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