1. There is more to clinical trials than chemotherapy and survival Alan P. Venook, M.D. University of California, SF

2. ASCO Colorectal Cancer Poster Discussion Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from CALGB 89803. Fuchs, et al. The impact of physical activity on patients with stage III colon cancer: Findings from CALGB 89803. Meyerhardt, et al. Effect of body mass index on outcomes in patients with Dukes B and C colon cancer: An analysis of NSABP randomized trials. Dignam, et al. Economic and demographic patterns influence access to high volume hospitals for surgical resection of colorectal cancer in NYC 2000. Graham, et al. Cost-effectiveness projections of FOLFOX vs. IFL in first-line therapy of metastatic colorectal cancer in the context of the US Health Care system. Hillner, et al. Cost-effectiveness analysis of oxaliplatin/5-FU/LV in adjuvant treatment of stage III colon cancer in the US. Aballea, et al.

3. What ELSE should I do ??

4. How much will it cost ??

5. What ELSE should I do ?? Will my insurance cover it??

6. What ELSE should I do ?? Will my insurance cover it?? Is it cost-effective ??

7. What ELSE should I do ?? Go to a big center Take aspirin Be physically active Be thin

8. Economic and Demographic Patterns Influence Access to High Volume Hospitals for Surgical Resection of Colorectal Cancer in New York City 2000 D. Graham, M. Weiser, D. Schrag, D. Wong Memorial Sloan Kettering Cancer Center, New York, NY

9. Categorization of Hospital by Volume of Cases of Colorectal Cancer Surgery Volume Categories (N=2716)HV # 1HV # 2HV # 3HV # 4HV # 5HV # 6 Volume Cases/year> 350200-349150-199100-14950-991-49 # Hospital(s)1114941 HV #1 HV# 2HV#3 HV#4HV#5HV#6 # Patients (%)368 (13.5)227 (8.4)156 (5.7)507 (18.7)638 (23.5)820 (30.2) In-hosp mort (%)0.31.81.92.82.03.9 Median LOS (days) 7 8 6.5 8 810

10. Categorization of Hospital by Volume of Cases of Colorectal Cancer Surgery Volume Categories (N=2716)HV # 1HV # 2HV # 3HV # 4HV # 5HV # 6 Volume Cases/year> 350200-349150-199100-14950-991-49 # Hospital(s)1114941 HV #1 HV# 2HV#3 HV#4HV#5HV#6 # Patients (%)368 (13.5)227 (8.4)156 (5.7)507 (18.7)638 (23.5)820 (30.2) In-hosp mort (%)0.31.81.92.82.03.9 Median LOS (days) 7 8 6.5 8 810

11. Demographics and Volume Race (%)HV # 1HV # 2HV # 3HV # 4HV # 5HV # 6Chi Square White856977815446 Black583101829 Asian616357 Other/Unknown5211452319p<0.0001 Insurance Status (%)HV # 1HV # 2HV # 3HV # 4HV # 5HV # 6 Chi Square Medicare475052565951 Medicaid56161017 Commercial Ins391744291417p<0.0001 Income AGI (%)HV # 1HV # 2HV # 3HV # 4HV # 5HV # 6Chi Square $18,999 $39,9991111.013153144 $40,000-$69,999333629304938 > $70,000565358551918p<0.0001 AgeHV#1HV#2HV#3HV#4HV#5HV#6Chi Square <=65 years old483829343136 >65 years old526271666964p<0.0001

12. Take Home Message Hospital volume may be an important predictor of outcomes for patients undergoing colorectal cancer surgery

13. Take Home Message Hospital volume may be an important predictor of outcomes for patients undergoing colorectal cancer surgery OR Patients who flock to a center of excellence may be a different group of patients and that may account for improved outcomes

14. Influence of regular aspirin use on survival for patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803. Charles S. Fuchs 1, Jeffrey A. Meyerhardt 1, Denise Brady 1, Donna Niedzwiecki 2, Donna Hollis 2, Andrew T. Chan 3, Leonard B. Saltz 4, Richard L. Schilsky 5, Robert J. Mayer 1 1 Dana-Farber Cancer Institute, Boston, MA; 2 CALGB Statistical Center, Durham, NC; 3 Massachusetts General Hospital, Boston, MA; 4 Memorial Sloan-Kettering Cancer Center, New York, NY; 5 University of Chicago, Chicago, IL.

15. The impact of physical activity on patients with stage III colon cancer: Findings from Intergroup trial CALGB 89803 Jeffrey A. Meyerhardt 1, Denise Brady 1, Donna Niedzwiecki 2, Donna Hollis 2, Leonard B. Saltz 3, Robert J. Mayer 1, Richard L. Schilsky 4, Charles S. Fuchs 1 1 Dana-Farber Cancer Institute, Boston, MA; 2 CALGB Statistical Center, Durham, NC; 3 Memorial Sloan-Kettering Cancer Center, New York, NY; 4 University of Chicago, Chicago, IL.

16. RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION 5-FU:500 mg/m 2 /wk x 6 wks, q 8 wks LV:500 mg/m 2 /wk x 6 wks, q 8 wks x 4 cycles (32 wks of therapy) (32 wks of therapy) CPT-11:125 mg/m 2 /wk x 4 wks, q 6 wks 5FU:500 mg/m 2 /wk x 4 wks, q 6 wks LV: 20 mg/m 2 /wk x 4 wks, q 6 wks x 5 cycles (30 wks of therapy) Treatment Arms (CALGB -- Adjuvant Study C89803) Stage III DiseaseN=635N=628

17. Addition of Irinotecan to 5-FU: No Benefit in Stage III Colon Cancer Similar disease-free, failure-free, and overall survival rates as 5-FU/LV alone NeutropeniaFebrile neutropenia Death during treatment 43% 4% 2.8% 5% 1% 0 10 20 30 40 50 Patients (%) P <.00001 P <.0005 P <.008 5-FU/LV + irinotecan 5-FU/LV alone Saltz LB, et al. 40th ASCO; June 5-8, 2004; New Orleans, Louisiana. Abstract 3500.

18. Methods Prospective questionnaires during adjuvant therapy & six months after completion –Diet, medications and lifestyle 131 food questions, smoking, BMI & wt change Analgesic usage, physical activity –98% completion first, 92% completed second –Analysis of patients free of recurrence at 2nd ASA use assessed on both Metabolic equivalents of exercise on second

19. Effect of Consistent Aspirin Use on Outcome: Stage III Aspirin Use Non-consistent users Consistent users † No. of Patients (%)771 (91.1%)75 (8.9%) Recurrence-free survival Unadjusted hazard ratio (95% CI) Adjusted hazard ratio (95% CI)* 1.0 0.48 (0.23-0.97) 0.45 (0.21-0.96) Disease-free survival Unadjusted hazard ratio (95% CI) Adjusted hazard ratio (95% CI)* 1.0 0.49 (0.25-0.96) 0.46 (0.23-0.95) Overall survival Unadjusted hazard ratio (95% CI) Adjusted hazard ratio (95% CI)* 1.0 0.63 (0.27-1.46) 0.49 (0.19-1.30) *Adjusted for age, gender, ECOG performance status, T-stage, N-stage, bowel perforation, bowel obstruction, baseline serum CEA, tumor differentiation, adjuvant treatment arm, other NSAID use and acetaminophen use. † Consistent aspirin users defined as those who reported aspirin use on both the 1 st and 2 nd questionnaires.

20. Impact of Physical Activity on Disease-Free Survival Adjusted for gender, age, depth of invasion through bowel wall (T stage), number of positive lymph nodes (N stage), presence of clinical perforation at time of surgery, presence of bowel obstruction at time of surgery, baseline CEA (  5 v > 5 ng/dL), grade of tumor differentiation, baseline performance status, treatment arm, weight change between 1st and 2nd questionnaire, body mass index at time of 2nd questionnaire, and time between study entry and completion of 2nd questionnaire. Median follow-up of alive patients 2.7 years from completion of questionnaire 2; 3.8 years from trial entry) Total MET-Hours / Week – Hazard Ratio (95% Confidence Interval) < 33-99-1818-27>27p trend Disease-free survival Unadjusted referent 0.94 (0.64-1.38) 0.89 (0.58-1.37) 0.51 (0.27-0.97) 0.58 (0.36-0.94) 0.01 Adjusted * referent 0.87 (0.58-1.29) 0.90 (0.57-1.40) 0.51 (0.26-0.97) 0.55 (0.33-0.91) 0.01

21. Table 5: Metabolic Equivalent Conversions METS for 1 hour of that activity Normal pace walking (2-2.9 mph)3 Brisk pace walking (3-3.9 mph)4 Very brisk pace walking (4+ mph)4.5 Jogging (slower than 10 minutes/mile)7 Running (faster than 10 min/mile)12 Bicycling7 Tennis, squash, racquetball7 Lap swimming7 Calisthenics, ski / stair machine, other aerobic6 Yoga, stretching, lower intensity exercise4 Other vigorous activities (lawn mowing)6

22. Why would ASA and physical activity decrease recurrence of colon cancer ?? Effect on cyclo-oxygenase pathway –No effect of NSAID’s, acetaminophen Effect on insulin pathways or People who take ASA and remain physically active have inherently more favorable tumor biology

23. Effect of Body Mass Index on Outcomes in Patients with Dukes B and C Colon Cancer: An Analysis of NSABP Randomized Trials James Dignam, Blase Polite, Greg Yothers, Peter Raich, Linda Colangelo, Michael O'Connell, Norman Wolmark; University of Chicago, Chicago, IL; NSABP Biostatistical Center, Pittsburgh, PA; AMC Cancer Research Center, Denver, CO; NSABP Operations Office, Pittsburgh, PA

24. Background: Impact of Obesity on Colon Cancer Mortality MenWomen BMI (kg/m 2 )RR (95%CI) 18.5-24.91.0 25-29.91.2 (1.1-1.3)1.1 (1.0-1.2) 30-34.91.5 (1.3-1.6)1.3 (1.2-1.5) 35+1.8 (1.4-2.4)1.4 (1.1-1.7) 40+1.5 (0.9-2.2) Calle EE, et al. NEJM. 2003;348:1625-38

25. NSABP Colon Cancer Adjuvant Trials Included NSABP C-04 and C-05 enrolled patients with resected stage II (Dukes B) and Stage III (Dukes C) Colon Cancer NSABP C-04 –Enrolled 2,151 patients from 1989-1990 –Compared: 5FU+LV vs. 5FU+Lev vs. 5FU+LV+Lev NSABP C-05 –Enrolled 2,176 patients from 1991-1994 –Compared: 5FU+LV vs. 5FU+ LV+interferon

26. Cumulative Incidence of Disease-Free Survival Events by BMI

27. What ELSE can I do? Compliance with questionnaires outstanding and it is worth the effort to embellish big studies There may be MANY confounding variables that confuse the survival endpoint and we cannot be oblivious to this Patients with resected colon cancer who are of average weight, take ASA regularly and are physically active appear to have better outcomes but there may not be a cause-effect relationship. These findings generate hypotheses but do not allow one to necessarily suggest interventions

28. What ELSE should I do ?? How much will it cost ??

30. What ELSE should I do ?? Will my insurance cover it?? Is it cost-effective ??

31. Cost-effectiveness Projections of FOLFOX vs. IFL in First-line therapy of Metastatic Colorectal Cancer Bruce E. Hillner, M.D. Deborah Schrag, M.D., Daniel J. Sargent, Ph.D., Richard M. Goldberg, M.D. Virginia Commonwealth University, Richmond, Memorial Sloan-Kettering Cancer Center, New York, Mayo Clinic, Rochester, MN, University of North Carolina at Chapel Hill. Corresponding Author: Hillner@mail2.vcu.edu

32. 9741: Overall Survival P=0.002 Goldberg et al, JCO, 2004

33. Post-hoc analysis, simulated cohorts

34. Cost-effectiveness analysis of oxaliplatin/ 5-FU/LV in adjuvant treatment of stage III colon cancer in the US 2005 ASCO Annual Meeting Aballéa S 1, Chancellor J 1, Raikou M 2, Drummond MF 1,3, Weinstein MC 1,4, Jourdan S 5, Carita P 5, Bridgewater J 6 Acknowledgements: Dr Carlos Beccera (Dallas), Dr Bert O’Neil (Chapel Hill)

35. MOSAIC: Disease-Free Survival Stage III patients DFS (months) 24% risk reduction in the FOLFOX4 arm Hazard ratio: 0.76 [0.62-0.92] FOLFOX4 (n=672) 72.2% LV5FU2 (n=675) 65.3% FOLFOX4 (n=672) 72.2% LV5FU2 (n=675) 65.3% 3-year Andre et al, NEJM, 2004

36. Cost-effectiveness of therapy ?? FOLFOX is cost-effective for stage III colon cancer - - $21,042 per life year gained FOLFOX is marginally cost-effective compared to IFL for stage IV cancer -- $80,407 per life year gained

37. What ELSE should I do ?? Will my insurance cover it?? Is it cost-effective ??

38. AWP: 100 mg vial = $585.60

39. AWP: 100 mg vial = $687.50 400 mg vial = $2750.00

40. Biologics in Adjuvant Colon Cancer NSABP C-08 (stage II/III): –FOLFOX +/- Bevacizumab (BV) qow X 26 doses N0147 (stage III): –FOLFOX +/- Cetuximab (C-225) qw X 24 Assume: average size patient; no drug wastage; no cost of infusion or chemotherapy; no hospitalizations; no missed doses. C-08 cost of BV: $62,536.50 per patient N0147 cost of C-225: $61,224.48 per patient

41. RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION N = 763 Advanced Colorectal Cancer: CALGB #80405 OX /IRI Adj rx Prior XRT N= 763 Stratify cetuximab cetuximab / bevacizumab bevacizumab Endpoints: OS -- 22 v. 27.5 mo PFS -- 12 v. 15.6 mo

42. Advanced Colorectal Cancer: CALGB 80405 Secondary endpoint: –PFS: 12 v. 15.6 months (chemo/BV +/- C-225) Assume: average size patient; no wastage; no cost of infusion or chemotherapy; no hospitalizations; no missed doses. 15.6 mos of BV + C-225 = $235,172.13

43. What ELSE should I do ?? How much will it cost ??

45. What ELSE should I do ?? Will my insurance cover it?? Is it cost-effective ??

46. Take Home Messages There is more to cancer management and outcome than chemotherapy and biologics Gathering prospective data on lifestyle and other factors is critical and feasible Cost-effectiveness is a societal question that needs to be acknowledged and there is undoubtedly a limit to the $$ to be spent