And What’s Next?

Jeffrey Meyerhardt, MD, MPHDana-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 1Grade 2Grade 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

Prop

ortio

n D

isea

se-F

ree

and

Aliv

e

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

10.87 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 >27Regular Physical Activity (met-hours per week)

Haz

ard

Rat

io R

ecur

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e or

Dea

th

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

azar

d R

atio

for C

ance

r Rec

urre

nce

or D

eath

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)

10.89

0.83

0.49

00.10.20.30.40.50.60.70.80.9

1

<22.8 22.8-27.1 27.2-33.1 >33.1Quintiles of plasma Vitamin D ng/mL

Haz

ard

Rat

io fo

r 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