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. Author manuscript; available in PMC: 2023 Jul 1.
Published in final edited form as: Clin Nutr. 2022 May 27;41(7):1600–1604. doi: 10.1016/j.clnu.2022.05.016

The Association of Abdominal Adiposity with Premature Discontinuation of Postoperative Chemotherapy in Colon Cancer

Justin C Brown 1,2,3, Jeffrey A Meyerhardt 4, Elizabeth M Cespedes Feliciano 5, En Cheng 5, Bette J Caan 5
PMCID: PMC9233150  NIHMSID: NIHMS1811327  PMID: 35671612

Abstract

Background & Aims:

Patients with colon cancer who prematurely discontinue postoperative chemotherapy may have an increased risk of disease recurrence and death. This study tested the hypothesis that the quantity and distribution of abdominal adipose tissue predict premature chemotherapy discontinuation.

Methods:

This cohort study included 533 patients with stage II-III colon cancer who initiated a planned regimen of 24-weeks of 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. The primary exposures were body mass index (BMI) and computed tomography-derived abdominal adiposity measures (e.g., visceral, subcutaneous, and intramuscular adipose tissue). The primary endpoint was premature chemotherapy discontinuation, defined as receiving <6 cycles of FOLFOX. Generalized linear models quantified the relative risk (RR) of premature chemotherapy discontinuation adjusted for age, sex, cancer stage, height, and muscle area, using two-sided statistical tests.

Results:

Forty-two patients [7.9% (95% CI: 5.7, 10.5)] prematurely discontinued chemotherapy. Visceral adipose tissue [RR: 3.27 (95% CI: 1.26, 8.49)] and intramuscular adipose tissue [RR: 2.79 (95% CI: 1.09, 7.12)] were statistically significantly associated with an increased risk of premature chemotherapy discontinuation. BMI [RR: 2.07 (95% CI: 0.75, 5.73)] and subcutaneous adipose tissue [RR: 2.32 (95% CI: 0.91, 5.94)] were not statistically significantly associated with premature chemotherapy discontinuation.

Conclusion:

Among patients with stage II-III colon cancer who initiate postoperative chemotherapy, excess visceral and intramuscular adiposity may be risk factors for the premature discontinuation of chemotherapy.

Keywords: adverse event, chemotherapy dosing, obesity, pharmacology

INTRODUCTION

In patients with resected high-risk stage II and stage III colon cancer, a postoperative chemotherapy regimen improves disease-free and overall survival versus surgery alone. For the past two decades, a postoperative regimen that combines a fluoropyrimidine and oxaliplatin has been the standard of care for patients with stage III disease and selected patients with high-risk stage II disease (1, 2). The duration of postoperative chemotherapy has evolved, initially being 12-months, then six months, and recently for low-risk patients, three months was non-inferior to six months (3, 4). No less than three months of chemotherapy is recommended for patients with stage III or high-risk stage II colon cancer (3, 4). One in ten patients with colon cancer who initiate postoperative 5-fluorouracil and oxaliplatin (FOLFOX) chemotherapy do not complete at least six cycles [e.g., three months; (5)], and those who prematurely discontinue chemotherapy have an increased risk of disease recurrence and death (6–8). Risk factors for premature chemotherapy discontinuation are limited and often not modifiable [e.g., age, female sex (9, 10)].

Obesity is a chronic, relapsing, and progressive disease characterized by excess adiposity (11). More than one-in-three patients with colon cancer have obesity (12), which may influence the tolerability and efficacy of chemotherapy (13). Obesity is commonly diagnosed using body mass index (BMI), which scales body weight to height, and does not distinguish muscle from distinct adipose tissue depots [e.g., visceral, subcutaneous, and intramuscular adiposity; (14)]. This is relevant because adiposity explains 14% of oxaliplatin pharmacokinetic variation in patients with gastrointestinal cancer, and patients with low muscle and excess adiposity are 45% more likely to experience severe dose-limiting toxicity (15). Low skeletal muscle is an established predictor of treatment-related toxicity in various solid tumors (16) and explains the pharmacokinetic variability of 5-fluorouracil in colorectal cancer (17). Adiposity is correlated with muscle, such that patients with a higher BMI have, on average, more adipose tissue and more skeletal muscle (18). However, it is not known if the quantity and distribution of adipose tissue predict premature chemotherapy discontinuation independently of muscle in patients with colon cancer (19).

This study tested the hypothesis that the quantity and distribution of adiposity, measured with abdominal computed tomography imaging, is associated with premature chemotherapy discontinuation in patients with stage II-III colon cancer who initiated postoperative FOLFOX chemotherapy.

MATERIALS & METHODS

Study Population and Design

The Colorectal, Sarcopenia, Cancer And Near-term Survival (C-SCANS) study was derived from the Kaiser Permanente Northern California (KPNC) cancer registry. The C-SCANS cohort included all patients aged 18 to 80 years diagnosed with stage I to III invasive colorectal cancer from 2006 to 2011 who underwent surgical resection with curative intent (20). The current study was restricted to patients with colon cancer who initiated FOLFOX chemotherapy within six months after surgical resection (21). When this cohort study was initiated, the oral fluoropyrimidine, capecitabine, was infrequently used in clinical practice at KPNC. The study investigators obtained a waiver of written informed consent. The KPNC institutional review board approved this study (CN-12BCaan-04-H).

Measures of Body Composition

Medical assistants measured height (m) and weight (kg) with standardized clinical procedures at diagnosis. Body mass index (BMI) was calculated as weight divided by the square of height (kg/m2). The quantity and distribution of adipose tissue were measured using preoperative computed tomography images initially collected for clinical purposes (e.g., diagnostic cancer staging) using sliceOmatic software (V5.0, TomoVision, Montreal, Canada). A single-slice transverse image at the third lumbar vertebra was used because cross-sectional tissue areas in this region correlate with whole-body skeletal muscle and adipose tissue volumes (22, 23). Tissues were defined with a semi-automated procedure using Hounsfield unit (HU) thresholds of −29 to 150 for skeletal muscle, −150 to −50 for visceral adipose tissue, and −190 to −30 for subcutaneous adipose tissue. Intramuscular adiposity was operationalized as the average radiation attenuation of skeletal muscle; in statistical regression models, this variable was scaled inversely to represent greater intramuscular adiposity [e.g., lower muscle radiation attenuation indicates greater accumulation of intramyocellular triglyceride (24, 25)]. Two blinded research staff members analyzed a randomly selected sub-sample of 50 computed tomography images. The coefficients of variation for visceral, subcutaneous, and intramuscular adiposity were 2.7%, 1.2%, and 0.7%, respectively (26). One blinded research staff member analyzed the remaining images.

Covariates

The KPNC electronic medical record was used to obtain information on age and sex at diagnosis. The KPNC cancer registry was used to obtain information on the cancer stage (American Joint Committee on Cancer [AJCC 7th edition; (27)], and body surface area (28, 29). Covariate data were 100% complete for all variables.

Study Outcomes

The primary endpoint of premature chemotherapy discontinuation was defined as receiving less than six cycles of FOLFOX, as documented in the electronic chemotherapy pharmacy infusion records (19). The threshold of six cycles of FOLFOX was selected since no less than three months (e.g., six cycles) of chemotherapy is recommended for patients with stage III or high-risk stage II colon cancer (3, 4). The endpoints databases were constructed by research staff blinded to the quantity and distribution of adipose tissue.

Statistical Analysis

Baseline characteristics are presented as means ± SDs or counts and percentages. The Pearson correlation coefficient (r) and coefficient of determination (R2) were used to quantify the strength of the association between BMI and visceral, subcutaneous, and intramuscular adipose tissue. The quantity and distribution of adipose tissue were modeled with restricted cubic splines. Cubic splines accommodate nonlinearity, provide statistically efficient and visually intuitive descriptions of associations, and eliminate the need to arbitrarily categorize continuously distributed variables (30). Generalized linear models were used to quantify the relative risk (RR) and absolute risk difference (ARD) of the association between adipose tissue and premature chemotherapy discontinuation (31). The RR and ARD were calculated from the regression spline model for two comparisons: 1) the 5th versus 95th percentile values of the adipose tissue distribution; and 2) each standard deviation increase in adipose tissue. Models were multivariable-adjusted for age, sex, cancer stage, patient height (14), and muscle area. Linearity and nonlinearity were examined visually using spline plots and statistically using likelihood ratio tests. All statistical tests were two-sided.

RESULTS

Characteristics of the Study Cohort

The average (SD) age of the 533 patients was 58.7 (11.3) years, 55.9% were women, and 85.6% had stage III colon cancer (Table 1). The mean (SD) body surface area was 1.89 (0.26) m2, BMI was 28.7 (6.3) kg/m2, visceral adipose tissue was 147.2 (101.4) cm2, subcutaneous adipose tissue was 229.3 (123.9) cm2, and muscle attenuation was 40.2 (9.4) HU. BMI was correlated with visceral adipose tissue [r =0.61 (95% CI: 0.56, 0.67); Figure S1A], subcutaneous adipose tissue [r = 0.86 (95% CI: 0.83, 0.88); Figure S1B], and muscle attenuation [r = –0.42 (95% CI: –0.49, –0.35); Figure S1C].

Table 1.

Baseline characteristics of the study population overall and stratified by premature chemotherapy discontinuation status

Characteristic Overall Cohort (n = 533) Premature Chemotherapy Discontinuation P
Yes (n = 42) No (n = 491)
Age, mean (SD), y 58.7 (11.3) 65.0 (11.6) 58.2 (11.1) <0.001
Sex 0.33
 Male 235 (44.1) 15 (35.7) 220 (44.8)
 Female 298 (55.9) 27 (64.3) 271 (55.2)
Stage 0.18
 II 77 (14.4) 9 (21.4) 68 (13.8)
 III 456 (85.6) 33 (78.6) 423 (86.2)
Mean Body Surface Area (SD), m2 1.89 (0.26) 1.84 (0.24) 1.89 (0.26) 0.18
Mean Body Weight (SD), kg 82.0 (20.7) 78.6 (19.6) 82.3 (20.8) 0.25
Mean Height (SD), m 1.68 (0.10) 1.67 (0.10) 1.68 (0.10) 0.41
Mean BMI (SD), kg/m2 28.7 (6.3) 28.0 (6.4) 28.8 (6.3) 0.44
Mean Muscle Area (SD), cm2 140.9 (37.1) 125.1 (29.8) 142.3 (37.4) 0.004
Mean Visceral Adipose Tissue Area (SD), cm2 147.2 (101.4) 153.8 (98.1) 146.7 (101.8) 0.66
Mean Subcutaneous Adipose Tissue Area (SD), cm2 229.3 (123.9) 231.7 (129.0) 229.1 (123.6) 0.90
Mean Muscle Attenuation (SD), HU 40.2 (9.4) 36.6 (9.7) 40.5 (9.3) 0.009
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Abbreviations: BMI, body mass index (calculated as weight [kg] divided by the square of height [m]; kg/m2); HU, Hounsfield units.

Forty-two patients [7.9% (95% CI: 5.7, 10.5)] prematurely discontinued chemotherapy. Those who prematurely discontinued chemotherapy had a similar body surface area [between group difference (Δ): 0.06 m2 (95% CI: –0.03, 0.14)], and received a similar first cycle relative dose intensity of 5-fluorouracil [Δ: –0.001% (95% CI: –0.04, 0.04)] and oxaliplatin [Δ: –0.01% (95% CI:–0.03, 0.01)], as compared with patients who did not prematurely discontinue chemotherapy.

Effects of Adipose Tissue Quantity and Distribution on Premature Chemotherapy Discontinuation

BMI was not statistically significantly associated with premature chemotherapy discontinuation [RR: 2.07 (95% CI: 0.75, 5.73); Figure 1A]; the RR of premature chemotherapy discontinuation for each SD (6.3 kg/m2) increase in BMI was 1.26 (95% CI: 0.93, 1.72). Visceral adipose tissue was statistically significantly associated with an increased risk of premature chemotherapy discontinuation [RR: 3.27 (95% CI: 1.26, 8.49); Figure 1B]; the RR of premature chemotherapy discontinuation for each SD (101.4 cm2) increase in visceral adipose tissue was 1.45 (95% CI: 1.06, 1.96). Subcutaneous adipose tissue was not statistically significantly associated with premature chemotherapy discontinuation [RR: 2.32 (95% CI: 0.91, 5.94); Figure 1C]; the RR of premature chemotherapy discontinuation for each SD (123.9 cm2) increase in subcutaneous adipose tissue was 1.32 (95% CI: 0.99, 1.76). Intramuscular adipose tissue was statistically significantly associated with an increased risk of premature chemotherapy discontinuation [RR: 2.79 (95% CI: 1.09, 7.12)]; Figure 1D]; the RR of premature chemotherapy discontinuation for each SD (9.4 HU) increase in intramuscular adipose tissue was 1.37 (95% CI: 1.02, 1.86). The conclusions of the above-described results were comparable on the ARD scale [Figure S2].

Figure 1.

Figure 1.

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Restricted cubic spline estimates of premature chemotherapy discontinuation on the relative risk scale as a function of body mass index (Panel A); visceral adipose tissue area (Panel B); subcutaneous adipose tissue area (Panel C); and intramuscular adipose tissue (Panel D).

Relative risk (RR) estimates in the text are the contrast of the 5th and 95th percentiles. Shaded regions indicate 95% confidence bands for risk of premature chemotherapy discontinuation. Estimates are adjusted for age, sex, cancer stage, height, and muscle area. Note distinct x-axis scales; y-axis plotted on the logarithmic scale.

DISCUSSION

In this population-based cohort study, 1-in-12 patients with stage II-III colon cancer received less than six cycles (e.g., three months) of postoperative chemotherapy, when at the time this study was conducted, the standard of care was 12 cycles [e.g., six months; (2, 32)]. Visceral and intramuscular adiposity were statistically significantly associated with an increased risk of premature chemotherapy discontinuation. The associations between adiposity and chemotherapy discontinuation were independent of skeletal muscle. BMI and subcutaneous adipose tissue were not statistically significantly associated with premature chemotherapy discontinuation.

The association between excess adiposity and premature chemotherapy discontinuation is pharmacologically plausible. The pharmacokinetic properties of chemotherapy may be altered in people with obesity (33). Excess adiposity increases the volume of distribution (Vd) of lipophilic drugs, such as oxaliplatin (34), which correlates with maximum drug concentrations and predicts severe dose-limiting toxicity (15). Consistent with our findings, cancer survivors treated with platinum-based chemotherapy (e.g., oxaliplatin) with a larger waist circumference have an increased risk of chemotherapy induced neuropathy symptoms (35). Waist circumference is an anthropometric surrogate for visceral adipose tissue (36), and neuropathy symptoms are one of the most common dose-limiting toxicities of oxaliplatin-based chemotherapy (3). Skeletal muscle is a determinant of chemotherapy pharmacokinetics and toxicity risk in patients with cancer (16, 17). The association between adiposity and premature chemotherapy discontinuation in the current study was independent of skeletal muscle.

BMI was not statistically significantly associated with premature chemotherapy discontinuation. In correlational analyses, BMI explained more variation in subcutaneous adipose tissue (R2 = 0.739) than visceral adipose tissue (R2 = 0.381) or intramuscular adipose tissue (R2 = 0.179). These results are consistent with analyses among healthy adults that quantify adipose tissue using whole-body magnetic resonance imaging (37). Subcutaneous adipose tissue was not statistically significantly associated with premature chemotherapy discontinuation; we hypothesize that this lack of an association may be attributable to the reduced blood flow to subcutaneous adipose tissue in people with obesity (38). Excess visceral and intramuscular adipose tissue in women with breast cancer is associated with poorer chemotherapy tolerance (39). The data from this study contribute to a growing literature that BMI alone may be insufficient to predict important clinical outcomes in patients with cancer (26).

The American Society of Clinical Oncology recommends that full, weight-based cytotoxic chemotherapy doses be used to treat patients with cancer who have obesity (13). In our study, patients who prematurely discontinued chemotherapy had a body surface area and received first cycle relative dose intensities of 5-fluorouracil and oxaliplatin that were not statistically significantly different from patients who did not prematurely discontinue chemotherapy. This strengthens the clinical relevance of our findings that visceral and intramuscular adiposity independently predict premature chemotherapy discontinuation in patients with colon cancer.

Patients with colon cancer who have excess visceral and intramuscular adiposity at diagnosis should continue to receive full weight-based cytotoxic chemotherapy dosing, consistent with the current American Society of Clinical Oncology recommendations (13). However, our finding that patients with excess visceral or excess intramuscular adiposity may be more prone to prematurely discontinue chemotherapy suggests that this patient group may be more susceptible to develop severe treatment-related toxicities. Consequently, this subgroup of patients may benefit from more rigorous surveillance during therapy ― such as the Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)―to enable prompt identification and treatment of emerging treatment-related toxicities (40).

It remains unknown if reducing visceral or intramuscular adiposity in patients with colon cancer will decrease the probability of premature chemotherapy discontinuation. Aerobic exercise reduces visceral adipose tissue and preserves lean tissue in patients with colon cancer (41). In 2019, the American College of Sports Medicine concluded that exercise is safe during chemotherapy, but the evidence that exercise improves chemotherapy tolerability is a significant research gap (42). To address this evidence gap, the National Cancer Institute launched the Exercise and Nutrition Interventions to Improve Cancer Treatment-Related Outcomes (ENICTO) in Cancer Survivors Consortium (https://grants.nih.gov/grants/guide/rfa-files/RFA-CA-21-031.html). The randomized trials of the ENICTO Consortium will quantify the efficacy of exercise and nutrition to modify body composition and improve treatment tolerability in cancer survivors. The totality of evidence generated from the ENICTO Consortium will provide definitive evidence to inform the future delivery of comprehensive evidence-based care to cancer survivors.

The principal limitation of this study is the observational design, which precludes our ability to rule out residual confounding. Body composition was measured at the third lumbar vertebrae at a solitary time point (e.g., diagnosis). The third lumbar region is strongly correlated with total body adipose tissue and skeletal muscle volumes (22, 23), however, whole-body measures may offer additional prognostic information and should be examined in future studies. We did not have comprehensive BMI and body composition measures before the diagnosis of colon cancer. Therefore, we cannot rule out that some patients may have experienced tumor-induced changes in BMI or body composition before cancer diagnosis. However, body composition at the time of diagnosis is most relevant to treatment planning and prediction of poor treatment tolerance.

The study cohort was restricted to patients who initiated FOLFOX within six months of surgical resection. Between 2006 and 2011, when cohort subjects were diagnosed, FOLFOX was the standard of care. Thus, we cannot comment on the association of adiposity with other chemotherapy regimens, such as capecitabine and oxaliplatin (CAPOX) or 5-fluorouracil and leucovorin (5-FU/LV). FOLFOX is used to treat various gastrointestinal malignancies. However, it is not known if our findings in patients with resected colon cancer can be generalized to patients with other types of malignancies or with advanced disease. Due to the real-world nature of our dataset, we were unable to determine why patients prematurely discontinued postoperative chemotherapy; nonetheless, interventions are needed to improve patient adherence to postoperative chemotherapy to maximize the efficacy and probability of cure.

The principal strengths of this study are the population-based sample and gold-standard measures of adipose tissue quantity and distribution. The use of real-world electric medical records and pharmacy data, combined with clinically acquired computed tomography images, enabled the identification of a novel and modifiable risk factor for the premature discontinuation of chemotherapy.

Conclusion

In conclusion, among patients with stage II and III colon cancer who initiate postoperative chemotherapy, excess visceral and intramuscular adiposity may be risk factors for the premature discontinuation of chemotherapy. Efforts to decrease the incidence of premature chemotherapy discontinuation are critical to maximize chemotherapy efficacy and reduce death attributable to colon cancer. If these findings are replicated, interventions to reduce excess adiposity may improve patient tolerance to evidence-based chemotherapy regimens and improve the probability of cure.

Supplementary Material

1

Funding Statement

The content is solely the authors’ responsibility and does not represent the official views of the National Institutes of Health. The funding agency had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Conflict of Interest

Dr. Brown reports receiving grants from the National Cancer Institute and the American Institute for Cancer Research during the conduct of the study. Dr. Cespedes Feliciano reports receiving grants from the National Cancer Institute during the conduct of the study. Dr. Meyerhardt reports receiving grants from the National Cancer Institute during the conduct of the study and reports receiving consulting fees from Cota Healthcare, and Taiho during the 36 months before publication (all fees <$5,000). Dr. Caan reports receiving grants from the National Cancer Institute during the conduct of the study. All other authors report no disclosures.

Footnotes

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