Body Mass Index at Diagnosis and Survival Among Colon Cancer Patients Enrolled in Clinical Trials of Adjuvant Chemotherapy

Introduction

The increasing prevalence of obesity and its association with both cancer risk and prognosis are of major public health importance. Approximately 34% of adults in the United States (US) are obese, as defined as having a body mass index (BMI)^1,2 of ≥30 kg/m². Rates of obesity have increased two-fold in adults and three-fold in children in the past 30 years in the US.³ While obesity is an established risk factor for colorectal cancer (CRC) incidence and death^{4–6,7, 8}, its association with mortality in survivors of CRC is less clear and inconsistent results have been reported^9–12. Within clinical trials of adjuvant chemotherapy in colon cancer patients, the obese subgroup has represented 17%–35% of the study cohorts which has limited the statistical power for comparison with survival outcomes. Evidence indicates that the time frame during which BMI is estimated or determined, ie., pre- vs post diagnosis may also influence its prognostic impact.¹³ To date, inconsistent data exist to whether the association of BMI with CRC survival might differ by patient sex.^{9, 11}

In this report, we determined the association of BMI with colon cancer prognosis and examined its potential predictive impact for the outcome of 5-FU-based adjuvant chemotherapy. We tested the hypothesis that obese patients have an increased risk of colon cancer recurrence and death compared to normal weight patients that may be more evident in men compared to women. We utilized the ACCENT database, a pooled resource of >20,000 participants in national and international colon cancer adjuvant chemotherapy trials.¹⁴ This database provides a unique opportunity to definitively address the impact of BMI upon a clinical outcome in colon cancer patients. Clarification of the role of BMI in prognosis can influence patient education and management, since body weight represents a modifiable factor that may influence patient outcomes.

Methods

Results

The study included 25,291 patients with curatively resected, TNM stages II and III colon cancer who participated in 21 randomized trials of 5-fluorouracil-based adjuvant chemotherapy (Table 1). BMI was measured at study entry and categorized as shown in Table 1; the median BMI was 25.4 (range: 10.0–70.3). After a median follow-up of 7.8 years in living patients, 32% had cancer recurrence and 32% (N=7,973) had died.

Across BMI categories, we found statistically significant but clinically modest associations between BMI and tumor stage, number of metastatic lymph nodes, age, sex, ECOG performance status (PS), and T-stage (all p<.0001) (Table 2). Tumors from obese vs normal-weight patients were more likely to be distal, stage III vs II, and T-stage_{1/2 vs 3/4} (all p<0.01; Table 2). Obese (vs. normal-weight) patients were more likely to have >3 metastatic regional lymph nodes (N2 disease) (p=.0001) (Table 2). A similar number of surgical removed lymph nodes were examined from obese patients compared to other BMI categories. Underweight (vs normal-weight) patients were significantly more likely to be younger (median 58 vs 61 yr, p<.0001), female (69% vs 48%, p<.0001) and to have a PS of 1–2 vs. 0 (24% vs. 19%, p<.0001) (Table 2).

In a univariate analysis, the categorical BMI was significantly associated with TTR, DFS, and OS across all adjuvant studies (Table 3). Overweight patients were not at increased risk of recurrence or mortality compared to normal-weight patients. Obese patients had shorter TTR and worse DFS and OS [OS HR 1.11 (1.04, 1.18), p=.0014] vs normal-weight patients (Table 3). Underweight patients also had shorter TTR and worse DFS [HR 1.11 (1.03, 1.20), p=.0093] and OS rates (Table 3). Patients with stage III vs II tumors, poor differentiation, and increased number of metastatic lymph nodes all had shorter TTR, DFS and OS (all p<.0001) (Table 3). Higher T-stage, but not primary tumor site, and worse ECOG PS were similarly associated with worse outcome (data not shown). Analysis by patient sex revealed that the categorical BMI was significantly prognostic in men for TTR (p=.0015), DFS (p<.0001), and OS (p<.0001), but not in women (all p >.20) (Table 3, Fig. 1A–D).

A significant interaction between obesity and patient sex was found wherein obese men (HR=1.14 [1.05, 1.24], p=.0023), but not women (HR=1.00, p=.9441), had significantly shorter TTR (Table 3, P_interaction=.0345). Furthermore, underweight and obese men had significantly poorer DFS and OS compared to women (Table 3, Fig. 1A–D). Men with class 2/3 obesity had significantly inferior outcomes for TTR (p=.0127), DFS (p=.0096), and OS (p=.0242) in contrast to women (all p > 0.45) (Table 3). The relationship between BMI and survival outcomes did not differ significantly by patient age or tumor stage (data not shown).

In a multivariable analysis, categorical BMI was significantly associated with TTR, DFS, and OS after adjusting for covariates (Table 4A). Obese (vs. normal-weight) patients had poorer DFS and OS (HR=1.10 [1.04, 1.17], p=.0023), even after adjusting for age, stage, treatment, and sex. Overweight and normal-weight patients had similar outcomes, while underweight patients had significantly worse TTR (p=.0044), DFS [HR=1.18 (95% CI: 1.09, 1.28), p<.0001], and OS [HR=1.21 (95% CI: 1.11, 1.32), p<.0001] after adjusting for covariates (Table 4A).

The categorical BMI was significantly prognostic in men (Table 4B, Fig. 1A,C) for TTR (p=.0009), DFS (p<.0001), and OS (p<.0001), but not in women (all p>.10) (Table 4C, Fig. 1B,D) (OS P_interaction=.0129). Obese and underweight men had significantly poorer clinical outcomes vs normal weight men (Table 4B). A greater impact of class 2/3 vs class 1 obesity on DFS and OS rates was found among men (Table 4B). The significant interaction between BMI and clinical outcome variables was primarily due to underweight men, but not women, having inferior TTR (HR 1.22 [1.05, 1.42], p=.0078), DFS (HR 1.31 [1.15, 1.50], p<.0001) and OS (HR 1.39 [1.21, 1.60], p<.0001; P_interaction=.0340) compared to normal-weight men.

We explored whether a curvilinear or quadratic relationship could describe the observed results for BMI. Using restricted cubic splines, we found that the continuous BMI (using 4 knots) displayed a significant curvilinear relationship with OS overall (p < 0.025; Fig. 2A) and by patient sex (P_interaction=0.05; Fig. 2B). Underweight men had worse OS compared to underweight women, and obesity played a lesser role in predicting poor OS (Fig. 2B). The relationship between the continuous BMI and DFS and TTR was more quadratic in nature, where only 3 knots were significant using restricted cubic splines. Given this finding, we modeled BMI as a quadratic variable in multivariate Cox models and found that the quadratic BMI was significantly associated with DFS (p<.0001) and TTR (p=.0008) after adjustment for age, stage, treatment, and sex.

We assessed whether BMI was predictive of benefit from 5-FU-based adjuvant chemotherapy among stage II and III patients. We examined eight adjuvant studies where a treatment benefit was observed. Among these eight trials, six evaluated 5-FU vs observation and two evaluated 5-FU plus oxaliplatin vs 5-FU. There was no statistically significant interaction for BMI and treatment for TTR, DFS, or OS in either univariate or multivariable analysis. The multivariate interaction models showed a continued treatment benefit across all BMI categories after adjusting for age, stage, and sex. Furthermore, there was no evidence for a differential treatment effect by adjuvant chemotherapy regimen.

Discussion

Using BMI measured by trained personnel at adjuvant study entry, we found that obese, but not overweight, patients had significantly poorer survival vs normal-weight patients after adjustment for covariates, and this effect was most evident among patients with severe (class 2/3) obesity. An important finding of our study is that adverse impact of obesity on colon cancer outcomes was limited to men. Severely obese men had a 16% increase in mortality relative to normal-weight patients. Another important finding is that underweight patients had increased cancer recurrence and inferior outcomes. Furthermore, a statistically significant interaction was found between underweight status and patient sex with underweight men having a 39% increase in all-cause mortality compared to normal-weight men or women. In prior studies, the inferior outcome among underweight cancer patients that have been attributed to noncancer–related deaths.^17,18 However, we observed a shorter TTR and DFS for underweight patients suggesting that the impact upon prognosis is cancer-related.

Inconsistent data exist for the impact of patient sex on outcome in obese colon cancer patients. In patients with stage II and III colon cancers, the association between obesity and mortality was stronger in women vs men ⁹. In contrast, no differences by sex were found in another study that also examined data from colon cancer adjuvant trials ¹². Our finding of a stronger association of obesity with adverse outcome in men vs women is consistent with the reported a higher rate of incident colon cancers among obese men vs women.^{4, 6, 19, 20} Mechanisms underlying this observation may be related to body fat distribution in that BMI is more closely related to abdominal or central adiposity in men.^{21, 22} Abdominal adiposity is associated with hyperinsulinemia, insulin resistance and the IGF axis as potential mediators of increased CRC risk and mortality.^23–25 The attenuated impact of obesity on colon cancer outcome observed in women vs men may be due to effect modification by estrogen. Estrogen levels correlate with BMI in postmenopausal women since their major source is conversion from androgens in adipose tissue.²⁶ The association of obesity with CRC risk is reduced after menopause,²⁷ and HRT is consistently associated with reduced colon cancer mortality.^28–30

Excess mortality among underweight patients with colon cancer have been attributed to noncancer causes, mainly to chronic respiratory conditions¹⁸. In our study, performance status differences based upon BMI were not clinically meaningful and strict eligibility criteria for the adjuvant studies exclude patients with significant comorbidities. Since BMI was recorded at adjuvant trial enrollment, it will be important to distinguish between patients who are underweight but have stable weight over time vs those who experienced significant cancer-related weight loss prior to trial enrollment. Significant cancer-related weight loss may identify a poor prognostic subgroup since cancer cachexia is associated with inferior outcomes.^31–33 Loss of adipose tissue accounts for the majority of the cancer-related weight loss, yet the preferential loss of skeletal muscle adversely impacts mortality.^34–36 While not included in the ACCENT database, cigarette smoking is associated with a lower BMI and current smokers who are underweight or obese have high mortality rates,³⁷ especially in men.^{38, 39}

Evidence suggests that time frame during which BMI is determined can influence its association with clinical outcome. A prospective cohort study found that self-reported BMI prediagnosis (mean of 7 years before CRC diagnosis) was independently associated with a statistically significant increase in risk of all-cause and cancer-specific mortality, whereas postdiagnosis BMI (mean interval of 1.5 years after diagnosis) was not.¹³ Prediagnosis BMI measurements have also shown a higher risk of all-cause mortality in obese vs normal weight women.^{17, 40}

We also detemined whether BMI was predictive of clinical benefit in patients receiving 5-FU-based adjuvant chemotherapy vs observation or no 5-FU. Our data indicate that adjuvant chemotherapy is beneficial for high risk and low risk BMI categories, with outcomes being similar among those receiving older vs more modern adjuvant regimens as well as among North American and European patients.

Strengths of our study include BMI measurements performed by trained staff and the rigorous collection of data on recurrence and survival within clinical trials over an extended follow-up period. Limitations include the retrospective study design and lack of data on smoking, diet, physical activity, menopausal status, or use of hormone replacement therapy (HRT) that may have independent associations with outcomes and may inform the interpretation of sex-related differences. Of note, neither lifestyle nor demographic factors impacted the association of the prediagnosis BMI with survival of colon cancer patients in a large cohort study¹³. While the large sample size within the ACCENT database indicates that modest absolute differences in clinical outcomes may be statistically significant, our results must be interpreted in that context.

In summary, obese and underweight BMI are associated with increased mortality in colon cancer survivors, especially among men. In underweight patients, shorter TTR and reduced DFS rates suggest increased tumor aggressiveness. Together, these data suggest that interventions to modify patient BMI after colon cancer diagnosis have the potential to improve patient outcomes.