Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA And What’s Next? Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA

New Developments in the Treatment of Colorectal Cancer Disclosures Research Funding NCI Bristol Myers Squibb (to DFCI) Astra Zeneca (to DFCI) Consultant Bayer

What Have We Learned So Far? Adjuvant therapy impacts outcome in stage III colon cancer 5-FU and Oxaliplatin impact disease-free and overall survival Irinotecan, bevacizumab and cetuximab do not

Four Groups of Stage III Colon Cancer Patients

What Are the Challenges and Next Steps? Challenge 1 – Some people get chemotherapy who don’t need it Challenge 2 –Toxicity of therapy Challenge 3 – Not everyone is cured - what else can move the bar Challenge 4 – Other things “to do” outside of medications

5 year Recurrence Risk based on Recurrence Score Category Challenges 1: Identifying Who Should Get Adjuvant Therapy in Stage III Colon Cancer Clinical features Molecular signatures NSABP C07 – O’Connell et al Abstract 3512 Oncotype Dx Colon 12 5 year Recurrence Risk based on Recurrence Score Category Low Intermediate High Stage IIIA/B 21% 29% 38% Stage IIIC 40% 51% 64 Interaction by oxaliplatin usage (P = 0.48)

Challenge 2: Toxicities 5-FU toxicities Primarily all short term - with exception of DPD deficiencies, most patients easily managed Oxaliplatin toxicities Increased bone marrow suppression - short term – rare life threatening Liver toxicities - ? Long term effects NEUROPATHY

Incidence of Neurosensory Symptoms during Treatment and Follow-up after FOLFOX Evaluable patients n=811 at 4 years Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7% Andre et al J Clin Oncol. 2009 Jul 1;27(19):3109-16.

Oxaliplatin Toxicity Neuroprotectants Duration of therapy

Intravenous Ca / Mg for Oxaliplatin-Induced Sensory Neurotoxicity: NCCTG N04C7 CONSORT flow diagram. AE, adverse event. Grothey A et al. JCO 2011;29:421-427

Intravenous Ca / Mg for Oxaliplatin-Induced Sensory Neurotoxicity: NCCTG N04C7 Time to grade 2 or worse sensory neuropathy as measured by (A) Common Toxicity Criteria for Adverse Events or by (B) an oxaliplatin-specific scale. CONSORT flow diagram. AE, adverse event. Grothey A et al. JCO 2011;29:421-427

Relapse-free Survival by Adjuvant Treatment Arms 6 Months of bolus 5FU/LV vs. 3 months of Continuous Infusion 5FU Relapse-free survival by treatment arms in all patients. 5-FU, 5-fluorouracil; PVI, protracted venous infusion; LV, leucovorin. Chau I et al. Ann Onco 2005

International Duration Evaluation of Adjuvant Chemotherapy (IDEA) group Three or Six Colon Adjuvant Trial (TOSCA) Activated June 2007. Goal 3,500 stage II/III colon Short Course Oncology Treatment (SCOT) Activated March 2008. Goal 9,500 stage II/III colon or rectal GERCOR Activated May 2009. Goal 2,000 stage III colon HORG Activated Oct 2010. Goal 1,000 stage II/III colon CALGB/SWOG 80702 Activated July 2010. Goal 2,500 stage III colon

International Duration Evaluation of Adjuvant Chemotherapy (IDEA) group All trials comparing 3 months FU/oxaliplatin versus 6 months FU/oxaliplatin (some include oral, most IV) At least 10,500 stage III colon cancer patients pooled DFS primary endpoint Noninferiority if 2 sided 95% CI comparing 3 to 6 months lies entirely below 1.10

Challenge 3: Not Everyone Is Cured What Else Can Move Bar? Moving from metastatic  adjuvant setting Approved but not been tested - Panitumumab Positive phase III data – Aflibercept, Regorafenib Cyclooxygenase inhibitors Associated with risk of colorectal cancer Prevent/reduce polyp # in patients with prior CRC or polyps Observational data associated with DFS

CALGB 89803: Aspirin Use and Disease-Free Survival in Stage III Colon Cancer 1.00 Consistent aspirin users Non-consistent users 0.75 Log rank, p = 0.03 Proportion Disease-Free and Alive 0.50 HR = 0.46 (95% CI, 0.23-0.95) 0.25 0.00 10 20 30 40 50 Months Fuchs ASCO 2005 Abstract 3530

Survival According to Aspirin Use After Diagnosis: Nurse’s Health Study Chan, A. T. et al. JAMA 2009;302:649-658.

CALGB/SWOG 80702 for Stage III Colon Cancer Celecoxib versus Placebo N = 2,500 Arm A 12 FOLFOX + Placebo daily Arm B 12 FOLFOX + Celecoxib 400 mg daily 6 versus 12 treatments FOLFOX Arm C 6 FOLFOX + Placebo daily Arm D 6 FOLFOX + Celecoxib 400 mg daily Celecoxib starts concurrently with FOLFOX and continue for 3 years 18

Challenge 4: Other things “to do” outside of medications Really extension of challenge 3 The questions many/most patients ask and we can’t answer (or can we?) What should I eat? Should I exercise? What about a multivitamin? What diet/lifestyle changes will help?

Data from Observational Studies for Stage I-III Disease Decrease risk of recurrence Physical activity Avoidance of Western pattern diet Avoidance of class II/ III obesity (BMI > 35 kg/m2) Aspirin or COX-2 inhibitor Higher vitamin D levels No association with recurrence to date Weight change (gain or loss) Obesity < 35 kg/m2 Smoking status or history Multivitamin Credits: Charles Fuchs Jeffrey Meyerhardt Brian Wolpin Kimmie Ng Andrew Chan Nadine McCleary Donna Niedzwiecki Donna Hollis CALGB

89803 and Exercise: Disease-Free Survival in Stage III Colon Cancer Survivors Hazard Ratio Recurrence or Death Regular Physical Activity (met-hours per week) Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

Statistical Considerations Reverse causality Is the exposure changing outcomes or the outcome changing exposure Restrict to events at least 90 days from exposure Sensitivity analyses to extend restriction to 6 months and 12 months Recall bias The clock starts at time of questionnaire completion – all events are prospective beyond the exposure data Limits generalizability – data speak to those that get to point of questionnaire

89803 and Exercise: Stratification Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006

NHS and Post-diagnosis Physical Activity Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

NHS and Post-diagnosis Physical Activity Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006

CHALLENGE: Colon Health and Life-Long Exercise Change trial High risk Stage II or stage III colon cancer - completed adjuvant chemotherapy within 2-6 months REGISTRATION Baseline Testing STRATIFICATION Disease stage high risk III; centre; BMI ≤ 27.5 vs. > 27.5; ECOG PS 0 vs. 1 RANDOMIZATION ARM 1 Physical Activity Program + General Good Health Education Material (Intervention Arm) ARM 2 General Health Education Materials (Control Arm) Assessment of disease-free survival every 6 months for first 3 years and annually from years 4-10 Courneya Curr Oncol.2008 Dec;15(6):271-8.

NSABP and Body Mass Index Disease-free and overall survival by body mass index (BMI) category in 4288 patients from National Surgical Adjuvant Breast and Bowel Project randomized clinical trials for Dukes B and C colon cancer Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654

Hazard Ratio (95% CI) or P value (compared to normal weight) Author Years N Outcome Hazard Ratio (95% CI) or P value (compared to normal weight) Tartter 1976-1979 279 Recur Rate P = 0.003 for above median weight Meyerhardt 1988-1992 3759 DFS 1.11 (0.94-1.30) BMI > 30 kg/m2 OS 1.11 (0.96-1.29) BMI > 30 kg/m 1990-1992 1792 rectal 1.10 (0.91-1.32) BMI > 30 kg/m2 1.09 (0.90-1.33) BMI > 30 kg/m2 Local Recur 1.31 (0.91-1.88) BMI > 30 kg/m2 Dignam 1989-1994 4288 1.06 (0.93-1.21) BMI 30-34.9 kg/m2 1.27 (1.05-1.53) BMI > 35 kg/m2 1999-2001 1053 1.00 (0.72-1.40) BMI 30-34.9 kg/m2 1.24 (0.84-1.83) BMI > 35 kg/m2 0.90 (0.61-1.34) BMI 30-34.9 kg/m2 0.87 (0.54-1.42) BMI > 35 kg/m2 Hines 1981-2001 496 0.77 (0.61-0.97) BMI > 25 all stages 0.92 (0.65-1.30) stage I-II 0.92 (0.59-1.45) stage III 0.58 (0.37-0.90) stage IV

Body Mass Index in Colon Cancer Patients over Past Decade < 21 21-24.9 25-29.9 30-34.9 > 35 INT-0089 (1988-92) 14 % 34 % 13 % 5 % 89803 (1999-2001) 8 % 26 % 36 % 20 % 10 % % change in a decade - 43% - 24% + 6% + 54% + 100%

89803 and Change in Weight Adjusted Hazard ratio (95% CI) > 5 kg weight loss 1.39 (0.69 – 2.79) 2.1 – 5 kg weight loss 1.15 (0.54 – 2.44) +/- 2 kg change Referent 2 – 4.9 kg weight gain 1.11 (0.66 – 2.06) > 5 kg weight gain 1.19 (0.73 – 1.94) Ptrend = 0.13 Ptrend = 0.90 Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15.

CALGB 89803: DFS By Dietary Pattern 4 1.2 2 2.2 3.9 Western diet P, trend < 0.001 3.5 3 2.5 2 Hazard Ratio for Cancer Recurrence or Death 1.5 1.3 1 1.1 0.7 1 Prudent diet 0.5 1 2 3 4 5 Quintiles of Dietary Pattern Meyerhardt, J. et al. JAMA 2007298(7):754-764.

CALGB 89803: Dietary Pattern Meyerhardt, J. et al. JAMA 2007;298:2263-a.

Plasma Vitamin D and Survival in Colorectal Cancer Patients: NHS/HPFS (N = 304) 1 1 0.9 0.89 0.83 0.8 P, trend = 0.01 0.7 0.6 Hazard Ratio for Death 0.5 0.49 0.4 (0.28-0.86) 0.3 People with highest level of vitamin D have 50% improvement in outcome 0.2 0.1 <22.8 22.8-27.1 27.2-33.1 >33.1 Quintiles of plasma Vitamin D ng/mL Ng et al J Clin Oncol. 2008 Jun 20;26(18):2984-91

Predicted Vitamin D Level Predicted Vitamin D Level* & Survival in Colorectal Cancer Patients: NHS/HPFS (N=1017) CRC Specific Mortality Overall Mortality * Based on race, geography, exercise, BMI, dietary vitamin D, supplement vitamin D Ng et al Br J Cancer. 2009 101: 916-23.

Conclusions Despite advances in adjuvant therapy in 80s, 90s and early 2000, bar has become stagnant We need to better define who needs therapy, who benefits and who needs other options Better understanding of complementary approaches will benefit our patients Potentially their colon cancer Other diseases down the road