The surprising lower total cancer mortality result previously reported for gastric bypass surgery (18
) served as motivation for the subsequent incidence and site-specific cancer mortality analyses contained in this paper. By linking the study subjects to more recent data in the UCR, we extended cancer mortality follow-up five additional years compared with the previous study. Total reduction in cancer mortality after mean follow-up of 12.5 years was 46% in the gastric bypass subjects compared to severely obese controls. The reduction in cancer mortality appeared to be due to a reduced cancer incidence and not cancer survival. In addition, although cancer incidence between the two groups appeared similar for in situ
and local staged cancers, incidence rates of regional and distant staged cancers were lower for the surgical group compared to the control group. Further, the reduction in incidence appeared to be greatest for cancers likely associated with obesity, whereas the mortality reduction was equally great for obesity-related cancers and cancers with less evidence for an association with obesity. These findings suggest that the weight loss associated with gastric bypass surgery may reduce the development of new cancers likely related to obesity. Although cancers were not diagnosed earlier in time for the surgical group, we suspect that cancers were diagnosed earlier in stage. Therefore, we surmise the regional and distant cancers that would have resulted without the surgery were detected in the in situ
and local stages and that in situ
and local stage cancers that would have occurred without surgery were prevented or delayed beyond the end of the follow-up period. The lack of significant reduction in cancer mortality seen in men may have been due to the low number of male subjects. Generally, <20% of gastric bypass patients are men (20
Convincing evidence from large prospective observational studies has shown significant association of obesity with risk for several cancers (7
). Because choosing cancers related to obesity varies as more literature is reported, this report attempted to include cancers where sufficient evidence exists for these cancers to be at least “likely” related to obesity. Evidence for biological mechanisms relating increased cancer risk with obesity has primarily focused on chronic inflammation, increased release of steroid hormones, and promotion of tumor growth stimulated by hyperinsulinemia in the face of insulin resistance (8
). Because few individuals maintain voluntary weight loss without surgical intervention (11
), analyzing cancer outcomes in large population groups maintaining long-term weight loss has been limited (9
). Our group reported a significant 60% reduction in cancer mortality when comparing postgastric bypass patients to severely obese controls (18
). With five additional follow-up years that more than doubled cancer deaths compared to the previous study, there was a 46% reduction in cancer mortality. This smaller risk reduction may relate to some degree of weight regain after surgery, or perhaps due to better mortality estimates resulting from the larger number of cancer deaths. Trentham-Dietz et al
. reported 30% reduction in risk for endometrial cancer for women who reported sustained weight loss (12
Several possibilities may have contributed to the 24% reduction in incident cancers and the 46% reduction in cancer mortality in the surgery group compared with controls. The severely obese controls had only self-reported height and weight from their driver’s licenses. Although each control had a reported BMI >35 kg/m2
, high BMI is known to be under-reported. Therefore, regression equations were derived from a subset of study subjects who had both measured and self-reported BMI, as has been previously discussed (18
). This report shows that using either reported or a regression-corrected BMI in the controls as a covariate had very little effect on the relative risk estimates for cancer mortality. In addition, BMI was not a significant covariate in the incidence or mortality proportional hazards model, suggesting that the findings are robust to this possible source of error.
Possible unknown health status differences between groups at study entry could also have affected the results. Because patients previously diagnosed with major cancer (within 5 years) are generally denied gastric bypass surgery, this restriction could result in a healthier surgical group at study entry. However, there were no differences in cancer prevalence between groups at study entry, suggesting that if there were underlying differences in risk factors for cancer, they were not manifest by increasing baseline cancer prevalence. The possibility exists that gastric bypass patients may have sought surgery because they were experiencing greater obesity-related illness or decreased quality of life compared to controls. On the other hand, prior to seeking gastric bypass surgery, the patients may have been healthier than controls due to socioeconomic or educational reasons, with subsequent increased access to health care. In terms of selection bias, however, the severely obese controls, randomly selected from the entire Utah population, were not contacted for study inclusion, eliminating self-selection for participation. Likewise, the surgical patients included all consecutive patients undergoing surgery over an 18-year period. Without detailed baseline data, one must rely on the observations that baseline age and a history of cancer are two of the strongest risk factors for cancer mortality. Because patients and controls were similar in age and all prevalent cancers at baseline were removed, additional underlying biases related to risk factors for cancer development should be minimized. For example, if smoking rates were different in the two groups, an increased prevalence of cancer would be expected at baseline, but was not seen. Utah has one of the lowest smoking rates in the United States, further minimizing the likelihood that smoking played an important role in the reported results. In addition, results from a prospective study of the health of similarly recruited Utah gastric bypass patients and severely obese controls in which several clinical variables were measured, demonstrated no differences in baseline blood pressure, lipids, glucose, smoking, weight, or sleep apnea assessment (data not shown). On the other hand, quality of life measures were significantly greater among the control group when compared to the surgical group prior to their gastric bypass procedure. These data, when applied to the current study, suggest equal or slightly better health in the controls than the patients at baseline, increasing confidence that the reported results are unbiased or perhaps even conservative.
At study entry and the years following study entry, additional group dynamics may have contributed to the cancer-related outcomes. Surgical patients may have been more likely to participate in preventive cancer screening or have increased medical surveillance than the control subjects. In addition to increased screening participation, a reduction in body weight and body fatness may have led to earlier self-detection of cancer by the postsurgery patients and/or improved screening accuracy. Heavier women have been shown less likely to undergo mammography screening (27
), and cancers self-detected by women with a high BMI are more likely to be at an advanced stage (11
). We note that cancer diagnosis and treatment were not performed at the bariatric surgeon’s clinic. Rather, cancer diagnosis and subsequent treatment for both study groups would have been conducted using general Utah cancer resources, independent of surgical status. Within the limitations of our retrospective cohort design, there was no significant difference in incidence of early stage cancers (in situ
and local) between the two study groups and no difference in time to first diagnosis of cancer comparing surgical and control groups at any stage. Furthermore, case-fatality after controlling for stage at diagnosis was not different in the two groups, suggesting little evidence of differential treatment of cancer. These findings suggest that new cancers, regardless of stage, were not likely to be diagnosed earlier in surgical patients than controls, implying that the potential for greater surveillance, improved detection, or earlier and more effective treatment were not likely major contributors toward reduced cancer mortality and incidence rates. Despite the very large sample sizes used in this study, giving good representation of the Utah severely obese population who do or do not choose surgery, the possibility remains that subtle differences between the two groups at baseline or during follow-up contributed to the significant results. To investigate whether the reduction in incident cancers or cancer deaths after gastric bypass surgery differed over the follow-up interval, the sample was split by median follow-up and reanalyzed. The results suggested similar protection in both subgroups, suggesting that gastric bypass surgery protects against cancer onset and death near- and long-term.
Further limitations to this study include the absence of follow-up BMI, preventing analysis of long-term weight loss to cancer incidence, lack of follow-up medical history, and small numbers of incident cancers and deaths for some cancer sites. We also recognize that information such as family history, smoking history, prior use of postmenopausal hormones, and whether or not postgastric bypass patients adhered to recommended dietary (including vitamin supplementation) and physical activity regimens are not available for analyses. These lifestyle practices may have been factors accounting for the cancer-related differences observed between the surgical and control groups.
In summary, our findings suggest that gastric bypass surgery may result in lower cancer incidence and mortality. We emphasize, however, that bariatric surgery is not an accepted therapy for cancer and in fact, history of an internal malignancy within a 5-year period is often considered a contraindication for obesity surgery. The cancer-related benefits of gastric bypass surgery were strongest in females. Because severe obesity is more prevalent in women than men (20
) and 80% of patients who undergo gastric bypass surgery are women, the results of our study have important medical and population implications. Although the benefit of reduced incidence was limited to cancers likely related to obesity, reduction of cancer mortality was seen for both obesity-related and nonobesity-related cancers. We conclude that recent national guidelines recommending weight loss to reduce future cancer risk are supported by results from this study.