Download - Adjuvant Treatment in Breast Cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Treatment in Adjuvant Treatment in Breast CancerBreast Cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Variables for PrognosisVariables for Prognosisof Early Breast Cancer and for of Early Breast Cancer and for
Adjuvant TreatmentAdjuvant Treatment
1. Axillary Lymph Node Status
2. Estrogen Receptor
3. Her-2/neu Status
4. Treatment
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* Neoadjuvant Treatment * Adjuvant Treatment * Palliative Treatment
Treatment Treatment Modalities for Breast CancerModalities for Breast Cancer
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Variables for Decision Variables for Decision of Adjuvant Therapy of Adjuvant Therapy
Adjuvant Adjuvant TherapyTherapy
Node-Negative / -PositiveNode-Negative / -Positive
ER-Positive / -NegativeER-Positive / -Negative
HER-2 as Predictive MarkerHER-2 as Predictive Marker
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Therapy of Adjuvant Therapy of Early Breast CancerEarly Breast Cancer
A. Endocrine InterventionsOvarian AblationTamoxifenAromatase Inhibitors
B. Polychemotherapy
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effects of Adjuvant Therapy Effects of Adjuvant Therapy for Early Breast Cancer: 1990 - .for Early Breast Cancer: 1990 - .
Treatment Effectivity
A. Endocrine InterventionsOvarian Ablation 10% Absolute Gain in 15 yr.-Survival
Tamoxifen 8% Absolute Gain in 15 yr.-Survival 50% Reduction in Contralateral cancer
Small Risk of Endometrial Cancer, DVT
Aromatase Inhibitors First Data (47 Months Follow-Up)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
A. ENDOCRINE TREATMENT
1. Role of hormone withdrawal in premenopausal patients.
2. Role of third generation aromatase inhibitors in postmenopausal patients.
Adjuvant Therapy in Patients with Adjuvant Therapy in Patients with Breast Cancer: Breast Cancer:
Unresolved Questions 2003.Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
The Estrogen Receptor in The Estrogen Receptor in Breast CancerBreast Cancer
1. Localised within the Tumour Cell.
2. Interaction with Estrogen Results in Signal Transduction and Tumour Cell Proliferation.
3. Blockade Results in Cancer Cell Death.
Consequence No. 1: Competitive Inhibition of Estrogen.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Reduction of Relapses and Mortality Reduction of Relapses and Mortality from Early Breast Cancer by 20 mg from Early Breast Cancer by 20 mg
Tamoxifen for 5 Years. *Tamoxifen for 5 Years. *
Relapse Mortality 2p
42 3% 22 4% <.00001/.00001
* EBCTCG, LANCET 351: 1451, 1998
Reduction of
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Estrogen Withdrawal Modalities
1. Premenopausal PatientsLH-RH Agonists+ Tamoxifen(+ Aromatase Inhibitors?)
2. Postmenopausal PatientsAromatase Inhibitors
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I Premenopausal Patients with Stage I
and II EBC: The ABCSG Trial. *and II EBC: The ABCSG Trial. *
1.034 Premenopausal PatientsHormone-Responsive DiseaseTreatment:
3 yrs. Goserelin plus 5 yrs. Tamoxifenvs.
6 Cycles of CMF
Analysis at 60-month Median Follow-Up
* R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I Premenopausal Patients with Stage I
and II EBC: The ABCSG Trial. *and II EBC: The ABCSG Trial. *
Treatment Relapses Local Recurrences RFS at 5 yrs.
Endocrine 17.2% 4.7% 81%
Cytotoxic 20.8% 8.0% 76%
p 0.0176 0.0029 0.037
* R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage I Premenopausal Patients with Stage I
and II EBC: The ABCSG Trial. *and II EBC: The ABCSG Trial. *
CONCLUSION
„The Goserelin-Tamoxifen Combination is Significantly More Effective than CMF in
Premenopausal Patients with Stage I and II ER-Positive EBC.“
* R. Jakesz et al., J. Clin. Oncol. 20: 4621-4627, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II Premenopausal Patients with Stage II
EBC: The ZEBRA Trial. *EBC: The ZEBRA Trial. *
Study Design
1640 Randomized Patients
Goserelin for 2 Years (n=817)vs.
6x CMF (n=823)
ER-Positive and ER-Negative PatientsMedian Follow-Up: 6 Years.
* W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage Premenopausal Patients with Stage
II EBC: The ZEBRA Trial. *II EBC: The ZEBRA Trial. *
Primary Efficacy of Goserelin vs. CMF
DFS OS
ER-positive p=0.94 (equal efficacy) p=0.92 (equal efficacy)
ER-negative p=0.0006 in favor of CMF p=0043 in favor of CMF
ER-unknown p=0.026 in favor of CMF p=0.14
* W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Premenopausal Patients with Stage II Premenopausal Patients with Stage II
EBC: The ZEBRA Trial. *EBC: The ZEBRA Trial. *
CONCLUSION
„Equal Efficacy of Goserelin Given for 2 Years and 6 Cycles of CMF in
Patients with ER-Positive Stage II Breast Cancer.“
* W. Jonat et al., J. Clin. Oncol. 20: 4628-4635, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Postmenopausal Patients with EBC: Postmenopausal Patients with EBC:
Design of the ATAC Trial* .Design of the ATAC Trial* .
Anastrozole (n=3125) vs.Tamoxifen (n=3116) vs.Anastrozole + Tamoxifen (n=3125)
Median follow-up: 47 months for DFS
* Arimidex, Tamoxifen, Alone or in Combination; A. Buzdar SABCC 2002, Abstr. #13
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Estrogen Withdrawal in Effectivity of Estrogen Withdrawal in Postmenopausal Patients with EBC: Postmenopausal Patients with EBC:
Results of the ATAC Trial*.Results of the ATAC Trial*.
Significance Anastrozole vs. Tamoxifen in ER+ Patients
DFS Estimates at 4 Years 89% vs. 86.1%Disease-free Survival 0.014Time to Recurrence 0.007Contralateral Breast Cancer 0.042
NB: Results of Anastrozole + Tamoxifen equal to Tamoxifen alone!
* Arimidex, Tamoxifen, Alone or in Combination; A. Buzdar SABCC 2002, Abstr. #13
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Side Effects of Anastrozole vs. Side Effects of Anastrozole vs. Tamoxifen in the ATAC Trial*.Tamoxifen in the ATAC Trial*.
Hot Flushes p<0.0001 in favor of AnastrozoleVaginal Bleeding and Discharge p<0.0001 in favor of AnastrozoleThromboembolic Events p=0.0006 in favor of AnastrozoleIschemic Cerebrovascular Event p=0.0006 in favor of AnastrozoleEndometrial Cancer p=0.02 in favor of Anastrozole
Osteoporotic Bone Fractures p<0.0001 in favor of TamoxifenMusculoskeletal Disorders p<0.0001 in favor of Tamoxifen
* The ATAC Trialists´ Group: Lancet 359: 2131-2139, 2002
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Endocrine Adjuvant Treatment of Endocrine Adjuvant Treatment of
Early Breast Cancer in Early Breast Cancer in Premenopausal Patients.Premenopausal Patients.
Nodal Status ER+ ER-
N0 Goserelin +/- TamoxifenChemotherapy
N1 Chemotherapy TamoxifenChemotherapy
(Goserelin + Tamoxifen)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Endocrine Adjuvant Treatment of Endocrine Adjuvant Treatment of Early Breast Cancer in Early Breast Cancer in
Postmenopausal Patients.Postmenopausal Patients.
Nodal Status ER+ ER-
N0 Tamoxifen Chemotherapy(Aromatase Inhibitor)
N1 Tamoxifen Chemotherapy+/- Chemotherapy(Aromatase Inhibitor)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Chemotherapy in Adjuvant Chemotherapy in Early Breast Cancer. *Early Breast Cancer. *
RELAPSE -23.5 2.1% <.00001 DEATH -15.3 2.4% <.00001
* EBCTCG, LANCET 352: 930, 1998.
REDUCTION OF ANNUAL RISK OF RELAPSE AND DEATH BY
CHEMOTHERAPY
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Early Breast Cancer Trialists Collaborative Early Breast Cancer Trialists Collaborative Group: Effect of Adjuvant Anthracycline-Group: Effect of Adjuvant Anthracycline-
Based Chemotherapy: Reduction of Annual Based Chemotherapy: Reduction of Annual Hazards. *Hazards. *
% of Reduction 2p
Anthracycline-Based Chemotherapy vs. CMF
Recurrences 12 4 <.006 Mortality 11 5 <.02
* EBCTCG, Lancet 352: 930, 1998.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Polychemotherapy for Early Breast Cancer: 1990 - .
Premenopausal Patients:
5-12% Absolute Gain in 10 yr.-Survival
Postmenopausal Patients:
2-4% Absolute Gain in 10 yr.-Survival
NIH 2000 Consensus Conference
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Anthracyclines in Anthracyclines in Adjuvant Therapy for Early Adjuvant Therapy for Early
Breast Cancer.Breast Cancer.
5 Years 10 Years
Additional Absolute Gain 1.7% 4%in OS with Anthracycline in N- Pats. in N+ Pats.-Based Chemotherapy
NIH 2000 Consensus Conference
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
% F
ree
of
Rec
urr
ence
Years
Simulation of Impact of Adjuvant Simulation of Impact of Adjuvant Chemotherapy in EBC.Chemotherapy in EBC.
Annual Odds of Recurrence:
Nil = 15% / Yr.
CMF = 11.4% / Yr. (Reduced by 24%)
AC = 10% / Yr. (Reduced by 12%)
0
20
40
60
80
100
0 2 4 6 8 10
AC
CMF
Nil
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
B. CHEMOTHERAPY
1. Role of Anthracyclines. 2. Role of Taxanes. 3. Dose density.
4. Combination with Endocrine Treatment.
Adjuvant Therapy in Patients Adjuvant Therapy in Patients with Breast Cancer: Unresolved with Breast Cancer: Unresolved
Questions 2003.Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
1. When is an Anthracycline-Based Regimen Preferable to CMF?2. Which Anthracycline Should be Used?3. Which Regimen? 2- or 3-Drug-Regimen? Dose? Schedule?4. How Many Cycles? 4 or 6?
Anthracyclines in the Adjuvant Anthracyclines in the Adjuvant Therapy of Patients with Breast Therapy of Patients with Breast
Cancer: Unresolved Questions 2003.Cancer: Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Review of Anthracyclines in the Adjuvant Review of Anthracyclines in the Adjuvant Chemotherapy of Breast Cancer: The Chemotherapy of Breast Cancer: The
Dilemma.Dilemma.
Authors Cytotoxics Results
Fisher et al. 1989 (B-11) PF(T) vs. PAF(T) Sign. OS&DFS for PAF vs. PF Fisher et al. 1990 (B-15) CMF (6Mo.) vs. AC (2Mo.) n.s.Moliterini et al. 1991 CMF vs. CMF->A n.s. for DFS & OSBudd et al. 1995 CMFVP vs. FAC-M Sign. DFS for CMFVPMisset et al. 1996 CMF vs. AVCF Sign. OS & DFS PremenopauseCoombes et al. 1996 CMF vs. FEC Sign. OS & DFS PremenopauseLevine et al. 1998 CMF vs. CEF Sig. OS & DFS PremenopauseMouridsen et al. 1999 CMF vs. CEF Sign. OS PremenopausePiccart et al. 2001 CMF vs. EC No Advantage of EC vs. CMF
Reconfirmation of Dose Response
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Anthracycline-Effectivity of Anthracycline-
Based Adjuvant Chemotherapy Based Adjuvant Chemotherapy in Breast Cancer.in Breast Cancer.
Effectivity Analysed in Premenopausal Patients Only Misset et al. 1996 Levine et al. 1998 Mouridsen et al. 1999
No Advantage for Postmenopausal Patients Misset et al. 1996 Piccart et al. 2001 (41-44% Postmenopausal Patients Included)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Chemotherapy of Adjuvant Chemotherapy of Primary Breast Cancer: Primary Breast Cancer: Some general remarks...Some general remarks...
• Adriamycin Doses < 40mg/m2 are Inferior to 60 mg/m2 (CALGB 8541).
• Cyclophosphamide Doses > 600 mg/m2 are not Superior (NSABP
B-22).
• Chemotherapy Seems More Effective in ER- Than ER+ Disease (EBCTCG).
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
DRUG PUBLICATION RECOMMENDATION
Adriamycin CALGB 9344 60mg/m2 q. 3 wks. in the AC Regimen
Epirubicin French Trial 100mg/m2 q. 3 wks. in the EC and Belgian Trial FEC
regimens for high risk (N+) women
Adjuvant Therapy with Anthracyclines in Adjuvant Therapy with Anthracyclines in Patients with Breast Cancer: Patients with Breast Cancer:
Dose Recommendations.Dose Recommendations.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Efficacy of Anthracycline-Based Efficacy of Anthracycline-Based Adjuvant Chemotherapy in Her-2/neu Adjuvant Chemotherapy in Her-2/neu Overexpressing Early Breast Cancer.Overexpressing Early Breast Cancer.
STUDY AUTHOR RESULTS IN HER-2/neu POSITIVE NEGATIVE
NSABP-B11 PAIK et al. 1998 DFS & OS SIGN. n.s.(PF vs. PAF) (Advantage Anthracycline)
NSABP-B15 PAIK et al. 2000 DFS & OS BORDERLINE n. s.(AC vs. CMF vs. AC->CMF) (Advantage Anthracycline)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
ENDOCRINE RESPONSIVE ENDOCRINE-NON-RESPONSIVE Likelihood of Response Risk Profile Low High Average High
FE(A)C d1 x6 AC x4 FE(A)C d1 x6CE(A)F d1+8 x6 CE(A)F d1+8 x6
Proposed Algorithm for Anthracycline Proposed Algorithm for Anthracycline Use as Adjuvant Therapy in Patients Use as Adjuvant Therapy in Patients
with Breast Cancer.with Breast Cancer.
? Her-2/neu +++
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
The use of anthracyclines increases DFS and OS, probably even more so in selected patient populations (premenopause, Her-2/neu overexpression, etc.), and is superior to CMF.
The routine use of anthracycline-based regimens is recommended in appropriate patient populations, optimal schedule and frequency of administration, however, are not clear at the moment.
Adjuvant Therapy with Adjuvant Therapy with Anthracyclines in Patients with Anthracyclines in Patients with
Breast Cancer: Conclusions.Breast Cancer: Conclusions.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Role of Taxanes
Available Studies:CALGB 9344NSABP-B27NSABP-B28BCIRG 001M.D. ANDERSON
Adjuvant Therapy in Patients Adjuvant Therapy in Patients with Breast Cancer: Unresolved with Breast Cancer: Unresolved
Questions 2003.Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
1. AC most active adjuvant chemotherapy.
2. Paclitaxel achieves responses in stage IV breast cancer in 52-59% of patients (22-30% in anthraycyline resistant patients)
3. Sequential chemotherapy is reasonable.
Role of PACLITAXEL in Adjuvant Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Chemotherapy of Patients with
Lymphnode-Positive Breast Cancer Lymphnode-Positive Breast Cancer (CALGB 9344): RATIONALE. *(CALGB 9344): RATIONALE. *
* I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Paclitaxel-induced Apopotosis is Paclitaxel-induced Apopotosis is Independent from p53 Mutation Independent from p53 Mutation
Status. *Status. *
Paclitaxel-induced Apoptosis is
Dependent on ERK p38 MAP Kinase Cascades
Independent from p53
* BACUS et al., Oncogene 20: 147, 2001
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
THERAPY
Doxorubicin 60, 75 or 90mg/m2 + Cyclophosphamide (AC) x 4, then randomised to
nil vs. sequential Paclitaxel (175mg/m2) x 4 (+/- Tamoxifen 20mg, 5 Years)
PATIENTS
3.170 Patients Randomised according to 3x2 factorial trial design Positive axillary lymph nodes (1 - >10 Lnn.), First Kaplan-Meier Analysis after 18 months
Role of PACLITAXEL in Adjuvant Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Chemotherapy of Patients with Node-Positive Breast Cancer (CALGB 9344)Positive Breast Cancer (CALGB 9344)
* I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Role of PACLITAXEL in Adjuvant Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Chemotherapy of Patients with Node-
Positive Breast Cancer (CALGB 9344): First Positive Breast Cancer (CALGB 9344): First Results. *Results. *
* I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.
AC AC->T p
DFS 86 1.2% 90 1% 0.0077 (= 22% Reduction of Relapses)
OS 95 0.7% 97 0.6% 0.039 (= 26% Reduction of Mortality)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Role of PACLITAXEL in Adjuvant Role of PACLITAXEL in Adjuvant Chemotherapy of Patients with Node-Chemotherapy of Patients with Node-Positive Breast Cancer (CALGB 9344): Positive Breast Cancer (CALGB 9344):
Results January 2003. *Results January 2003. *
* L. Norton, tAnGo Trialists‘ Meeting January 2003
p Overall Survival 0.01Survival Receptor Positive Tumours 0.4808Survival Receptor Negative Tumors 0.0034
Disease Free Survival (DFS) 0.0018DFS Receptor Positive Tumors 0.2501DFS Receptor Negative Tumors 0.0006
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
CALGB 9344: TOXICITY. *CALGB 9344: TOXICITY. *
* I.C. Henderson et al., Proc. ASCO 17: 390A, 1998.
Diagnosis % Patients
Transient Myelosuppression 21 Chemotherapy-associated Cardiotoxicity 6 Neuropathy 5Pain 5 Hyperglycemia 5
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
The NSABP B-28 Trial: Paclitaxel for The NSABP B-28 Trial: Paclitaxel for Adjuvant Treatment of Breast Cancer.Adjuvant Treatment of Breast Cancer.
Sequential AC T
3060 Node-Positive Patients
Median Follow-Up: 34 Months
NO SURVIVAL ADVANTAGE
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
The MD Anderson Trial on Paclitaxel The MD Anderson Trial on Paclitaxel for Adjuvant Treatment of Breast Cancer.for Adjuvant Treatment of Breast Cancer.
Sequential P FAC
524 Patients
Median Follow-Up: 43 Months
NO SURVIVAL ADVANTAGE
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Phase III Trial Comparing TAC with FAC in Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast the Treatment of Node Positive Breast Cancer: Interim Analysis of BCIRG 001 Cancer: Interim Analysis of BCIRG 001
Study. *Study. *
* J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002
Median Observation: 33 Months
TAC (745 Patients)Taxotere (75mg/m2), Doxorubicin (50mg/m2), Cyclophosphamide (500mg/m2)
FAC (746 Patients)Fluorouracil (500mg/m2), Doxorubicin (50mg/m2), Cyclophosphamide (500mg/m2)
q. 21 Days x6ER-Positivity: Tamoxifen for 5 Years
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
* J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002
TAC vs. FAC P-VALUEDisease Free SurvivalAdjusted for Nodal Status 0.68 0.00111-3 Nodes 0.50 0.00024+ Nodes 0.86 0.33
Overall Survival Adjusted for Nodal Status 0.76 0.111-3 Nodes 0.46 0.0064+ Nodes 1.08 0.75
Phase III Trial Comparing TAC with FAC in Phase III Trial Comparing TAC with FAC in the Treatment of Node Positive Breast the Treatment of Node Positive Breast
Cancer: Interim Analysis of Cancer: Interim Analysis of BCIRG 001 Study. *BCIRG 001 Study. *
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Phase III Trial Comparing TAC with FAC in Phase III Trial Comparing TAC with FAC in
the Treatment of Node-Positive Breast the Treatment of Node-Positive Breast Cancer (BCIRG 001 STUDY): Toxicity. *Cancer (BCIRG 001 STUDY): Toxicity. *
* J.M. Nabholtz et al., Proc. Am. Soc. Clin. Oncol. 21: 141, 2002
TAC FAC
Febrile Neutropenia 24% 2%Neutropenia Grades 3/4 3% 1%Septic Deaths 0 0Nausea / Vomitus Grades 3/4 n.a. 16%Asthzenia 11% 5%Stomatitis 7% n.a.Cardiomyopathy 1% 0.1%
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
The NSABP B-27 Trial: Efficacy The NSABP B-27 Trial: Efficacy of Docetaxel in Adjuvant of Docetaxel in Adjuvant
Treatment of Breast Cancer.Treatment of Breast Cancer.
Sequential AC D, Neoadjuvant
2411 T1-T3 Patients with Operable Breast Cancer
Median Follow-Up: 39 Months
TOO EARLY FOR DFS AND OS
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Role of Taxanes
…. is unclear, yet …. side effects? …. possible benefit weighed against risks
…. in clinical trials only
Adjuvant Therapy in Patients with Breast Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.Cancer: Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
DOSE DENSITY
Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
1
102
104
106
108
1010
1012
10 765432
““Normal” Dose Intensity vs. Normal” Dose Intensity vs. Increased Dose DensityIncreased Dose Density
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Months
Cel
l Num
ber
1
102
104
106
108
1010
1012
10 765432
Sequential Therapy is Sequential Therapy is Dose Dense.Dose Dense.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Intergroup/CALGB 9741: Intergroup/CALGB 9741: Node-Positive Stage II-IIIANode-Positive Stage II-IIIA
Doxorubicin (A) 60 mg/m2
Paclitaxel (T) 175 mg/m2
Cyclophosphamide (C) 600 mg/m2
3-Week Cycles 2-Week Cycles (w/ G-CSF)
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
CALGB 9741: 3-YEAR RESULTS OF DOSE-DENSITY CALGB 9741: 3-YEAR RESULTS OF DOSE-DENSITY vs. CONVENTIONAL DOSE AND SEQUENTIAL vs. vs. CONVENTIONAL DOSE AND SEQUENTIAL vs. COMBINATION CHEMOTHERAPY, 2205 PATIENTS COMBINATION CHEMOTHERAPY, 2205 PATIENTS
WITH N+ DISEASE. *WITH N+ DISEASE. *
* CITRON et al., SABCC 2002
TREATMENT TREATMENT DURATIONq. 2 wks. + G-CSF q. 3 wks.
SEQUENTIAL A-T-C x4, resp. 24 wks. 36 wks.CONCURRENT AC T x4, resp. 16 wks. 24 wks.
DISEASE-FREE SURVIVAL 82% 75% p=0.007OVERALL SURVIVAL 92% 90% p=0.014
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
INCREASE IN DOSE DENSITY
…. Exciting, but not for Routine Use
Adjuvant Therapy in Patients with Breast Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.Cancer: Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
CHEMOTHERAPY PLUS ENDOCRINE TREATMENT
Adjuvant Therapy in Patients with Breast Adjuvant Therapy in Patients with Breast Cancer: Unresolved Questions 2003.Cancer: Unresolved Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
REDUCTION OF RECURRENCE AND REDUCTION OF RECURRENCE AND
MORTALITY BY TAMOXIFEN AND MORTALITY BY TAMOXIFEN AND CHEMOTHERAPY IN BREAST CANCER.*CHEMOTHERAPY IN BREAST CANCER.*
RECURRENCE MORTALITY
5 YEARS TAMOXIFEN vs. 0 -46 4 -22 5
5 YEARS TAMOXIFEN + CHEMOTHERAPY vs. CHEMOTHERAPY -52 8 -47 9
* EBCTCG, LANCET 351: 1451, 1998
% REDUCTION OF
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Sequence of Chemotherapy and Sequence of Chemotherapy and Tamoxifen in Early Breast Cancer.Tamoxifen in Early Breast Cancer.
INT 0100 TRIAL GEICAM TRIAL (n=1116) (n=485)
Median Follow-Up 8 Years 4.5 YearsChemotherapy CAF x6 EC x4
Disease-Free SurvivalCTX T 67% 64%CTX + T 62% 57%p-Value 0.03 n.s.
Toxicities No DifferenceOverall Survival No Difference
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
COMBINED CHEMOTHERAPY AND ENDOCRINE TREATMENT
…. should be Administered Sequentially
Adjuvant Therapy in Patients with Adjuvant Therapy in Patients with Breast Cancer: Unresolved Breast Cancer: Unresolved
Questions 2003.Questions 2003.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Effectivity of Adjuvant Chemotherapy Effectivity of Adjuvant Chemotherapy in Breast Cancer: Conclusion and in Breast Cancer: Conclusion and
Review of Conflicting Issues.Review of Conflicting Issues.
1. Polychemotherapy significantly reduces the annual risk of relapse and mortality both for N0- as well as N1-breast cancers.
2. Anthracycline-based regimens have been shown to have a significant advantage over non-anthracycline-regimens in premenopausal patients.
3. Use of taxanes continues to be controversial.
4. Dose density is becoming a decisive issue and deserves attention in future trials.
Clinical Division of OncologyDepartment of Medicine I
Medical University ofVienna, Austria
Adjuvant Therapy in Breast Cancer: Adjuvant Therapy in Breast Cancer: Final Conclusion.Final Conclusion.
Recruit Patients into Clinical Trials!