This study showed that greater weight, waist, and WHR before diagnosis (at baseline) were risk factors for all-cause mortality of women diagnosed with colon cancer. These associations were independent of age at diagnosis, education, smoking, and stage. The hazard ratio of all-cause mortality was also increased among those in the “obese” BMI category and among those few women in the “underweight” BMI category compared to women of normal weight. This pattern is similar to the relationship between BMI and all-cause mortality among all IWHS women (7
There were also statistically significant positive associations of colon-cancer mortality with waist circumference and WHR. Women in the highest tertiles of waist and WHR had a 30-40% greater colon-cancer mortality (similar to all-cause mortality) compared with the lowest tertiles. However, BMI and weight were not significantly associated with colon-cancer mortality. Thus, WHR, which reflects abdominal obesity, and waist circumference, which characterizes both abdominal and general obesity, better predict colon-cancer death than are more general markers of obesity – weight and BMI. Of note, the positive relations between anthropometric characteristics and colon cancer death were similar for proximal and distal cancers. Our study was among the first to examine the effects of abdominal adiposity, measured by waist and WHR, on colon cancer mortality.
The magnitude of the associations between anthropometric characteristics and all-cause mortality held for each stage at diagnosis. In contrast, for colon-cancer mortality, there were no associations with any of the anthropometric measures among women diagnosed with in situ/local stage of colon cancer. This could be explained by the fact that colon cancer patients at this stage mostly survive their colon cancer and die from other causes, such as cardiovascular disease, which is also associated with obesity. This can diminish the association between colon cancer death and obesity.
Most studies investigating the influence of obesity on survival of colon cancer patients used BMI at diagnosis. Three of them that included participants enrolled in clinical trials of adjuvant chemotherapies showed inconsistent results. Meyerhardt et al (2003) reported that obese women (BMI ≥30 kg/m2
) with colon cancer in stages II and III had a significantly increased risk of overall mortality (by 34%) compared to normal-weight women (BMI 21-24.9 kg/m2
). Similarly, Dignam et al (2006) examined colon cancer patients with stages II and III and observed an increase in overall mortality (by 28%) and colon cancer death (by 36%) for very obese (BMI≥35 kg/m2
) patients as well as an increase for underweight patients (49% for overall, and 23% for colon cancer mortality) compared to those with normal weight (10
). Contrary to these results, a recent study by Meyerhardt et al (2008), which included patients with stage III colon cancer, detected no statistically significant associations between BMI and cancer recurrence or death (14
). Although it is difficult to compare our findings with the results of these studies because of different study designs (these studies included colon cancer patients with stages II and III participating in clinical trials of chemotherapy and used BMI measured after cancer diagnosis), our findings for overall and colon-cancer mortality are consistent with the findings by Meyerhardt et al (2003) and Dignam et al (2006) (10
Another study from Wisconsin included 633 postmenopausal women with colorectal cancer (cases from a case-control study) who were followed prospectively (11
). All-cause mortality was 50% higher for overweight and underweight women compared to normal-weight women. The HR of colon-cancer death was 2.1 (95%CI, 1.1;3.8) for those with BMI>30 kg/m2
, and HR=2.3 (95%CI, 1.0;5.4) for patients with BMI<20 kg/m2
compared to colon cancer patients with normal BMI. These results agree with our data in direction but the HR of colon-cancer mortality for the highest BMI was stronger than in our study (2.3 versus 1.4, respectively). This could be potentially explained by differences in study design and study populations.
None of the above-mentioned studies explored the association of abdominal obesity with survival of cancer patients; even though abdominal obesity measured by waist circumference or WHR may be better predictors of colon cancer incidence and death (3
). To our knowledge, the only study that investigated the association of pre-cancer abdominal and general obesity with survival of colorectal cancer patients was an Australian prospective cohort study of 526 patients with anthropometrics measured at baseline (12
). Similar to our study, they found higher waist circumference and increased percent body fat to be associated with increased overall and disease-specific death. HRs for mortality from colorectal cancer were 1.33 (95% CI, 1.04;1.71) per 10 kg-increase in body fat and 1.20 (95% CI, 1.05;1.37) per 10 cm-increase in waist circumference. In parallel to our study, Australian cohort study did not observe significant association of colorectal cancer-specific mortality with BMI.
Possible mechanisms of the relation between mortality of colon cancer patients and anthropometric characteristics are not clear. Comorbidities and advanced stage at diagnosis may partially explain these associations: in IWHS, women with the highest BMI or in the third WHR tertile tended to have more comorbidities and were somewhat more likely to be diagnosed with later stage disease compared to women with normal BMI or low WHR, respectively (). However, the observed positive relations persisted after adjustment for stage and measured comorbidities. We speculate that some other factors may explain these associations. Obese patients often start therapy later than normal-weight patients or receive different treatments (14
). For instance, in the IWHS, women with colon cancer were less likely to undergo surgery for colon cancer if they had higher baseline WHR: in a model adjusted for stage and age at diagnosis, odds ratio of surgery was 0.75 for the 2nd
and 0.45 for the 3rd
WHR tertile versus the lowest tertile (p-trend=0.08). This explanation agrees with the slight attenuation of associations between colon cancer death and waist and WHR after adjusting for first course treatment, which is usually surgery for most colon cancer patients. In addition, the absorption of hydrophilic and hydrophobic medications is altered in obese patients often resulting in incorrect dosages of medication for these patients (23
). Overweight women could have different pathophysiology of colon cancer making it more aggressive, its treatment less effective or leading to unusual complications after treatment.
Furthermore, since we observed a potentially adverse effect of WHR and waist not only on all-cause but also on colon cancer mortality, abdominal obesity may have a direct biological effect (12
). The exact mechanism of this effect is unknown but abnormal glucose tolerance, high levels of insulin, IGF1, and leptin, and increased oxidative stress, typical for patients with abdominal obesity, are known to promote colon cancer progression and increased mortality of colon cancer patients (27
Of note, increased all-cause and colon-cancer mortality for underweight colon cancer patients, which is in agreement with several other studies (10
), may be explained by the same factors that account for higher mortality of underweight people in general: worse recovery after respiratory and infectious diseases, and worse tolerance of treatment (32
). Low numbers of underweight women with colon cancer did not allow us to examine this group in more detail. The main strength of our study is that we were able to measure general and abdominal obesity using several anthropometric characteristics before cancer diagnosis and examine their role on both all-cause and colon-cancer mortality. However, our study has important limitations. For some patients, the anthropometric characteristics had been measured a long time before cancer diagnosis and could have changed over time. However, in the sensitivity analysis including the measures of weight and BMI closest to diagnosis, associations did not markedly change. Additionally, when participants were stratified into two groups by time between baseline and cancer diagnosis based on the median of about 11y, the trends between anthropometric characteristics and mortality were observed in each group. Another limitation is that anthropometric measures were self- or friend-measured, and although this is a limitation, studies including those conducted in the IWHS cohort showed these characteristics to be valid and reliable (19
). The main weakness of our study is that we lack information about the molecular profile of tumors, about cancer recurrence, and about confounders after cancer diagnosis: we have data only about first course of treatment, rather than full treatment or medications, the list of measured covariates after cancer diagnosis was not comprehensive, and the data about comorbidities such as diabetes or heart disease were collected only by self-report. Further, we had only limited statistical power to evaluate associations in subgroups of study participants, particularly among subgroups of women defined by tumor stage. Finally, our findings were observed for white postmenopausal women and may not generalize to other subgroups of the population.
Our results give further evidence that obesity is not only a risk factor for colon cancer incidence, but it may also increase mortality of postmenopausal women after colon cancer diagnosis. Our findings suggest that abdominal obesity is more predictive of mortality from colon cancer than general obesity. If true, pre-diagnostic obesity may be a modifiable risk factor for death in patients diagnosed with colon cancer, providing another reason for postmenopausal women to keep their weight and WHR within normal limits.