physical activity and colorectal cancer...
TRANSCRIPT
Physical Activity, Energy Balance and Colorectal Cancer Survivorship
Jeffrey Meyerhardt, MD, MPH
Dana-Farber Cancer Institute
Disclosures
• None
Colorectal Cancer Epidemiology
• Estimated 136,830 new cases in 2014 • Fourth most common cancer in the United
States • Third most commonly diagnosed cancer in men • Third most commonly diagnosed cancer in women
• Estimated 50,310 deaths from CRC in 2014 –Second leading cause of cancer deaths in the
United States
Siegel R et al. Ca Cancer J Clin. 2014;63:9–29.
Colorectal Cancer:
Risk Factors Overview
Decrease Risk Increase Risk Uncertain Impact
Screening Family history Statins
Exercise
Aspirin / NSAIDs
Ulcerative colitis/
Crohn’s Disease
Fiber
Glycemic load
Vitamin D Diabetes Fruits/Vegetables
Post-menopausal
estrogen
Obesity
Red meat
Folic Acid
Calcium Western diet
Alcohol
Smoking
Energy Balance
Calorie Intake
Modified by ingestion and/or
absorption (e.g., changes in
microflora, surgery,
pharmacologic agents)
Resting Metabolic Rate
Energy needed to maintain body function at rest. Accounts for ~60-75% of expenditure. Modified by
lean body mass (age), and external/internal temperature.
Physical Activity
Energy needed for activity.
Usually accounts for 15-30%
of expenditure, but most
modifiable component
Thermic Effect of Food
Energy needed for digestion or metabolism. Accounts for <10%
of expenditure. Modified somewhat by digestibility,
capsaicin, caffeine.
Body Weight
Gain
Stable
Loss
Energy Intake
(energy in)
Total Energy Expenditure
(energy out)
From Demark-Wahnefried et. al. Cancer Epidemiol Biomarkers Prev. 2012 Aug;21(8):1244-59.,
Physical Activity and Colon Cancer Risk
Boyle T et al. JNCI J Natl Cancer Inst 2012;104:1548-1561
Relative risk of colon cancer per 5-unit
increase in BMI (in kg/m2)
Larsson S C , and Wolk A Am J Clin Nutr 2007;86:556-565
Meta-analysis of red and processed meats
consumption and the risk of colorectal cancer
Chan DSM, Lau R, Aune D, Vieira R, et al. (2011) Red and Processed Meat and Colorectal Cancer Incidence: Meta-Analysis of
Prospective Studies. PLoS ONE 6(6): e20456.
What about Cancer Patients/Survivors
Adherence to Lifestyle Behavior Recommendations in Colorectal Cancer
Patients/Survivors • 9,105 survivors of 6 difference cancers (1,918
CRC) within 10 years of diagnosis
Cancer Group Physical
Activity * (%) 5 fruit/vege-
A-Day (%) Smoking
cessation (%)
Breast 37.1 18.2 88.1
Prostate 43.2 15.6 91.6
Colorectal 35.0 15.9 91.3
Bladder 36.0 16.3 82.6
Uterine 29.6 19.1 91.1
Skin melanoma
47.3 14.8 89.0
JCO May 1, 2008 vol. 26 no. 13 2198-2204
* at least 150 minutes of moderate-to-strenuous or 60 minutes of strenuous PA per week
Trajectory of Cancer Survivorship
• Active Treatment and Recovery
• Living after recovery, including disease-free and stable disease
• Advanced cancer and end of life
CA: A Cancer Journal for Clinicians; 62: 242-274, July / August 2012
Trajectory of Cancer Survivorship
• Active Treatment and Recovery
• Living after recovery, including disease-free and stable disease
• Advanced cancer and end of life
CA: A Cancer Journal for Clinicians; 62: 242-274, July / August 2012
Physical Activity Immediately After Surgery
Int J Colorectal Dis. 2013 May;28(5):643-51 StretchingCore Resistance Ambulation
Physical Activity Immediately After Surgery
Int J Colorectal Dis. 2013 May;28(5):643-51
Exercise group Usual care
p value Effect size Median (IQR)
Mean (SD) Median (IQR)
Mean (SD)
Time to flatus (h)
50.9 (38.6–64.4)
52.2 ± 21.6 73.87 (47.5–95.8)
71.9 ± 29.2 0.036 0.68
Time to liquid diet intake (h)
69.8 (64.9-91.7)
76.9 ± 24.4 86.74 (80.7–100.0)
86.0 ± 20.7 0.177 0.44
Role of Physical Activity during Active Treatment and Recovery
• Numerous studies have examined association of physical activity to quality of life and overall health
• 9 published physical activity only intervention trials and 2 multiple behavioral intervention trials published – Timing of initiation varied
– Type of intervention varied
– Several trials with multiple cancer types
Randomized Study of Exercise v Usual Care in Colorectal Cancer Survivors
Personalized Exercise Counseling v Usual care 16 weeks
Most on adjuvant therapy
Eur J Cancer Care (Engl). 2003 Dec;12(4):347-57. 3
Randomized Study of Exercise v Usual Care in Colorectal Cancer Survivors
Adherence in exercise group – 25%; Contamination in control group – 50%
Control Group (n=31) Exercise Group (n=62) P
Mild exercise 56.53 (65.18) 43.30 (103.41) 0.518
Moderate exercise 116.21(181.50) 145.24 (106.50) 0.334
Strenuous exercise 7.38 (36.33) 4.99 (20.23) 0.684
Moderate/strenuous exercise combined
123.59 (182.73) 150.23 (109.67) 0.383
Total exercise 180.12 (185.82) 193.52 (146.36) 0.705
% > 60 Moderate/strenuous exercise
51.6 75.8 0.019
% > 150 Moderate/strenuous exercise
32.3 41.9 0.366
Eur J Cancer Care (Engl). 2003 Dec;12(4):347-57. 3
Randomized Study of Exercise v Usual Care in Colorectal Cancer Survivors
Eur J Cancer Care (Engl). 2003 Dec;12(4):347-57. 3
Adherence in exercise group – 25%; Contamination in control group – 50%
Variable Baseline P-value Post-intervention
Mean change D in mean change [95% CI]
P-value
Intent-to-Intent
FACT-C (0–132)
Exercise group
106.0 (14.0) 107.4 (16.5) 1.4 (15.7)
Control group 107.0 (16.0) 0.756 109.8 (18.8) 2.7 (12.5) −1.3 [−7.8 - 5.1]
0.679
Ancillary Analyses
Increased fitness group
106.9 (15.6) 110.9 (14.9) 4.3 (13.2)
Decreased fitness group
105.9 (13.0) 0.796 103.7 (19.8) −2.2 (16.1) 6.5 [0.4 - 12.6]
0.038
Role of Physical Activity during Active Treatment and Recovery
• Among exercise only intervention trials mix of outcomes – Backman et al – no effect on HRQOL, anthropometry
or biomarkers for 10 week intervention of daily 10,000 steps and weekly group walks
– Lin et al – improved strength, fitness, physical function, social function, fatigue and pain but none statistically significant in 12 week aerobic and resistance supervised sessions
– Cheville et al – improved mobility, fatigue and sleep quality with home based program
Acta Oncol. 2014 Apr;53(4):510-20; Cancer Nurs. 2014 Mar-Apr;37(2):E21-9; J Pain Symptom Manage. 2013 May;45(5):811-21
Trajectory of Cancer Survivorship
• Active Treatment and Recovery
• Living after recovery, including disease-free and stable disease
• Advanced cancer and end of life
CA: A Cancer Journal for Clinicians; 62: 242-274, July / August 2012
Role of Physical Activity during Living after Recovery Phase
• Multiple exercise only studies with mixed results
– Pinto et al used telephone based intervention - but no intervention effect on fatigue, physical function, or QOL
– Ligibel et al used telephone based intervention – improvement in fitness and physical function
Psychooncology. 2013 Jan;22(1):54-64; Breast Cancer Res Treat. 2012 Feb;132(1):205-13.
Role of Physical Activity during Living after Recovery Phase
• 2 multiple behavioral change studies
– CanChange (CRC within 12 months) - telephone based intervention focusing on physical activity, weight management, dietary habits, alcohol, and smoking
• ↑PA, ↓BMI, ↓Energy from total fat, ↑Vegetable intake
• No significant difference in QOL, fatigue
– RENEW (elderly > 5 yrs from dx – prostate, breast, CRC) - telephone based intervention focusing on physical activity, moderate weight loss and improved diet quality
• Reduced rate of self report functional decline
J Clin Oncol. 2013 Jun 20;31(18):2313-21; JAMA. 2009 May 13;301(18):1883-91.
Role of Physical Activity during Living after Recovery Phase
• Physical activity and risk of recurrence
– Data from prospective cohort study
– Studies vary on timing of physical activity measurement (before or after diagnosis)
– Intervention studies have focused on potential biomarkers
Physical Activity and
Colorectal Cancer Specific Survival
• Cohort study from Australia of 526 colorectal cancer patients
with pre-diagnosis physical activity assessment
Colorectal cancer specific survival
Gut. 2006 Jan;55(1):62-7
CALGB 89803
• NCI-sponsored adjuvant therapy trial for stage III colon cancer
• Patients randomized to Roswell Park 5-FU/LV or IFL (bolus 5-
FU/LV/Irinotecan)
• 1264 enrolled between 1999 and 2001
Patients enroll on adjuvant therapy trial
0 2 4 6 8 10 12 14 16
chemotherapy
Complete questionnaire
Complete questionnaire
every 3 month f/u
J Clin Oncol; 25:3456-3461 2007
CALGB 89803
J Clin Oncol. 2007 Aug 10;25(23):3456-61.
89803 and Exercise: Disease-Free Survival
in Stage III Colon Cancer Survivors
J Clin Oncol; 24:3535-3541 2006
Regular Physical Activity (met-hours per week)
Haz
ard
Rat
io R
ecu
rre
nce
or
De
ath
89803 and Exercise: Disease Free Survival
J Clin Oncol; 24:3535-3541 2006
89803 and Exercise: Stratification
J Clin Oncol; 24:3535-3541 2006
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
NHS and Post-diagnosis Physical Activity
J Clin Oncol; 24:3527-3534 2006
NHS and Post-diagnosis Physical Activity
J Clin Oncol; 24:3527-3534 2006
NHS and Pre-diagnosis Physical Activity
J Clin Oncol; 24:3527-3534 2006
NHS and Change in Physical Activity
J Clin Oncol; 24:3527-3534 2006
Meta-Analysis of Pre-Diagnosis Physical
Activity and Colorectal Cancer Outcomes
Int J Cancer. 2013 Oct 15;133(8):1905-13.
Meta-Analysis of Post-Diagnosis Physical
Activity and Colorectal Cancer Outcomes
Int J Cancer. 2013 Oct 15;133(8):1905-13.
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.
Lee, Meyerhardt, Giovannucci, Jeon, PLOS One, In Press
Body Mass Index and Stage I-III
Colorectal Cancer
CALGB 89803: DFS By Dietary Pattern
1 1 1.1 1 0.7
1.3
0
0.5
1
1.5
2
2.5
3
3.5
4
1 2 3 4 5 Quintiles of Dietary Pattern H
azar
d R
atio
fo
r C
ance
r R
ecu
rren
ce o
r D
eath
Prudent diet
1.2
2 2.2
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.
Dietary Patterns
• Study of 529 colorectal cancer patients in Newfoundland
• Pre-diagnosis diet
Zhu et al BMJ Open 2013 Feb 7;3(2).
DFS – CRC Colon Rectal
Glycemic Load
in Colon Cancer Patients
Quintiles of Glycemic Load Haz
ard
Rat
io f
or
Can
cer
Rec
urr
ence
or
Dea
th
Meyerhardt, J. et al JNCI 2012
Glycemic Load
in Colon Cancer Patients
Quintiles of Glycemic Load Haz
ard
Rat
io f
or
Can
cer
Rec
urr
ence
or
Dea
th
Meyerhardt, J. et al JNCI 2012
1
0.650.81
10.91
1 0.991.07
1.7
2.26
0
0.5
1
1.5
2
2.5
1 2 3 4 5
BMI < 25
BMI > 25
Sugar Sweetened Beverage
in Colon Cancer Patients
Sugar Sweetened Beverage Intake
Haz
ard
Rat
io f
or
Can
cer
R
ecu
rren
ce o
r D
eath
Fuchs MA et al, PLOS One 2014
P trend = 0.03
Insulin-related Growth Factors
and Outcomes
JCO 2009;27:176-185
C-peptide IGFBP-1
Colorectal cancer-specific survival (years) Colorectal cancer-specific survival (years)
Overall survival (years) Overall survival (years)
All stage I-III cases with nuclear CTNNB1(+)
All stage I-III cases with nuclear CTNNB1(-)
Log-rank p=0.0054
Log-rank p=0.029
Log-rank p=0.73
Log-rank p=0.60
A C
B D
Even
t p
rob
abili
ty
Even
t p
rob
abili
ty
Even
t p
rob
abili
ty
Even
t p
rob
abili
ty
≥18 MET-hours/w
<18 MET-hours/w
≥18 MET-hours/w
<18 MET-hours/w
≥18 MET- hours/w
<18 MET- hours/w
≥18 MET-hours/w
<18 MET-hours/w
Association between Physical Activity and Outcomes by CTNNB1 (b catenin) Status
JAMA. 2011 Apr 27;305(16):1685-94
WNT-CTNNB1 signaling adipogenesis, obesity, and metabolic diseases.
Inactive WNT-CTNNB1 signaling pathway associated with energy balance Active WNT-CTNNB1 signaling pathway independent of energy balance
Cancer Epidemiol Biomarkers Prev 2013;22:1142-1152
Association between Physical Activity and Outcomes by PTGS2 (COX-2) Status
TGS2 and its enzymatic product, PGE2, inflammatory responses and associated with colorectal cancer development and progression Physical activity modulate PGE2 synthesis
Role of Physical Activity in Advanced Cancer and End of Life Phase
• Active Treatment and Recovery
• Living after recovery, including disease-free and stable disease
• Advanced cancer and end of life
CA: A Cancer Journal for Clinicians; 62: 242-274, July / August 2012
Role of Physical Activity in Advanced Cancer and End of Life Phase
• Limited data on impact of physical activity in advanced disease patients in terms of quality of life and tolerance to chemotherapy
• Jeon et al – CALGB 89803 – for those patients that recurred, increased physical activity associated with nonsignficant improved survival (Hazard ratio 0.71 (95% CI, 0.46-1.11); P trend = 0.052)
J Support Oncol. 2009 Jan-Feb;7(1):27-34; Clin Colorectal Cancer. 2013 Dec;12(4):233-8.
Conclusions
• Emerging data of association/impact of physical activity and other energy balance factors across the colorectal cancer continuum
• Many unanswered question
– Timing of initiation of therapy
– Length of intervention – lifelong versus more critical in peri-diagnosis phase
– Level of physical activity and what diet necessary for benefit
– Best approach to use to study – supervised, remote
– Secondary gains (other comorbidities, other cancers)