Prediagnostic Weight Loss Explains CRC Obesity Paradox
Key Takeaways
- Among 5,521 patients with colorectal cancer in southwest Germany, overweight at diagnosis was associated with better overall survival before earlier weight change was considered.
- Prediagnostic weight loss greater than 10% was associated with worse overall, colorectal cancer-specific, and recurrence-free survival.
- When body mass index at diagnosis and prediagnostic weight change were modeled together, the earlier apparent survival advantage for overweight disappeared, and obesity estimates also remained non-significant.
- The adverse association of substantial prediagnostic weight loss was also observed across sex and stage strata.
Mandic et al in JAMA Network Open analyzed 5,521 adults with histologically confirmed CRC from the Darmkrebs: Chancen der Verhütung Durch Screening (DACHS) study, a multicenter, population-based case-control study with prospective follow-up in southwest Germany. Participants were recruited between 2001 and 2016, reported height and weight at diagnosis, and recalled past weight at decennial ages; investigators grouped BMI at diagnosis into underweight, normal weight, overweight, obesity class I, and obesity class II-III and categorized prediagnostic weight change across a recalled interval 5 to 14 years before diagnosis. Delayed-entry Cox models adjusted for demographic, lifestyle, tumor, treatment, and comorbidity factors assessed overall survival (OS), colorectal cancer-specific survival (CSS), and recurrence-free survival (RFS).
In adjusted analyses, overweight versus normal weight at diagnosis was associated with better OS (HR, 0.89; 95% CI, 0.81-0.98). Underweight was associated with worse OS, and obesity estimates were directionally similar but not statistically significant. The next question was whether BMI at diagnosis was capturing prognosis itself or the effects of weight decline before CRC was recognized.
Prediagnostic weight loss greater than 10% was associated with worse OS (HR, 1.55; 95% CI, 1.39-1.72), and the same adverse pattern extended to CSS and RFS. After mutual adjustment for BMI at diagnosis and prediagnostic weight change, the overweight association attenuated to null (HR, 0.95; 95% CI, 0.87-1.05), while substantial weight loss remained associated with worse OS (HR, 1.54; 95% CI, 1.37-1.72). Similar adverse associations were seen across women and men, across CRC stages, and in sensitivity analyses, and downward BMI trajectories before diagnosis also tracked with worse survival.
Because the analysis was observational, it could not show that prediagnostic weight loss caused poorer survival or that reversing weight loss would improve outcomes. The authors noted that height and weight were self-reported, the prediagnostic weight window varied from 5 to 14 years because recalled weights were available only at decennial ages, delayed-entry modeling reduced but did not eliminate survivor bias, and BMI could not distinguish fat mass from lean mass or body-fat distribution. They framed reverse causation and weight-loss-related bias, rather than a protective effect of higher BMI, as a major explanation for the obesity-paradox signal.
The authors concluded that the apparent survival advantage of overweight and obesity at CRC diagnosis was largely explained by prediagnostic weight loss. They wrote that BMI measured near diagnosis may misrepresent prognosis when antecedent weight decline is not taken into account.
Clinician Questions
Why did the colorectal cancer analysis define prediagnostic weight change over a 5- to 14-year window?
Investigators estimated prediagnostic weight change from body weight recalled at decennial ages beginning at age 20, so the interval varied with each patient’s age at CRC diagnosis. They used a window starting at least 5 years before diagnosis because CRC can have a multiyear preclinical phase, making weight measured closer to diagnosis more vulnerable to disease-related decline.
Was the BMI-survival association the same across smoking groups in colorectal cancer?
In smoking-stratified analyses, better overall survival with overweight at diagnosis was seen only among never-smokers, whereas underweight was associated with worse survival among former and current smokers. The authors cautioned that some smoking strata had limited numbers of events, which constrained precision in those subgroup comparisons.
What prediagnostic BMI trajectories were linked with worse overall survival in colorectal cancer?
Worse overall survival was observed among patients whose BMI shifted from normal to underweight and among those whose BMI shifted from overweight to normal before diagnosis. By contrast, remaining in the overweight category was not associated with worse survival.
How far do these colorectal cancer findings extend beyond the DACHS cohort?
The findings come from an observational cohort of adults aged 30 years or older with histologically confirmed colorectal cancer recruited from hospitals in southwest Germany, with only about half of eligible regional cases enrolled. That context supports the results as evidence from this regional cohort rather than as universally generalizable proof across all care settings and populations.
Recommended Reading
- For more on cancer nutritional assessment: CT Body Composition Misses Cancer Nutritional Risk