and what’s next? jeffrey meyerhardt, md, mph dana-farber cancer institute boston, ma
TRANSCRIPT
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And What’s Next?
Jeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Boston, MA
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Disclosures
· Research Funding· NCI· Bristol Myers Squibb (to DFCI)· Astra Zeneca (to DFCI)
· Consultant· Bayer
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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
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Four Groups of Stage III Colon Cancer Patients
Cured with Surgery Alone
Cured with Surgery andFluoropyrimidine
Cured with Surgery,Fluoropyrimidine,OxaliplatinRecur
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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
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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)
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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
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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.
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Oxaliplatin Toxicity
• Neuroprotectants
• Duration of therapy
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Intravenous Ca / Mg for Oxaliplatin-Induced Sensory Neurotoxicity: NCCTG N04C7
Grothey A et al. JCO 2011;29:421-427
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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.
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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
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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
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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
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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
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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
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Chan, A. T. et al. JAMA 2009;302:649-658.
Survival According to Aspirin Use After Diagnosis: Nurse’s Health Study
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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
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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?
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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
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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
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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
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89803 and Exercise: Stratification
Meyerhardt, J. A. et al. J Clin Oncol; 24:3535-3541 2006
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NHS and Post-diagnosis Physical Activity
Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006
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NHS and Post-diagnosis Physical Activity
Meyerhardt, J. A. et al. J Clin Oncol; 24:3527-3534 2006
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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.
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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
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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
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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%
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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
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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.
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CALGB 89803: Dietary Pattern
Meyerhardt, J. et al. JAMA 2007;298:2263-a.
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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
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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
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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