There is more to clinical trials than chemotherapy and survival Alan P. Venook, M.D. University of California, SF.
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What ELSE should I do ??
Influence of regular aspirin use on Influence of regular aspirin use on survival for patients with stage III colon survival for patients with stage III colon cancer: Findings from Intergroup trial cancer: Findings from Intergroup trial
CALGB 89803CALGB 89803..
Charles S. Fuchs1, Jeffrey A. Meyerhardt1, Denise Brady1, Donna Niedzwiecki2, Donna Hollis2, Andrew T. Chan3, Leonard B. Saltz4, Richard L. Schilsky5, Robert J. Mayer1
1Dana-Farber Cancer Institute, Boston, MA; 2CALGB
Statistical Center, Durham, NC; 3Massachusetts General Hospital, Boston, MA; 4Memorial Sloan-Kettering Cancer Center, New York, NY; 5University of Chicago, Chicago, IL.
The impact of physical activity The impact of physical activity on patients with stage III colon on patients with stage III colon
cancer: Findings from cancer: Findings from Intergroup trial CALGB 89803Intergroup trial CALGB 89803
Jeffrey A. Meyerhardt1, Denise Brady1, Donna Niedzwiecki2, Donna Hollis2, Leonard B. Saltz3, Robert J. Mayer1 , Richard L. Schilsky4, Charles S. Fuchs1
1Dana-Farber Cancer Institute, Boston, MA; 2CALGB Statistical
Center, Durham, NC; 3Memorial Sloan-Kettering Cancer Center, New York, NY; 4University of Chicago, Chicago, IL.
RRAANNDDOOMMIIZZAATTIIOONN
5-FU:5-FU: 500 mg/m500 mg/m22/wk x 6 wks, q 8 wks/wk x 6 wks, q 8 wksLV:LV: 500 mg/m500 mg/m22/wk x 6 wks, q 8 wks/wk x 6 wks, q 8 wks
x 4 cyclesx 4 cycles (32 wks of therapy)(32 wks of therapy)
CPT-11: 125 mg/m2/wk x 4 wks, q 6 wks
5FU: 500 mg/m2/wk x 4 wks, q 6 wks
LV: 20 mg/m2/wk x 4 wks, q 6 wks
x 5 cycles (30 wks of therapy)
Treatment Arms(CALGB -- Adjuvant Study C89803)
Stage III Stage III Disease Disease
N=635N=635
N=628N=628
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
Neutropenia Febrile neutropenia
Death during treatment
43%
4% 2.8%5%
1% 1%0
10
20
30
40
50
Pat
ien
ts (
%)
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.
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
Effect of Consistent Aspirin Use on Outcome: Stage IIIAspirin 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
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
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
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, *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.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 1Consistent aspirin users defined as those who reported aspirin use on both the 1 stst and 2 and 2ndnd questionnaires. questionnaires.
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)
< 3 3-9 9-18 18-27 >27 p
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
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
Bicycling 7
Tennis, squash, racquetball 7
Lap swimming 7
Calisthenics, ski / stair machine, other aerobic 6
Yoga, stretching, lower intensity exercise 4
Other vigorous activities (lawn mowing) 6
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
Cumulative Incidence of Disease-Free Survival Events by BMI
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
What ELSE should I do ??
How much will it cost ??
What ELSE should I do ??
Will my insurance cover it??
Is it cost-effective ??
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
9741: Overall Survival
P=0.002
Goldberg et al, JCO, 2004
All patients begin in the “Start 1st line IFL or FOLFOX” oval. On a daily basis, patients move to alternative health states until death. Treatment complications leading to death or hospitalization were considered in the first 60 days and 6 months respectively. For non-fatal treatment complications treatment was not stopped. * Indicates that every 6 weeks for IFL and 2 weeks for FOLFOX, patients with stable or responding disease could be treated with 1st-line therapy. The rate of treatment decreased with time. Patients with progression of their metastatic colorectal cancer could or could not receive second-line chemotherapy.
2nd line Chemotherapy for Metastatic CRC
Stable or Responding Metastatic CRC*
Start 1st line IFL or FOLFOX
Treatment Associated Hospitalization within
First 6 months
Death from Metastatic CRC
Palliative Care for Metastatic CRC
Treatment Associated Death
within 60 days
Treat or defer 1st-line IFL or FOLFOX*
Progression of Metastatic CRC
Post-hoc analysis,
simulated cohorts
Cost-effectiveness analysis of oxaliplatin/
5-FU/LV in adjuvant treatment of stage III colon cancer in the US
2005 ASCO Annual Meeting
Aballéa SAballéa S11, Chancellor J, Chancellor J11, Raikou M, Raikou M22, Drummond MF, Drummond MF1,31,3, , Weinstein MCWeinstein MC1,41,4, Jourdan S, Jourdan S55, Carita P, Carita P55, Bridgewater J, Bridgewater J66
Acknowledgements: Dr Carlos Beccera (Dallas), Dr Bert O’Neil (Chapel Hill)Acknowledgements: Dr Carlos Beccera (Dallas), Dr Bert O’Neil (Chapel Hill)
MOSAIC: Disease-Free Survival Stage III patients
0,5
0,6
0,7
0,8
0,9
1
0 10 20 30 40 50DFS (months)
24% risk reduction in the FOLFOX4 arm
Hazard ratio: 0.76 [0.62-0.92]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
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
What ELSE should I do ??
Will my insurance cover it??
Is it cost-effective ??
AWP: 100 mg vial = $585.60
AWP: 100 mg vial = $687.50
400 mg vial = $2750.00
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
RRAANNDDOOMMIIZZAATTIIOONN
N = 763N = 763
Advanced Colorectal Cancer:CALGB #80405
OX /IRIOX /IRIAdj rxAdj rx
Prior XRTPrior XRT
N= 763N= 763
N =763N =763
StratifyStratify
cetuximab
cetuximab / bevacizumab
bevacizumab
Endpoints:
OS -- 22 v. 27.5 mo
PFS -- 12 v. 15.6 mo
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
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