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And What’s Next?
Jeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
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
Cured with Surgery Alone
Cured with Surgery andFluoropyrimidine
Cured with Surgery,Fluoropyrimidine,OxaliplatinRecur
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
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%
0
10
20
30
40
50
60
DuringTx
6months
1-year 2-year 3-year 4-year
Grade 1
Grade 2
Grade 3
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
Grothey A et al. JCO 2011;29:421-427
Intravenous Ca / Mg for Oxaliplatin-Induced Sensory Neurotoxicity: NCCTG N04C7
Grothey A et al. JCO 2011;29:421-427
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.
Relapse-free Survival by Adjuvant Treatment Arms6 Months of bolus 5FU/LV vs. 3 months of Continuous
Infusion 5FU
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
0.00
0.25
0.50
0.75
1.00
0 10 20 30 40 50
CALGB 89803: Aspirin Use and Disease-Free Survival in Stage III Colon Cancer
Pro
po
rtio
n D
isea
se-F
ree
and
Ali
ve
Log rank, p = 0.03
Months
Consistent aspirin users
Non-consistent users
HR = 0.46 (95% CI, 0.23-0.95)
Fuchs ASCO 2005 Abstract 3530
Chan, A. T. et al. JAMA 2009;302:649-658.
Survival According to Aspirin Use After Diagnosis: Nurse’s Health Study
CALGB/SWOG 80702 for Stage III Colon Cancer
Celecoxib starts concurrently with FOLFOX and continue for 3 years
6 versus 12 treatments FOLFOX
Arm A12 FOLFOX
+Placebo daily
Celecoxib versus Placebo
Arm B12 FOLFOX
+Celecoxib
400 mg daily
Arm C6 FOLFOX
+Placebo daily
Arm D6 FOLFOX
+Celecoxib
400 mg daily
N = 2,500
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 FuchsJeffrey MeyerhardtBrian WolpinKimmie NgAndrew ChanNadine McClearyDonna NiedzwieckiDonna HollisCALGB
89803 and Exercise: Disease-Free Survivalin Stage III Colon Cancer Survivors
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
1
0.87 0.9
0.51 0.55
0
0.2
0.4
0.6
0.8
1
1.2
<3 3-8.9 9-17.9 18.26.9 >27
Regular Physical Activity (met-hours per week)
Haz
ard
Rat
io R
ecu
rren
ce o
r D
eath
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
STRATIFICATIONDisease stage high risk III; centre; BMI ≤ 27.5 vs. > 27.5;
ECOG PS 0 vs. 1
RANDOMIZATION
ARM 1Physical Activity Program + General Good Health
Education Material (Intervention Arm)
ARM 2General 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
Dignam, J. J. et al. J. Natl. Cancer Inst. 2006 98:1647-1654
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
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
Meyerhardt 1990-1992 1792rectal
DFS 1.10 (0.91-1.32) BMI > 30 kg/m2
OS 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 DFS 1.06 (0.93-1.21) BMI 30-34.9 kg/m2
1.27 (1.05-1.53) BMI > 35 kg/m2
Meyerhardt 1999-2001 1053 DFS 1.00 (0.72-1.40) BMI 30-34.9 kg/m2
1.24 (0.84-1.83) BMI > 35 kg/m2
OS 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 OS 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 % 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
Meyerhardt J Clin Oncol. 2008 Sep 1;26(25):4109-15.
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
CALGB 89803: DFS By Dietary Pattern
11 1.1 10.7
1.3
0
0.5
1
1.5
2
2.5
3
3.5
4
1 2 3 4 5Quintiles of Dietary PatternH
aza
rd R
atio
for
Ca
nce
r R
ecu
rre
nce
or
De
ath
Prudent diet
1.2
22.2
3.9
Western diet
P, trend < 0.001
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
0.890.83
0.49
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
<22.8 22.8-27.1 27.2-33.1 >33.1
Quintiles of plasma Vitamin D ng/mL
Haz
ard
Rat
io f
or
Dea
th
(0.28-0.86)
P, trend = 0.01
People with highest level of vitamin D have 50% improvement in outcome
Ng et al J Clin Oncol. 2008 Jun 20;26(18):2984-91
Predicted Vitamin D Level* & Survival in Colorectal Cancer Patients: NHS/HPFS (N=1017)
Ng et al Br J Cancer. 2009 101: 916-23.
CRC Specific Mortality Overall Mortality
* Based on race, geography, exercise, BMI, dietary vitamin D, supplement vitamin D
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
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