Table 2.

Design and interpretation concerns for studies examining energy balance and cancer recurrence and survival

Determination of the optimal cancer outcome to evaluate, e.g., recurrence, progression to metastases, or cancer death. The decision rests on the following factors: an ability to capture biology and the greatest clinical impact the type of treatment and management a patient receives, which is partly dependent on the pathologic characteristics of the tumor at diagnosis the time required to observe outcomes

Inclusion of a comparison group to account for social interaction/placebo effects, which may be particularly important for trials targeting patient-reported outcomes.

Control for confounding by pathologic characteristics (e.g., cancer stage, grade); if obesity is associated with worse pathologic characteristics of the cancer, and these characteristics are strong prognostic factors, then adjustment is essential to determine whether obesity independently influences outcome.

Control for confounding or effect modification for factors that may co-occur with obesity, e.g., physical activity, energy intake, diabetes and other comorbid conditions, and smoking

Knowledge that treatment and management of cancer might affect the interpretation of the results if: the presentation or selection of treatment options varies by weight status the treatment success varies by weight status, e.g., whether the chance of positive surgical margins and thus recurrence varies by weight status potential for reverse causation as some treatments, e.g., hormonal therapy, can lead to an increase in body fat accumulation, especially centrally, and metabolic perturbations

Recognition that the effects of energy balance on cancer may differ depending on: Cancer type and stage Treatment Race/ethnicity of the host Body fat distribution Other co-factors (e.g., smoking, co-morbidity, medications) Awareness that findings of studies conducted in non-Hispanic white survivors of non-metastatic breast, prostate, or colorectal cancers (i.e., most studies conducted to date) may not generalize to survivors of other race-ethnicity, cancer type, or advanced cancer.

Awareness that the effects of adiposity on cancer may differ depending on: Body fat distribution and extent of body fatness Volitional vs. non-volitional weight loss Rapid vs. slower weight change Intermittent vs. continual exposure

Realization that the effects of negative energy balance on cancer may differ depending on: Diet composition Type of physical activity The magnitude of energy deficit

Awareness that the measurement of diet and physical activity is difficult, and discrepancies in methods pose a challenge for pooling of data or performing meta-analyses.

Consideration of the relationships between obesity, comorbidity, and treatment (which may or may not be independent) in the analysis and interpretation of results.

Consideration within the study design and analysis to reduce and account for potential measurement error (e.g., energy intake, physical activity, obesity).

Lack of control for all components of energy balance (i.e., both energy intake and physical activity, as well as BMI).

Lack of characterization of the study population regarding accrual (enrollees vs. larger pool of cancer survivors) and attrition (completers vs. dropouts).

Adherence and long-term change in behavior.

Adequate power to detect significant associations.