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

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

3. 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

4. Four Groups of Stage III Colon Cancer Patients

5. 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

6. 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)

7. 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

8. 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 Jul 1;27(19):

9. Oxaliplatin Toxicity
Neuroprotectants
Duration of therapy

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

11. 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:

12. 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

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

14. 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

15. 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

16. 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 = (95% CI, )
0.25
0.00 10 20 30 40 50
Months
Fuchs ASCO 2005 Abstract 3530

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

18. 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

19. 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?

20. 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

21. 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:

22. 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

23. 89803 and Exercise: Stratification
Meyerhardt, J. A. et al. J Clin Oncol; 24:

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

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

26. 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.

27. 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 :

28. 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
279
Recur Rate
P = for above median weight
Meyerhardt
3759
DFS
1.11 ( ) BMI > 30 kg/m2 OS
1.11 ( ) BMI > 30 kg/m
1792
rectal
1.10 ( ) BMI > 30 kg/m2
1.09 ( ) BMI > 30 kg/m2
Local Recur
1.31 ( ) BMI > 30 kg/m2
Dignam
4288
1.06 ( ) BMI kg/m2
1.27 ( ) BMI > 35 kg/m2
1053
1.00 ( ) BMI kg/m2
1.24 ( ) BMI > 35 kg/m2
0.90 ( ) BMI kg/m2
0.87 ( ) BMI > 35 kg/m2
Hines
496
0.77 ( ) BMI > 25 all stages
0.92 ( ) stage I-II
0.92 ( ) stage III
0.58 ( ) stage IV

29. Body Mass Index in Colon Cancer Patients over Past Decade
< 21
> 35
INT-0089
( )
14 %
34 %
13 %
5 %
89803
( )
8 %
26 %
36 %
20 %
10 %
% change in a decade
- 43%
- 24%
+ 6%
+ 54%
+ 100%

30. 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 Sep 1;26(25):

31. CALGB 89803: DFS By Dietary Pattern4
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 (7):

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

33. 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
( )
0.3
People with highest
level of vitamin D have 50% improvement
in outcome
0.2
0.1
<22.8
>33.1
Quintiles of plasma Vitamin D ng/mL
Ng et al J Clin Oncol Jun 20;26(18):

34. 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 :

35. 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