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antonio.di-meglio@gustaveroussy.fr
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Outline and learning objectives
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1. Obesity: Definition and Prevalence
Attributable risk percent of cancers Quickly overtaking tobacco as the leading preventable cause of cancer
4% of all cancers in men (38,000 cancers/year)
due to obesity:
7% of all cancers in women (50,500 cancers/year)
If every person in the US decreased BMI 73,000-127,000 fewer cancers based on current rates of obesity
by 1 unit (about 2.2 lbs) there would be: 573,000-627,000 fewer cancers based on increasing rates of obesity
% Of obesity % Of obesity
40% 40,0
35% 35,0
30% 37%
31% 33% 30% 30,0
20,9
20,3
25%
19,2
25,0 Diagnosis
20% 26%
23% 23% 21% 20,0 Year 1
15% 15,0
10% 17% 16% Year 2
10,0
5% 5,0
0% 0,0
Biological
substrate of
cancer in
the obese
Obesity and Obesity as a
financial risk factor
burden for cancer
The link
Obesity as
Impact on Obesity-Cancer prognostic
quality of
factor for
life
cancer
Impact on
Risk of
treatment
second
delivery cancers
and toxicity
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3. The link Obesity-Cancer
Biological
The link substrate of
cancer in the
Obesity-Cancer obese
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Obesity, lifestyle factors, and cancer:
underlying biological mechanisms
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Obesity as a risk factor in cancer
Multiple studies found strong evidence supporting the association between obesity and cancers,
although the strength of the association and the types of cancers vary somewhat across studies
- Positive association of increasing BMI with cancers
occurring in a wide range of sites.
- A male-specific association
colorectal cancer (p = 0.023),
- A female-specific association
brain (p = 0.025) 13
kidney (p = 0.035). Adapted from: Fang X, IJC 2018
Obesity as a risk factor in cancer
- Recent pooled individual-level data analysis of 758,592 women / Data from 19 prospective cohort studies (1963-2013)
- Inverse association between increasing BMI and decreased risk of breast cancer 14
- Universal and across strata of other risk factors and cancer subtypes Adapted from: Schoemaker MJ, JAMA Oncology 2018
3. The link Obesity-Cancer
Obesity as
The link prognostic
factor for
Obesity-Cancer cancer
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Obesity as a prognostic factor in cancer
- Data linking obesity to poor outcomes is strongest in breast, colorectal, and prostate cancer
- Emerging data suggest that obesity might be a prognostic factor also in other malignancies, including childhood leukemia
ER/PgR + ER/PgR –
Obese vs. normal weight
HR (95% CI) HR (95% CI)
BCRT, 2012 Total Mortality 1.31 (1.17–1.46) 1.18 (1.06–1.31)
- Meta-analysis of 21 studies Breast Cancer Mortality 1.36 (1.20-1.54) 1.46 (0.98-2.19)
- HR+ and HR- cancers
- No evidence of a significant interaction with HR status Significant and consistent relationship between obesity and
poor outcomes in women with early stage breast cancer
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Obesity as a prognostic factor in cancer
- Mixed data regarding the relationship between BMI and colon cancer outcomes
- In a metanalysis of 7 adjuvant chemotherapy trials for patients with stage II and III colorectal cancer (N= 25,291) treated
with fluoro-uracil based therapy within the Adjuvant Colon Cancer Endpoints (ACCENT) database:
- BMI was significantly prognostic in men for DFS (P< .0001) and OS (P < .0001), but not in women (all P > .10)
- There was a significant interaction BMI-sex for OS (Pinteraction = .0129)
Sinicrope FA, Cancer 2013
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Obesity as a prognostic factor in cancer
- Obesity is associated with the development of biologically adjRRs (95% CI) vs. normal Mortality
more aggressive and advanced prostate cancer Overweight 1.25 (0.87-1.80)
- A significant elevation in prostate cancer mortality was
Obese I 1.46 (0.92-2.33)
observed at higher BMI levels
Obese II 2.12 (1.08-4.15)
- Adj HRs (95% CI) for events = 1.5 (1.1 - 2.1; P=.009) obese vs. not obese
- Adj HRs (95% CI) for relapses and = 1.5 (1.2 - 2.1; P=.013) obese vs. not obese
Log-rank P = .01
N = 1003 (obese n=95)
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Obesity and risk of second malignancies
- Together with other modifiable lifestyle factors, obesity is associated with higher risk of second primary breast cancer
ORs (95% CI) of developing N= 365 patients with ER+ breast cancer
Lifestyle factor (at diagnosis)
contralateral breast cancer N= 726 matched controls
Obesity 1.4 (1.0-2.1)
Consumption of 7+ alcohol servings/week 1.9 (1.1-3.2)
Being current smoker 2.2 (1.2-4.0) Li CI, J Clin Onc 2009
- In the French national CANTO cohort, overweight and obesity at diagnosis were associated with a higher rate of breast
cancer recurrences (local, nodal, or distant) and second cancers (N. Events 221).
% Of overweight and obesity (N=5098) Cancer recurrence rates (%)
Proportion of patients (%)
40,0
29,8
29,7
28,9
35,0
30,0 8,0
20,9
25,0
5,3
20,0 6,0 adjusted OR (95% CI)
1.41 (1.05-1.91)
15,0
4,0 3,4 vs. Underweight/Normal
10,0
5,0 2,0
0,0
Overweight Obese 0,0 Di Meglio A, ESMO Congress 2018
Diagnosis Year 1 Year 2 Underweight/Normal Overweight/Obese 20
3. The link Obesity-Cancer
Impact on
The link cancer
treatment
Obesity-Cancer delivery and
toxicity
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Obesity and delivery of cancer treatment:
Increased treatment toxicity and morbidity
- Delay in seeking medical care and less likelihood to participate in screening programs
Maruthur NM, Journal of General Internal Medicine 2009
Fagan H, J Obes 2011
- Among 2258 patients who underwent major abdominal cancer surgery, higher BMI was associated with higher rates of post-surgical
complications and wound infections
Underweight Normal weight Overweight Obese I Obese II Obese III
Outcome p (ANOVA)
(n=55) (n=819) (n=811) (n=357) (n=137) (n=79)
Morbidity rate 21.8 23.1 26.0 29.1 29.9 32.9 0.11
Complications 9.1 13.1 14.2 16.8 18.2 25.3 0.023
Wound infections 7.3 10.0 12.5 16.5 13.1 19.0 0.0084 22
Mullen T, Ann Surg Oncol 2008
3. The link Obesity-Cancer
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Obesity and Quality of life of cancer patients
- Obesity and unfavourable energy balance can adversely impact several physical and psychological outcomes, including:
- Poor physical functioning
- Reduced capacity for physical activity
- Dimished sexual functioning
- Fatigue
Kolotkin RL, Surg Obes Relat Dis 2009
- Dyspnea
Martinelli LM, Clinics 2008
- Poor body image
- The Women’s Healthy Eating and Living (WHEL) Study found that obesity was
significantly associated with
- Worse physical functioning in all study participants (p=.001)
- Worse physical health, vitality, pain, and overall health-related QoL
in white study participants (all p=.001)
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3. The link Obesity-Cancer
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Obesity and financial toxicity
- In a recent analysis of costs and admission rates in relation to BMI at recruitment among over 1 million women in the UK NHS:
- Increasing BMI at diagnosis was associated with higher hospital admission rates and care costs
- Overweight and obesity were associated with increased hospital costs for most diagnostic categories, including neoplasms
- Many cancer survivors experience weight gain after cancer diagnosis, particularly:
- in individuals treated with chemotherapy, (especially if it includes steroid)
- when chemotherapy results in premature menopause for a previously premenopausal woman
- women treated with chemotherapy gain 2-5 kg and up to 10 Kg of weight in the first 1-2 years after breast cancer diagnosis
Reddy SM, Br J Cancer 2013
Caan BJ, CEBP 2012
- Change in body composition and «sarcopenic obesity» (loss of muscle mass and concomitant gain of adipose tissue):
- common in individuals receiving chemotherapy
- can be seen in patients receiving androgen deprivation therapy for prostate cancer
Timilshina N, Cancer 2012
At 2 years post-diagnosis
Patient and treatment characteristics
% pts gaining Mean n.
At diagnosis of breast cancer adjOR (95% CI)
≥5% weight Kg gained
Total - 24.0 +6.6 -
Age at diagnosis <50 years 35.5 +7.1 1.98 (1.28-3.06)
≥50 and <65 years 23.6 +6.3 1.95 (1.45-2.64) Data from the French national CANTO cohort:
≥65 years 11.3 +5.9 Ref. 5800 patients with early breast cancer
Receipt of CT Yes 29.0 +6.9 1.62 (1.29-2.04) Diagnosed from 2012-2014
No 18.1 +6.2 Ref.
Receipt of ET Yes 23.8 +6.6 1.29 (0.99-1.67) Di Meglio A, ESMO Congress 2018
No 24.7 +6.5 Ref.
PA exposure < 10 MET-hrs/week 25.5 +6.9 1.24 (1.01-1.52)
≥ 10 MET-hrs/week 22.0 +6.3 Ref.
Weight gain at year 1 For each 1-Kg gained - - 1.56 (1.50-1.62)
For each 6-Kg gained - - 14.41 (11.39-18.07) 27
4. Weight gain among cancer patients
- Weight gain after breast cacer may be associated with risk of recurrence but studies have reported inconsistent results
- Older studies reported that women with breast cancer who were overweight or gained weight after diagnosis were at
greater risk for breast cancer recurrence and death compared with lighter women (Chlebowski RE, J Clin Onc 2002)
- Results of 2 larger studies addressing this question have reported conflicting results:
vs. women maintaining their weight vs. women maintaining their weight
Gain 0.5-2.0 Kg/m2 – median gain 6.0 lb Moderate weight gain 5-10%
RR of breast-cancer death 1.35 (0.93-1.95) HR of breast cancer recurrence 0.8 (0.6-1.1)
Gain >2.0 Kg/m2 – median gain 17.0 lb Large weight gain >10%
RR of breast-cancer death 1.64 (1.07-2.51) HR of breast cancer recurrence 0.9 (0.7-1.2)
Similar findings for breast cancer recurrence Impact of weight gain on overall survival or
and all-cause mortality risk of other cancers not addressed
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Weight changes, physical and psychosocial patient reported outcomes (PRO)
Among 993 obese breast cancer patients in the CANTO cohort, weight gain occurring between cancer diagnosis and
completion of primary treatment was associated with highest prevalence of impaired and deteriorated PROs
Weight Gain Stable Weight Weight Loss
60,0
55,0
44,3
42,5
50,0
39,5
32,8
40,0 Domain/Scale Stable Weight - 67.3% Weight Loss - 18.6%
29,8
35,0
27,0
26,2
23,8
22,6
30,0
19,2
Physical Function 0.45 (0.24-0.83) 0.37 (0.17-0.79)
17,7
25,0
16,6
15,2
20,0 Role Function 0.64 (0.37-1.13) 0.48 (0.23-0.99)
10,1
15,0 Pain 0.55 (0.33-0.92) 0.34 (0.18-0.65)
10,0
5,0 Dyspnea 0.45 (0.25-0.80) 0.21 (0.09-0.48)
0,0
Global Health Physical Role Function Pain Dyspnea
Function
45,0 36,9
ORs for deterioration (decrease of ≥10 points on EORTC QLQ) vs weight gain
32,8
40,0
Domain/Scale Stable Weight (67.3%) Weight Loss (18.6%)
28,4
27,8
35,0 27,7
26,2
26,0
22,6
25,0
16,6
- A number of small-to-moderate sized studies have looked at the feasibility and benefits of lifestyle and weight loss interventions
- Calorie restriction, increased physical activity and behavioral counselling are the cornerstones of weight management and should be
recommended as the primary means of achieving weight loss
- Lifestyle change produces weight loss of 5-7% of body weight: weight loss of this magnitude reduces the incidence of other diseases
(diabetes and cardiovascular)
Guide to selecting weight loss treatment
* * *
* * *
Lifestyle Intervention Study for Adjuvant Treatment of Early breast cancer (LISA)
- The largest weight loss intervention study reported
- Breast cancer patients (n=338) receiving adjuvant letrozole
- BMI ≥ 24 kg/m2
- 2-year, telephone-based intervention vs. control
- Individualized goals:
- 10% weight loss
- calorie restriction of 500-1000 kcal/day
- 150-200 minutes of moderate-intensity physical activity/week
Individualized Lifestyle
Weight (in kg) Control group telephone based p-value
Intervention
n Mean (SD) n Mean (SD)
Baseline 167 81.2 (14.5) 171 82.7 (15.3)
To Month 6 155 -0.6 (4.1) 161 -4.3 (4.1)
Change
To Month 12 147 -0.6 (5.7) 142 -4.5 (5.4) <0.001
from
To Month 18 144 -0.8 (6.1) 135 -3.8 (5.8)
Baseline
To Month 24 131 -0.3 (5.3) 133 -3.1 (6.2)
- A few pilot studies evaluated the feasibility of using cooperative clinical trials systems for the conduct of lifestyle intervention research
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Weight loss and lifestyle interventions
Primary endpoint:
Reduction in Invasive disease free survival
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Do cancer survivor behave different than other individuals?
• Cancer survivors should follow survivor-specific guidelines written by an expert panel convened by the American College of Sports Medicine
• The panel recommended that individuals avoid inactivity and return to normal activity as soon as possible after diagnosis or treatment.
• Increase knowledge about existing evidence on the role of energy balance in cancer risk and prevention
• Integrate weight management into the oncology fellowship trainig curriculum
• Develop practical recommendations based on evidence to help oncology providers address obesity
Research promotion
• Support development of robust reseatch to evaluate the benefits of weight loss in cancer survivors and
best practices to help them make behavioral changes after diagnosis
• Advocate for increased funding for research in key gap areas
• Advocate for policy systems change to addres societal factors contributing to obesity and improve
access to nutrition and exerise counseling services for patients with cancer
• Promote coverage of and access to obesity screening, diagnosis, and treatment services
Adapted from: American Society of Clinical Oncology Position Statement on Obesity and Cancer. Ligibel JA, J Clin Oncol 2014
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Implementation of weight loss and weight maintenance strategies
A practical approach to weight management in cancer patients and survivors proposed by ASCO
1. Assess
- BMI is a easily done assessment not requiring any special equipment
- BMI should be evaluated during each office visit
2. Advise
- Approach weight management in a neutral manner, including BMI as part of review of systems during visits
- Discuss exercise habits and introduce diet and weight issues
- Acknowledge the challenges and struggles that patients may face in trying to lose weight
«I’ve tried everything and just can’t lose weight»
«I’m already stressed in dealing with my cancer»
«Now it is not a good time to talk about my weight and my physical activity»
3. Refer
- Oncologists are in a unique position to optimize the «teachable moment» and help patients make healthy lifestyle choices
- Nevertheless, it is crucial to identify local resources: dietitians and nutritionists who are appropriately trained
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Towards an integrated model for energy balance interventional obesity research
Existing model
Proposed model
Recommendations for Obesity Clinical Trials in Cancer Survivors: American Society of Clinical Oncology Statement. 40
Ligibel JA, J Clin Oncol 2015
Obesity and Cancer - Take Home Messages
1. Obesity has reached epidemic levels worldwide: 1/3 adults in US is categorized as obese
2. Obesity is becoming the leading preventable cause of cancer
- Prevalence of obesity among cancer patients reaches up to 40%
3. There is a strong link Obesity-Cancer
- There is compelling evidence that obesity acts as a risk and prognostic factor in cancer
- Obesity negatively impacts treatment toxicity, quality of life, and financial burden in cancer care
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