIIB/IV patients under the age of 60 who received this agent as a switch maintenance strategy after platinum chemotherapy versus best supportive care. Despite this, there was no difference in survival in the overall intent-to-treat population. It is important to note that further studies are needed before this drug can be viewed as a real therapeutic option in patients, and this will take time. My understanding is that there is currently a partnership between Roswell Park and the Center for Molecular Immunology in Havana that will hopefully expedite its clinical development in the US.

Moderator: What potential do third-generation EGFR TKIs have of being utilized as frontline therapy? What emerging data do we have supporting that concept, and is this strategy being evaluated in a subset of patients with T790M or all patients with lung cancer?Dr Levy: Now that third-generation EGFR TKIs have been ap-proved for EGFR-positive patients who develop resistance to first- or second-generation TKIs who harbor T790M, the next research initiative has been to exploit their efficacy in treatment-naïve, EG-FR-positive patients. The early data on this strategy looks prom-

ising, with recent reports demonstrating a response rate of 77% and progression-free survival (PFS) of 19.3 months with osimerti-nib. This is one of the most competitive outcomes that we have witnessed with any first-line agent in these patients. Given that first-generation TKIs generally yield a PFS of 12 to 13 months, the results of first-line T790M-directed therapies should not be over-looked. If these data hold up in ongoing phase III trials, this may lead to drug approval in the first-line setting and a shift in the stan-dard of care for these patients.

Moderator: Does CAR-T cell therapy have a role in the treatment of lung cancer? Could this be combined with other immunothera-peutic approaches? Why or why not?Dr Levy: CAR-T cell therapy is an innovative approach for the treatment of multiple malignancies. The strategy, termed “adoptive T-cell transfer,” works by isolating T cells from patients, genetically modifying them, and then reintroducing them in an effort to better augment T-cell responses against cancer antigens. This technology is beginning to take shape in many liquid tumors, including lymphoma and leukemia. Recent preclinical data suggest that CAR-T cell thera-py could be successful at targeting Erb2, a protein that is expressed in both breast and lung cancer. However, preliminary data utilizing this strategy in solid tumor patients have not been as successful as that witnessed in liquid tumors. With further refinement of this strategy, there may be a day when CAR-T cell therapy could be effective in NSCLC patients. However, there is still a lot of work that needs to be done in the clinical space, and we need to gain a better under-standing of how best to exploit this strategy (which proteins to target, combination strategies) before it’s ready for prime time.

Moderator: Based on recent developments, how do you envision the treatment of NSCLC evolving in the coming few years?Dr Levy: I hope to see a day in the near future when we are no longer routinely using chemotherapy to treat our patients with both early- and late-stage disease. This will require further study into potential actionable mutations that could be wedded to targeted therapies, as well as better refinement and optimization of immu-notherapy approaches. I also envision a time when liquid biopsies may circumvent the need for tissue biospies in both treatment-naïve and refractory patients. We are certainly not there yet, but as liquid platforms become more accurate, they may be able to serve as a reliable molecular proxy of disease and allow treatment decisions to be made in lieu of tissue procurement.

REFERENCES1. American Cancer Society. Cancer facts and figures 2016. ACS website. http://www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed April 7, 2016.2. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF. Manage-ment of non-small-cell lung cancer: recent developments. Lancet.

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2013;382(9893):709-719. doi: 10.1016/S0140-6736(13)61502-0.3. Sweis RF, Thomas S, Bank B, Fishkin P, Mooney C, Salgia R. Concurrent EGFR mutation and ALK translocation in non-small cell lung cancer. Cureus. 2016; 8(2): e513. doi: 10.7759/cureus.513.4. Rolfo C, Passiglia F, Ostrowski M, et al. Improvement in lung cancer outcomes with targeted therapies: an update for family phy-sicians. J Am Board Fam Med. 2015 ;28(1):124-133. doi: 10.3122/jabfm.2015.01.140072.5. Rothschild SI. Targeted therapies in non-small cell lung can-cer-beyond EGFR and ALK. Cancers (Basel). 2015;7(2):930-949. doi: 10.3390/cancers7020816.6. NCCN Guidelines. Non-small cell lung cancer. Version 4.2016. National Comprehensive Cancer Network website. http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed Jan-uary 31, 2016.7. Stewart EL, Tan SZ, Liu G, Tsao MS. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations-a review. Transl Lung Cancer Res. 2015;4(1):67-81. doi: 10.3978/j.issn.2218-6751.2014.11.06.8. Liao BC, Lin CC, Yang JC. Second and third-generation epider-mal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Curr Opin Oncol. 2015;27(2):94-101. doi: 10.1097/CCO.0000000000000164.9. Van Assche K, Ferdinande L, Lievens Y, Vandecasteele K, Sur-mont V. EGFR mutation positive stage IV non-small-cell lung can-cer: treatment beyond progression. Front Oncol. 2014;4:350. doi: 10.3389/fonc.2014.00350.10. Yang JC, KimD, Planchard D, et al. Updated safety and efficacy from a phase I study of AZD9291 in patients with EGFR- TKI resis-tant non-small cell lung cancer. Ann Oncol. 2014;25(4s):iv146-iv164. doi: 10.1093/annonc/mdu331.9.11. Zou HY, Li Q, Engstrom LD, et al. PF-06463922 is a potent and

selective next-generation ROS1/ALK inhibitor capable of block-ing crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci U S A. 2015;112(11):3493-3498. doi: 10.1073/pnas.1420785112.12. Patel MR, Bauer TM, Liu SV, et al. STARTRK1: Phase 1/2a study of entrectinib, an oral PanTrk, ROS1, and ALK inhibitor, in patients with advanced solid tumors with relevant molecular alter-ations. J Clin Oncol. 2015;33(suppl; abstr 2596).13. Brinkmann K, Emenegger J, Tannous B. Exosomal RNA-based liquid biopsy detection of EML4-ALK in plasma from NSCLC pa-tients. Poster presented at: 2015 16th World Conference on Lung Cancer; September 6-9, 2015; Denver, CO. Poster 2591.14. Li Y, Bahassi EM. Biofluid-based circulating tumor molecules as diagnostic tools for use in personalized medicine. J Mol Biomark Diagn. 2013;5:157. doi:10.4172/2155-9929.1000157.15. Sacher AG, Paweletz C, Dahlberg SE, et al. Prospective valida-tion of rapid plasma genotyping for the detection of EGFR and KRAS mutations in advanced lung cancer. JAMA Oncol. 2016 Apr 7. [Epub ahead of print] doi: 10.1001/jamaoncol.2016.0173.16. Ogunleye F, Ibrahim M, Stender M, et al. Epidermal growth factor receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer - A paradigm shift in stage IV non-small cell lung cancer treatment. Am J Hematol Oncol. 2015;11(1):16-25.17. Coco S, Truini A, Vanni I, et al. Next generation sequencing in non-small cell lung cancer: new avenues toward the personalized medicine. Curr Drug Targets. 2015;16(1):47-59.18. Massarelli E, Papadimitrakopoulou V, Welsh J, Tang C, Tsao AS. Immunotherapy in lung cancer. Transl Lung Cancer Res. 2014;3(1): 53-63. doi: 10.3978/j.issn.2218-6751.2014.01.01.19. Stevens A, Fisher SA, Robinson BW. Immunotherapy for lung cancer. Respirology. 2016;1-13. doi: 10.1111/resp.12789.m

The rapid pace of discovery in the field of oncology presents practicing oncologists with the difficult challenge of implementing novel research findings into clinical practice. To accelerate the translation of academic advances to community-based practice, The American Journal of Hematology/Oncology® aims to provide practical interpretations of the latest advances in medical and hematologic oncology and to help practicing oncologists gain a better understanding of how these advances are changing the treatment landscape for both solid and hematologic malignancies. The editors are pleased to consider manuscripts on a wide range of topics related to the journal’s mission. Articles of interest include:• Original research• Reviews

- State-of-the Art Updates- On the Horizon- Emerging Guidelines

• Editorials and perspectives- Clinical Controversies - Looking Forward- Brief Reports- Pivotal Trials- New Technologies- Meeting Updates - Case Reports- Survivorship Issues- Team Approaches (Allied Health/Care Extenders)

- Pharmacology Updates- Oncology Practice Issues

Detailed descriptions of each category can be found in the Instructions for Authors at www.ajho.com

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BREAST CANCERAccelerated Partial-Breast Irradiation: Outcomes and Future PerspectivesChirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

TREATMENT-RELATED DIARRHEAEffective Management and Prevention of Neratinib-Induced DiarrheaFederico Ustaris, MD, Cristina Saura, MD, Jack Di Palma, MD, Richard Bryce, MBChB, MRCGP, MFPM, Susan Moran, MD, Linda Neuman, MD, and Rolando Ruiz, MD

DUCTAL CARCINOMADuctal Carcinoma In Situ: Review of the Role of Radiation Therapy and Current ControversiesFrank Vicini, MD, FACR, and Chirag Shah, MD

HEAD AND NECK CANCERMoving Forward in the Management of Squamous Cell Carcinoma of the Head and Neck: Promising Immuno-Oncology ApproachesBarbara Burtness, MD

A m e r i c a n

J o u r n a l

H e m a t o l o g y /

O n c o l o g y ®

A Peer-Reviewed Resource

for Oncology Education

ajho

www.AJHO.com ISSN 1939-6163 (print) ISSN 2334-0274 (online)

Volume 11 Number 11 11.15

TRIPLE-NEGATIVE BREAST CANCER CME-certified enduring materials sponsored by Physicians’ Education Resource®, LLC

Evolving Management Strategies for Triple-Negative Breast Cancer

All manuscripts will undergo peer review, and authors of accepted articles will receive an honorarium and will be required to sign an authorship form disclosing any possible conflicts of interest. To submit an article to The American Journal of Hematology/Oncology® or if you wish to speak to an editor, please e-mail Howard Whitman at [email protected]

Call for Papers

· BREAST CANCER ·

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NOVEMBER 2015

Accelerated Partial-Breast Irradiation:

Outcomes and Future Perspectives

Chirag Shah, MD, Vivek Verma, MD, Michael A. Weller, MD, Eric Westerbeck, BS, Kyle Reilly, BS, and Frank Vicini, MD, FACR

Introduction

Breast-conserving therapy (BCT) represents one of the most sig-

nificant advances in breast cancer treatment over the past sev-

eral decades. With more than 20 years of follow-up, BCT has

been shown to have equivalent rates of local control and overall

survival (OS) compared with mastectomy, with improvements in

patient quality of life.1-5 Randomized trials comparing BCT and

mastectomy have consistently utilized whole-breast irradiation

(WBI) with or without a tumor bed boost. Whole-breast irradia-

tion typically requires 5 to 6 1/2 weeks of adjuvant radiotherapy

(RT) for its completion. This lengthy duration of therapy is one

factor responsible for many women failing to undergo adjuvant

RT following breast-conserving surgery (BCS), despite the im-

provement in breast cancer mortality associated with RT.4,6

Over the past 2 decades, alternatives to standard WBI have

emerged, including hypofractionated WBI (15–16 fractions) and

accelerated partial-breast irradiation (APBI). Accelerated par-

tial-breast irradiation is a technique that treats only the lumpec-

tomy cavity plus a small area surrounding the surgical bed (mar-

gin of tissue), rather than the whole breast. This concept is based

upon patterns of failure data demonstrating that the majority of

ipsilateral breast failures occur in close proximity to the lumpec-

tomy cavity.7,8 The purpose of this review is to examine the data

supporting the utilization of APBI, as well as clinical guidelines

and future directions to help clinicians decide on appropriate

adjuvant RT techniques for their patients with early stage breast

cancer.

Results of Clinical Trials

Clinical Outcomes

The earliest technique utilized to deliver APBI was interstitial

brachytherapy (IB). This was initially used as either a boost fol-

lowing WBI or as the sole radiation modality; consequently, it

represents the technique with the most mature data. A random-

ized study of 258 women from Hungary compared WBI with

APBI delivered with either IB or electrons. At 10 years of fol-

low-up, no difference in clinical outcomes, including local re-

currence (5.1% vs 5.9%), was noted. Improvement in cosmetic

outcomes compared with WBI was seen for those women treated

with IB (81% vs 63%).9 These findings were consistent with a

prospective study of 45 patients from the same institution: 12-

year outcomes demonstrated a 9% rate of local recurrence, 78%

excellent/good cosmesis, and low rates of toxicity, including a

2% rate of grade 3 fibrosis.10

A large, multi-institutional phase 3, noninferiority random-

ized trial compared IB-based APBI to WBI, randomizing 1184

patients with low-risk, early stage breast cancer and was recent-

ly published. With a median follow-up of 6.6 years, there was

no difference in the 5-year rates of local recurrence (1.44% with

APB–I vs 0.92% with WBI; P = 0.42) and no difference in the

rates of regional recurrences, distant metastases, disease-free sur-

vival, breast cancer mortality, or OS was noted. With respect

to toxicity, WBI was associated with increased grade 2–3 breast

Abstract

Accelerated partial-breast irradiation (APBI) is an adjuvant

radiotherapy technique that allows for the completion of

radiation therapy (RT) in 1 week or less for women under-

going breast conservation. Traditionally delivered using

interstitial brachytherapy, APBI can also be performed

using newer techniques that include applicator-based

brachytherapy and external-beam techniques (3D-con-

formal RT, intensity-modulated RT). Long-term outcomes

with APBI encompass data from randomized trials, pro-

spective data, and single-institution series, which have

highlighted the efficacy as well as comparable recurrence

risks compared with whole-breast irradiation (WBI). Pro-

spective randomized comparisons of APBI with WBI have

demonstrated similar rates of tumor control, although

toxicity results vary based on the technique used with the

potential for improved toxicity with brachytherapy based

techniques. Moving forward, studies are under way to

evaluate shorter courses of APBI, with evidence-based

guidelines evolving to the increasing literature support-

ing the technique.

Key Words: breast cancer, radiation therapy, breast-con-

serving therapy, accelerated partial-breast irradiation,

brachytherapy

· BREAST CANCER ·

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NOVEMBER 2015

TABLE. Key Accelerated Partial-Breast Irradiation StudiesStudy Type Patients

(n)Median Follow-Up (months)

Technique Local Recurrence

ToxicityInterstitialNational Institute of Oncology, Hungary

Randomized 258 122 HDR (n=88)/ electrons (n=40)

10-year LR (5.1% WBI vs. 5.9% PBI, NS)

Improved excellent/good cosmesis with partial breast 81% vs 63%

GEC-ESTRO Randomized 1184 78 HDR/PDR 5 year LR (0.9% WBI vs. 1.4% APBI, NS)

Reduced breast pain and trend for reduced grade 2-3 late skin toxicity with APBI

RTOG 9517 Prospective 99 73 HDR (n=66)/ LDR (n=33)

5-year LR 3%/6% (HDR/LDR)13% grade 3 skin toxicity, 37% skin dimpling, 45% fibrosis, 45% telangiectasias, 15% symptomatic fat necrosis, 66% excellent/good cosmesis

Harvard University Prospective 50 134 LDR (dose-escalation)

12-year LR 15% 67% excellent/good cosmesis, 35% fat necrosis, 34% telangiectasias, 22% grade 3/4 skin toxicity

William Beaumont HospitalMatched-Pair Analysis

199 127 HDR 12-year LR (3.8% WBI vs 5% APBI, NS), no difference in RR, DFS, CSS, OS

ApplicatorMammoSite Initial Trial Prospective 70 (43

treated)65 (n=36) Single-Lumen 5-year LR 0% 9.3% infection, 33% seroma, 12% symptomatic seroma, 4 patients with fat necrosis, 83% excellent/good cosmesis

MammoSite Registry

Prospective 1449 63 Single-Lumen 5-year LR 3.8% (3.7% invasive, 4.1% DCIS)

91% excellent/good cosmesis, 9.6% infection, symptomatic seroma 13%, 13% telangiectasias, 2.5% fat necrosis

External BeamNSABP B-39/RTOG 0413; 2011

Randomized 1367 37 3D-CRT3% Grade 3+ fibrosis

RAPIDRandomized 2135 36 3D-CRT

Increased adverse cosmesis with APBI, Grade 3 toxicity 1.4%, increased grade 1/2 toxicity with APBI

University of Florence

Randomized 520 60 IMRT 5-year IBTR 1.5%, no difference with WBI

Reduced acute and chronic toxicity with APBI, improved cosmetic outcome with APBI

RTOG 0319 Prospective 52 63 3D-CRT 4-year LR 6% 64% excellent/good cosmesis at 3 years, 5.8% grade 3 toxicity

William Beaumont HospitalRetrospective 192 56 3D-CRT 5-year LR 0% 81% excellent/good cosmesis, 7.5% grade 3 fibrosis, 7.6% telangiectasias

Tufts University Retrospective 60 15 3D-CRT8% grade 3/4 fibrosis, 82% excellent/good cosmesis

University of Michigan

Prospective 34 60 3D-CRT 5-yr LR 3% 73% excellent/good cosmesis, 0% grade 3 fibrosisAPBI=accelerated partial-breast irradiation; CRT= conformal radiotherapy; CSS=cancer-specific survival; DCIS=ductal carcinoma in situ;

DFS=disease-free survival; HDR=high dose rate; IBTR= ipsilateral breast tumor recurrence; IMRT=intensity-modulated radiotherapy;

LDR=low dose rate; LR=local recurrence; NS=nonsignificant; OS=overall survival; PBI=partial-breast irradiation; RR=regional recurrence;

3D-CRT=3-dimensional conformal radiotherapy; WBI=whole-breast irradiation.

AJHO_CallForPapers_12'15.indd 5 12/9/15 10:14 AM

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