RETRACTED ARTICLE: The ‘obesity paradox’ and survival after colorectal cancer: true or false?

Abstract

Body mass index (BMI), as an approximation of general adiposity, is an established risk factor for incidence of several adult cancer types, including colorectal cancer (CRC). There is a common perception that these relationships extrapolate directly as adverse prognostic factors after diagnosis, but evidence for this is lacking. The paper from Sclesinger et al. in this issue of the journal adds a new dimension to this debate focusing on relationships of post-diagnosis BMI (as a marker of the steady-state weight among survivors) and survival, and provides evidence on a decreased mortality risk among overweight (post-diagnosis BMI 25.0-29.9 kg/m(2)) compared with normal weight (post-diagnosis BMI 18.5-24.9 kg/m(2)) CRC survivors-an example of an 'obesity paradox.' The observation of the 'obesity paradox' is well documented in the methodology literature, but perhaps, less familiar to the cancer readership. Three broad classes of explanation are posited: (1) the associations are true and plausible; (2) the associations are false and reflect methodological issues; or (3) the observations represent a specific form of selection bias, known as collider bias. The present author argues that the obesity paradox reflects the latter-a product of a statistical bias-and emphasizes that, while these findings are hypothesis generating, they will not alter clinical practice or recommendations.

Severe obesity prior to diagnosis limits survival in colorectal cancer patients evaluated at a large cancer centre

“…With careful consideration of important risk and prognostic factors, the association between prediagnostic BMI and OS in all CRC patients was modest. Our most robust and consistent findings were for more extreme levels of obesity and among patient subgroups, as observed previously ( Parkin et al , 2014 ; Renehan, 2014 ; Wu et al , 2014 ). Among patients with local or locally advanced disease and among patients diagnosed aged <50 years, both class I and class II obesity were associated with a two-fold to five-fold increased risk of death as compared with overweight patients.…”

“…Inclusion of older patients and patients reporting weight loss appeared to attenuate or mask associations observed between obesity and OS in all CRC patients; however, none of these factors appeared to strongly impact PFS. One potential explanation is that advanced-stage patients, and similarly older patients or patients experiencing weight loss, represent a group more susceptible to the physiologic stress of cancer as well as aggressive treatment modalities, whereas, obese patients who survive the cancer experience are simply more likely to develop and die from other obesity-related causes ( Renehan, 2014 ). In a recent pooled prospective analysis of BMI and subsequent cancer risk in CRC survivors, individuals who were overweight or obese were at moderate increased risk of developing subsequent obesity-associated cancers.…”

“…Survival curves were generated using the Kaplan–Meier method and statistical significance was measured using the log-rank test. We also assessed whether associations with BMI varied by CRC risk and prognostic factors mentioned in previous reports ( American Cancer Society, 2014 ; Parkin et al , 2014 ; Renehan, 2014 ; Wu et al , 2014 ), including age, sex, smoking status, history of diabetes, weight change, and tumour stage. Statistical tests for interaction evaluated the significance of categorical cross-product terms in the multivariable adjusted models.…”

“…The American Cancer Society recommendations for cancer patients and survivors are similar to those for cancer prevention and state that in addition to not smoking, eating a healthy diet, and being physically active, individuals maintain a normal weight ( Doyle et al , 2006 ). However, a U-shaped relationship with improved survival among overweight, as compared with normal and underweight, CRC patients has also been observed ( Hines et al , 2009 ; Sinicrope et al , 2010 ; Baade et al , 2011 ; Min et al , 2012 ; Schlesinger et al , 2014 ; Wu et al , 2014 ), and suggests that moderate adiposity or overweight status may be protective for initially enduring the arduous cancer process ( Parkin et al , 2014 ; Renehan, 2014 ; Schlesinger et al , 2014 ). With tumour stage, treatment, and cancer-associated weight loss linked to inconsistencies in prior analyses of BMI and CRC cancer patient survival ( Simkens et al , 2011 ; Parekh et al , 2012 ; Bardou et al , 2013 ; Boyle et al , 2013 ; Sinicrope et al , 2013 ; Azvolinsky, 2014 ; Parkin et al , 2014 ), clarifying whether obesity is an independent prognostic factor and what is not a healthy weight for cancer patients remains both a clinically relevant and timely concern.…”

Association of Weight Change after Colorectal Cancer Diagnosis and Outcomes in the Kaiser Permanente Northern California Population

“…(6, 7, 9, 13) Further, some studies have demonstrated a U-shaped curve with potential optimal BMI in the overweight range. (14) Studies have also varied in timing of ascertainment of exposure (prior to diagnosis, at diagnosis and after diagnosis/surgery). (15)…”