Improving Outcomes from Colorectal Cancer: Diet, Lifestyle, and Chemoprevention

Transcription

1 Improving Outcomes from Colorectal Cancer: Diet, Lifestyle, and Chemoprevention Kimmie Ng, MD, MPH Director of Clinical Research Director, GI Biobank and Biospecimen Research Gastrointestinal Cancer Center Dana-Farber Cancer Institute Harvard Medical School Boston, MA 2018 Master Class Course

2 Disclosure Disclosure I have nothing to disclose. Off Label/Investigational Discussion In accordance with Annenberg Center policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

3 Audience Response Question #1 Observational studies suggest that diet and lifestyle modification can reduce the risk of developing colorectal cancer by: (A) 10% (B) 25% (C) 40% (D) 55% (E) 70%

4 Audience Response Question #2 Observational studies suggest that stage III colon cancer patients who comply with American Cancer Society Nutrition and Physical Activity Guidelines improve their disease-free survival by: (A) No improvement in disease-free survival (B) 30% (C) 50% (D) 70% (E) 90%

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7 AJCC Stage and Five Year Survival Edge SB, et al. AJCC Cancer Staging Manual; 2010.

8 Doc, What should I eat? Should I exercise? What else can I do?

9 Colonoscopy: Effective But With Limits No screening Colonoscopy screening Incident CRC ( ) Distal colorectum ( ) Proximal colon ( ) Death from CRC ( ) Distal colorectum ( ) Proximal colon ( ) Nishihara R, et al. N Engl J Med 2013; 369(12): 1095.

10 Diet and Colorectal Cancer Risk The relationship between diet and cancer development has been a topic of great interest for over a century A recent search for diet and cancer in the PubMed database produced 44,240 citations (3/22/18) Geographic variation in colorectal cancer incidence Highest in Western countries 40-fold difference between U.S. and Africa Emigration studies: Migrants from low- to highincidence areas assume the incidence of the host country within one generation Many studies report conflicting results

11 Ongoing Prospective Cohort Studies Nurses Health Study (N = 121,700) OC s Smoking Weight/Ht Med. Hist. Diet Diet Diet Diet Diet Diet Diet Diet Blood samples Health Professionals Follow-Up Study (N = 52,000) Diet Diet Diet Diet Diet Diet Blood samples

12 Red Meat Intake and Risk of Colon Cancer in Women Relative Risk for Colorectal Cancer [ ] 1.50 [ ] 1.84 [ ] 2.49 [ ] P trend = 0.01 <1/month 1-4/month 2-4/week 5-6/week Servings of Beef, Pork, or Lamb >1/day Willett WC, et al. N Engl J Med 1990; 323:

13 Physical Activity and Risk of Colon Cancer Kyu HH, et al. BMJ 2016; 354: i3857.

14 Aspirin and Colorectal Cancer: Weight of the Evidence > 100 Case control and cohort studies 5 RCTs of aspirin for adenoma recurrence WHS RCT of aspirin for CV and cancer prevention CAPP2 RCT of aspirin in Lynch Syndrome > 50 CV prevention RCTs of aspirin linked with cancer outcomes

15 Aspirin and Adenoma Trials TRIAL Baron, NEJM 2003 Sandler, NEJM 2003 Benamouzig, Gastro 2003 Logan, Gastro 2008 Ishikawa, Gut 2014 NO. PATIENTS 1121 prior adenoma 635 prior CRC 272 prior adenoma 945 prior adenoma 311 prior adenoma DURATION 3 years DOSE 81 mg 325 mg RELATIVE RISK 0.83 ( ) 0.96 ( ) 3 years 325 mg 0.65 ( ) 1 year 160 mg 300 mg 0.85 ( ) 0.61 ( ) 3 years 300mg 0.79 ( ) 2 years 100 mg 0.60 ( )

16 COX-2 Inhibitors and Adenoma Trials APC TRIAL (Bertagnolli, 2006) NO. PATIENTS 2,035 Celecoxib AGENT DOSE RELATIVE RISK 200 mg BID 400 mg BID 0.67 ( ) 0.55 ( ) Arber, ,561 Celecoxib 400 mg QD 0.64 ( ) Baron, Rofecoxib 25 mg 0.76 ( )

17 More Seems To Be Better Multivariate Relative Risk for Colorectal Cancer P trend = Subjects using >14 tablets of aspirin per week had a 54% lower risk of developing colorectal cancer >14 Number of Aspirin Tablets Per Week Chan, AT, et al. N Engl J Med 2007; 356:

18 Longer Seems To Be Better Multivariate Relative Risk for Colorectal Cancer P trend < Subjects using aspirin the longest had a 42% lower risk of developing colorectal cancer >20 Years of Regular Aspirin Use Chan, AT, et al. N Engl J Med 2007; 356:

19 British Doctors Trial & UK-TIA Trial (n=7,588): Pooled Analysis Pooled HR 0.74 (95% CI, ) No aspirin Aspirin 300-1,200 mg/day Flossman E, et al. Lancet 2007; 369:

20 Aspirin Reduces Colorectal Cancer in Lynch Syndrome: CaPP2 Trial Participants completing 2 years of tx: HR 0.41 (95% CI ); P=0.02 Poisson IRR 0.37 (95% CI ); P=0.008 Poisson IRR 0.56 P=0.05 Burn J, et al. Lancet 2011; 378:

21 Aspirin for Colorectal Cancer: Making the Grade in 2016 The USPSTF recommends low-dose aspirin use for the primary prevention of cardiovascular disease and colorectal cancer Bibbins-Domingo K, et al. Ann Int Med 2016.

22 Vitamin D and Colorectal Cancer Vitamin D inhibits cell proliferation and angiogenesis, induces cell differentiation and apoptosis, and has anti-inflammatory effects Vitamin D receptor (VDR) and 1-α-hydroxylase are expressed in colorectal cancer (CRC) cells 1 Well-differentiated CRC cell lines have high VDR levels 2 Anti-proliferative effects of VitD are greatest in cell lines that express high levels of VDR 2 Animal studies: CRC-prone rats maintained on a high VitD diet develop fewer tumors and metastases than controls Treatment of APC min mice with VitD decreases tumor burden 3 Adenoma numbers and size increase in VDR-null APC min mice 4 1 Giovannucci E. Cancer Causes Control 2005; 16: Huerta S, et al. Cancer Res 2002; 62: Evans SR, et al. Clin Cancer Res 1998;4: Zheng W, et al. Int J Cancer 2011.

23 Plasma 25(OH)D and Risk of Colorectal Cancer 33% decrease in colorectal cancer with higher levels of vitamin D Ma Y, et al. J Clin Oncol 2011; 29:

24 Women s Health Initiative Trial of Vitamin D + Calcium n = 36,282 healthy post-menopausal women R A N D O M I Z A T I O N Vitamin D 400 IU/day + Calcium 1,000 mg/day Average treatment duration = 7 years Placebo Primary Endpoint: Incidence of Hip Fractures Secondary Endpoint: Incidence of Colorectal Cancer Wactawski-Wende J, et al. NEJM 2006; 354(7):

25 Secondary Endpoint: Incidence of Colorectal Cancer But. Low dose of vitamin D Short duration of supplementation Insufficient follow-up time Low adherence: Only 60% of subjects took at least 80% of required pills Wactawski-Wende J, et al. NEJM 2006; 354(7):

26 Randomized Trial of Vitamin D + Calcium n = 1,179 healthy post-menopausal women living in Nebraska R A N D O M I Z A T I O N Vitamin D 1,100 IU/day + Calcium 1,500 mg/day Calcium 1,500 mg/day Placebo Primary Endpoint: Incidence of Fractures Secondary Endpoint: Incidence of Cancer Lappe JM, et al. Am J Clin Nutr 2007; 85:

27 Secondary Endpoint: Cancer-Free Survival Ca+D Arm RR = 0.23 ( ) P <0.005 Lappe JM, et al. Am J Clin Nutr 2007; 85:

28 Follow-Up Randomized Trial of Vitamin D + Calcium n = 2,303 healthy post-menopausal women living in Nebraska R A N D O M I Z A T I O N Vitamin D 2,000 IU/day + Calcium 1,500 mg/day Placebo 4 years Primary Endpoint: Incidence of All-Type Cancer Lappe JM, et al. JAMA 2017; 317(12):

29 Incidence of Invasive and In-Situ Cancer But. Short duration of supplementation Insufficient follow-up time Use of vitamin D outside of study Mean baseline 25(OH)D was 32.7 ng/ml in placebo arm Low number of incident cancers 109 total, 8 CRC No power to assess individual cancers Lappe JM, et al. JAMA 2017; 317(12):

30 VITAL: VITamin D and OmegA-3 TriaL R A N D O M I Z A T I O N Vitamin D3 2,000 IU/d Placebo 24,000 healthy individuals across the U.S. with oversampling for African-Americans R A N D O M I Z A T I O N R A N D O M I Z A T I O N Omega-3 Fatty Acid 1 g/day Placebo Omega-3 Fatty Acid 1 g/day Placebo Primary Endpoints: Cardiovascular disease and/or Cancer

31 What Proportion of Colon Cancer Would Be Eliminated if Middle-Aged Men. Had a normal body-mass index Exercised >15 MET-hours/week Took a daily multivitamin containing folate Consumed <15 g of alcohol per day ( 1 drink per day) Did not smoke Ate 2 servings of red meat per week 71% Platz, et al. Cancer Causes Control 2000.

32 What is the role of diet and lifestyle among patients with established colon cancer?

33 CALGB 89803: Phase III Clinical Trial of Adjuvant Chemotherapy R A N D O M I Z A T I O N IFL Bolus 5-FU + leucovorin + irinotecan Roswell Park 5-FU + leucovorin NCI-sponsored adjuvant chemotherapy trial for stage III colon cancer 1,264 patients enrolled between 1999 and 2001 No significant difference found between treatment arms Saltz LB, et al. J Clin Oncol 2007; 25:

34 CALGB 89803: Diet, Lifestyle, and Medication Use Companion Study Complete 1 st questionnaire Complete 2 nd questionnaire Patients enroll on adjuvant therapy trial chemotherapy every 3 month f/u Included questions on: Diet and supplements Smoking Physical activity Medication use Other information

35 CALGB 89803: Physical Activity and Disease-Free Survival (n=832) Hazard Ratio for Recurrence or Death P trend = Subjects walking 6 hours per week had a 45% improvement in DFS < Physical Activity (MET-hours/week) >27 Meyerhardt JA, et al. J Clin Oncol 2006; 24:

36 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 (n=962) 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 KS, et al. Curr Oncol 2008;15(6):271-8.

37 Dietary Pattern and Colorectal Cancer Dietary patterns better reflect the real-world complexities of diet Account for interactions and synergy among dietary components Two major dietary patterns Western pattern = red meat, processed meat, refined grains, sweets and dessert, French fries, high-fat dairy products Prudent pattern = vegetables, fruit, legumes, whole grains, fish, poultry Western and prudent diet patterns predict risk of heart disease, diabetes, and colon cancer risk

38 CALGB 89803: Dietary Pattern and Disease-Free Survival (n=1,009) Hazard Ratio for Recurrence or Death Western diet Prudent diet P trend < Quintiles of Dietary Pattern 5 Meyerhardt JA, et al. JAMA 2007: 298(7):

39 Energy Balance and Colorectal Cancer Overconsumption GH Abdominal Obesity Physical Activity Insulin Resistance Competent β-cells Western Pattern Diet High Glycemic Diet Fasting Hyperinsulinemia Postprandial Hyperinsulinemia

40 5-Year Recurrence-Free Survival Non-diabetics 64% Diabetics 56% Hazard Ratio = 1.21 ( ) Meyerhardt JA, et al. J Clin Oncol 2003; 21:

41 CALGB 89803: Dietary Glycemic and Insulin Load and Disease-Free Survival Hazard Ratio for Recurrence or Death Glycemic Index: Measure of food-induced rise in plasma glucose Insulin Index: Measure of food-induced rise in plasma insulin Glycemic and Insulin Load: Total dietary intake Insulin load 1.8 Glycemic load Quintiles of Dietary Glycemic and Insulin Load Meyerhardt JA, et al. J Natl Cancer Inst Morales-Oyarvide V, et al. under review.

42 ACS Nutrition and Physical Activity Guidelines for Cancer Survivors Body-mass index <25 kg/m2 Exercise 150 minutes per week Limit red meat intake Eat 2.5 cups each of vegetables and fruits per day Choose whole grains instead of refined grains Developed point system based on ACS recommendations (0-6): 0 = poor compliance; 6 = best compliance Van Blarigan E, et al. JAMA Oncol 2018; in press.

43 CALGB 89803: ACS Score and Disease-Free Survival Hazard Ratio for Recurrence or Death P trend = Subjects with the highest compliance with ACS guidelines have a 31% improvement in DFS ACS Guidelines Score Van Blarigan E, et al. JAMA Oncol 2018; in press.

44 Aspirin Reduces Colon Cancer Mortality in Cardiovascular Trials mg daily BDAT (500 mg) UK-TIA (120 mg) mg daily UK-TIA (300 mg) TPT (75 mg) SALT (75 mg) Subtotal Total ( ) Odds Ratio (95% CI) 2 P=0.002 (sig) P=0.84 (het) Rothwell PM, et al. Lancet 2011; 377:

45 Post-Diagnosis Aspirin and Colorectal Cancer Survival in NHS/HPFS n = 1,279 stage I-III colorectal cancer patients Chan AT, et al. JAMA 2009; 302:

46 CALGB 89803: Aspirin Use and Disease-Free Survival Consistent aspirin use (n=75) Non-consistent aspirin use (n=724) Adjusted HR 0.51 (95% CI, ) Ng K, et al. J Natl Cancer Inst 2015.

47 Aspirin and Risk of Gastrointestinal Bleeding 2.4 Multivariate Relative Risk P trend < Number of Aspirin Tablets Per Week Huang, et al. Am J Med 2011.

48 Can we exploit mechanism to personalize chemoprevention and treatment?

49 Aspirin: Potential Mechanisms of Anti-Cancer Activity

50 Effect of Aspirin by Intratumoral COX-2 Expression Non- Users Regular Users All incident CRCs ( ) COX-2 positive ( ) COX-2 negative ( ) CRC-Specific Mortality ( ) COX-2 positive ( ) COX-2 negative ( ) P heterogeneity Chan AT, et al. N Engl J Med 2007; 356: Chan AT, et al. JAMA 2009; 302:

51 Aspirin and Colorectal Cancer Survival by PIK3CA Mutation Status Non- Users Regular Users P interaction CRC-Specific Mortality in NHS & HPFS ( ) PIK3CA mutant ( ) PIK3CA wild-type ( ) RFS in VICTOR ( ) PIK3CA mutant ( ) PIK3CA wild-type ( ) Liao X, et al. N Engl J Med 2012; 367: Domingo E, et al. J Clin Oncol 2013; 31:

52 CALGB/SWOG 80702: Phase III Trial of Adjuvant Therapy Resected Stage III Colon Cancer N = 2,500 R A N D O M I Z E 6 treatments of mfolfox6 12 treatments of mfolfox6 R A N D O M I Z E Celecoxib 400 mg daily Placebo Celecoxib 400 mg daily Placebo Celecoxib starts concurrently with FOLFOX and continues for 3 years

53 Plasma 25(OH)D and Colorectal Cancer Survival in NHS/HPFS Hazard Ratio for Death P trend = Subjects with the highest levels of vitamin D have a 48% improvement in survival < Plasma 25(OH)D (ng/ml) 33.1 Adjusted for age, gender, stage, grade, site, year of diagnosis, season of blood draw, BMI, and post-diagnosis physical activity) Ng K, et al. J Clin Oncol 2008; 26(18):

54 CALGB/SWOG 80405: Original Design mcrc 1st-line Strata: FOLFOX/FOLFIRI Prior adjuvant chemo Prior XRT FOLFIRI or FOLFOX MD choice Chemo + Cetuximab Chemo + Bevacizumab Chemo + Bevacizumab and Cetuximab n = Endpoint: Overall Survival Presented by: Kimmie Ng, MD, MPH

55 80405: Higher 25(OH)D Associated with Improved Survival 1.0 Quintile mos (months) 95% CI Overall Survival Probability Log rank P = 0.01 Adjusted HR 0.65 (95% CI, ) Median 25(OH)D 17.2 ng/ml n = 1,043 No. at Risk Quintiles 1 & 2 Quintiles 3 & 4 Quintile Time (years) Ng K, et al. J Clin Oncol 2015; 33 (suppl): abstract 3503.

56 80405: Higher 25(OH)D Associated with Improved PFS 1.0 Quintile mpfs (months) 95% CI Progression-Free Survival Probability Adjusted HR 0.79 (95% CI, ) Log rank P = 0.02 No. at Risk Quintiles 1 & 2 Quintiles 3 & 4 Quintile Time (Years) Ng K, et al. J Clin Oncol 2015; 33 (suppl): abstract 3503.

57 SUNSHINE: Randomized Phase II Trial Previously Untreated Metastatic CRC n=139 April 2012 November 2016 Ng K, et al. ASCO R A N D O M I Z A T I O N 1:1 FOLFOX-bevacizumab + Vitamin D3 8,000 IU/day x 2 weeks (loading dose), followed by Vitamin D3 4,000 IU/day (maintenance dose) FOLFOX-bevacizumab + Vitamin D3 400 IU/day Primary Endpoint PFS Secondary Endpoints OS RR Toxicity Plasma 25(OH)D Data lock April 25, 2017 Presented by: Kimmie Ng, MD, MPH

58 High-Dose Vitamin D Resulted in Improved PFS Arm Median PFS (months) % CI Unadjusted HR 0.69 (95% CI, ) Adjusted HR 0.67 (95% CI, ) Log rank P = 0.04 Ng K, et al. ASCO Presented by: Kimmie Ng, MD, MPH

59 Randomized Trial of Preoperative Vitamin D: Determining Transcriptional Targets Co-investigators: Surgical oncology: Thomas Clancy, MD Colorectal surgery: Ronald Bleday, MD; Joel Goldberg, MD Pathology: Jason Hornick, MD, PhD

60 Colorectal Cancer: Reducing Incidence and Mortality Decrease Risk of Developing CRC: BMI 25 mg/k2 Physical activity 15 METhours/week Alcohol <15 g/day Don t smoke Red meat 2 servings/week Consider aspirin Improve CRC Patient Survival BMI 25 mg/k2 Physical activity 15 METhours/week Avoid high glycemic and insulin load diet Avoid excessive Western diet Vitamin D 30 ng/ml Consider aspirin