1. Memorial Sloan-Kettering Cancer Center
TAXOL® (paclitaxel) for Adjuvant Treatment of Node Positive Breast Cancer Oncologic Drug Advisory Committee Adjuvant Chemotherapy of Breast Cancer
Larry Norton, M.D.
Memorial Sloan-Kettering Cancer Center
New York, New York

2. Adjuvant Chemotherapy of Primary Breast Cancer: What We Know
Chemotherapy Improves Disease-Free and Overall Survival
Polychemotherapy > Monochemotherapy
Multiple Cycles > Single Exposure
No Major Advantage to Durations > 3 Months
Anthracycline Combinations > CMF

3. Early Breast Cancer Trialists’ Collaborative Group
Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of...
Comparison (N)
CMF vs. Nil (8,150)
CMF+ vs. Nil (3,218)
Anthracyclines+ vs. CMF (6,950)
Longer vs. Shorter (6,104)
Recurrence
+24 ± 3
+20 ± 5
+12 ± 4
+7 ± 4
Death
+14 ± 4
+15 ± 5
+11 ± 5
-1 ± 5
Lancet Vol. 352, 9/98

4. Simulation of Impact of Chemotherapy
Annual Odds of Recurrence:
Nil = 15%/Yr
CMF = 11.4%/Yr (Reduced by 24%)
AC = 10%/Yr (Reduced by 12%)
100 80 60
% Free of Recurrence 40 AC
CMF 20
Nil 2 4 6 8 10
Years

5. Adjuvant Chemotherapy of Primary Breast Cancer: What Else We Know
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)

6. Early Breast Cancer Trialists’ Collaborative Group
Impact of Prolonged Polychemotherapy On Reducing (in % ± SD) Annual Odds of...
Subgroup (N)
Age < 50, ER- (1398)
Age < 50, ER+ (1115)
Age  50, ER- (3240)
Age  50, ER+ (6793)
Recurrence
+40 ± 7
+33 ± 8
+30 ± 5
+18 ± 4
Death
+35 ± 9
+20 ± 10
+17 ± 6
+9 ± 5
Lancet Vol. 352, 9/98

7. Adjuvant Chemotherapy of Primary Breast Cancer: How To Improve
Dose-Escalate Anthracycline?
Integrate New Agents?
Chemotherapy?
Biological Agents?
Improve Drug Scheduling?
Dose-Density, Sequential?

8. Recently Approved New Drugs for the Treatment of (Advanced) Breast Cancer:
Paclitaxel
Docetaxel
Capecitabine
Trastuzumab

9. Adjuvant Chemotherapy of Primary Breast Cancer: Why Paclitaxel?
Active as First Chemotherapy for Stage IV: % Response Rates (M.D. Anderson, MSKCC et al.)
Active after Extensive Prior Chemotherapy, Including Anthracycline-Resistant Disease: % Response Rates (NCI, MSKCC et al.)

10. “Normal” Dose Intensity & Dose Escalation1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

11. “Normal” Dose Intensity & Dose Escalation1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

12. “Normal” Dose Intensity & Increased Dose Density
B1&3 1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

13. “Normal” Dose Intensity & Increased Dose Density1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

14. Alternating Therapy is Not Dose Dense
C4&5
Alternating Therapy is Not Dose Dense 1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

15. Sequential Therapy is Dose Dense
3&6 1
102
104
106
108
1010
1012 7 6 5 4 3 2
Months
Cell Number

16. Stage II Breast Cancer with 4 Involved Axillary Lymph Nodes
Doxorubicin
CMF
Bonadonna et al., JAMA, 1995

17. Stage II Breast Cancer with >4 Involved Axillary Lymph Nodes
% at 10 Years
p = .002
Bonadonna et al., JAMA, 1995

18. CALGB 9141 (Pilot) Node-Positive Stage II-IIIA (N=172)
Cyclophosphamide
2000 mg/m2
Paclitaxel 175 mg/m2
+ G-CSF
Doxorubicin
75 mg/m2
130/145 (89.7%)of Patients Starting Paclitaxel Completed Rx.
On Paclitaxel:
25% Grade IV Leukopenia
4% Grade IV Thrombocytopenia
Demetri et al., ASCO-1997

19. Intergroup 0148/CALGB 9344 Node-Positive Stage II-IIIA
Cyclophosphamide
Paclitaxel 175 mg/m2
600 mg/m2
Tamoxifen forHR(+) 60
Randomize
Doxorubicin mg/m2 75
No Further Chemotherapy 90
G-CSF

20. Relationship of CALGB 9344 (Int 0148) to Current U. S
Relationship of CALGB 9344 (Int 0148) to Current U.S. Cooperative Group Trials

21. NSABP B-28 Node-Positive Stage II-IIIA
Paclitaxel 225 mg/m2
Doxorubicin
Cyclophosphamide
600 mg/m2
60 mg/m2
(Survival)
No Further Chemotherapy
Concomitant Tamoxifen x 5 Years for HR(+) or Postmenopausal (Age  50)

22. Intergroup/CALGB 9741 Node-Positive Stage II-IIIA
3-Week Cycles
2-Week Cycles (w/ G-CSF)
Doxorubicin (A) 60 mg/m2
Paclitaxel (T) 175 mg/m2
Cyclophosphamide (C) 600 mg/m2

23. Intergroup/SWOG 4-9 LN+ TrialC T A
Randomize
STAMP I or
STAMP V C A

24. Intergroup/ECOG Stage II Trial HER2 (-)
Paclitaxel
Tamoxifen if HR(+)
Cyclophosphamide 600 mg/m2
Doxorubicin 60 mg/m2
Docetaxel

25. Integration of Biological Agent: Trastuzumab (Herceptin)

26. NSABP Stage II Trial HER2 (+)
Paclitaxel
Cyclophosphamide 600 mg/m2
Tamoxifen if HR(+)
Doxorubicin 60 mg/m2
Etc.
Herceptin

27. Intergroup/NCCTG Stage II Trial HER2 (+)
Paclitaxel
Cyclophosphamide 600 mg/m2
Tamoxifen if HR(+)
52 wks
Doxorubicin 60 mg/m2
52 wks
Herceptin

28. CALGB Stage IIIB Trial (HER2+)
Cyclophosphamide 600 mg/m2
Paclitaxel 90 mg/m2
Surgery
& RT
Tamoxifen if HR(+)
Doxorubicin 60 mg/m2
Herceptin for a Year or Not
Dexrazoxane or Not
Herceptin or Not

29. Summary of Advantages of This Approach
Integrates Paclitaxel
Active as a Single Agent
Active Post-Anthracycline
Minimizes Incremental Toxicity
Allows Integration of Biological Therapy