Body Composition, Adherence to Anthracycline and Taxane-Based Chemotherapy, and Survival After Nonmetastatic Breast Cancer

Abstract

Importance: Although most chemotherapies are dosed on body surface area or weight, body composition (ie, the amount and distribution of muscle and adipose tissues) is thought to be associated with chemotherapy tolerance and adherence.

Objectives: To evaluate whether body composition is associated with relative dose intensity (RDI) on anthracycline and taxane-based chemotherapy or hematologic toxic effects and whether lower RDI mediates the association of adiposity with mortality.

Design, setting, and participants: An observational cohort study with prospectively collected electronic medical record data was conducted at Kaiser Permanente Northern California, a multicenter, community oncology setting within an integrated health care delivery system. Participants included 1395 patients with nonmetastatic breast cancer diagnosed between January 1, 2005, and December 31, 2013, and treated with anthracycline and taxane-based chemotherapy. Data analysis was performed between February 25 and September 4, 2019.

Exposures: Intramuscular, visceral, and subcutaneous adiposity as well as skeletal muscle were evaluated from clinically acquired computed tomographic scans at diagnosis.

Main outcomes and measures: The primary outcome was low RDI (<0.85), which is the ratio of delivered to planned chemotherapy dose, derived from infusion records; in addition, hematologic toxic effects were defined based on laboratory test values. To evaluate associations with overall and breast cancer-specific mortality, logistic regression models adjusted for age and body surface area were fit as well as Cox proportional hazards models adjusted for age, race/ethnicity, adiposity, Charlson comorbidity index score, and tumor stage and subtype. The mediation proportion was computed using the difference method.

Results: The mean (SD) age at diagnosis of the 1395 women included in the study was 52.8 (10.2) years. Greater visceral (odds ratio [OR], 1.19; 95% CI, 1.02-1.39 per SD) and intramuscular (OR, 1.16; 95% CI, 1.01-1.34 per SD) adiposity were associated with increased odds of RDI less than 0.85. Greater muscle mass was associated with a decreased odds of hematologic toxic effects (OR, 0.84; 95% CI, 0.71-0.98 per SD). Relative dose intensity less than 0.85 was associated with a 30% increased risk of death (hazard ratio, 1.30; 95% CI, 1.02-1.65). Lower RDI partially explained the association of adiposity with breast cancer-specific mortality (mediation proportion, 0.20; 95% CI, 0.05-0.55).

Conclusions and relevance: Excess adiposity, presenting as larger visceral or intramuscular adiposity, was associated with lower RDI. Lower RDI partially mediated the association of adiposity with worse breast cancer-specific survival. Body composition may help to identify patients likely to experience toxic effects and subsequent dose delays or reductions, which could compromise chemotherapeutic efficacy.

Figure 1.. Two Patients With Identical Body Surface Area (BSA) and Body Mass Index (BMI), but Different Body Composition

Although both patients have a dosing BSA of 2 m² and BMI of 29 (calculated as weight in kilograms divided by height in meters squared), patient A may have a higher risk of toxic effects and dose reduction than patient B. Patient A has greater visceral (211 cm²) and intramuscular (muscle radiodensity 34 Hounsfield units [HU]) adiposity and smaller muscle area (132 cm²) than patient B (visceral adipose area 80 cm², muscle radiodensity 50 HU, and muscle area 148 cm²).

Figure 2.. Risk of Low Relative Dose Intensity of Anthracycline and Taxane-Based Chemotherapy by SD of Body Composition Exposures

Odds ratios are per SD exposure from logistic regression models adjusted for age at diagnosis and initial dosing body surface area. Greater intramuscular and visceral adiposity are associated with a higher risk of low relative dose intensity less than 0.85.

Figure 3.. Overall Survival and Cumulative Incidence of Breast Cancer Death by Relative Dose Intensity (RDI) on Anthracycline and Taxane-Based Chemotherapy

Lower overall survival (A) and higher cumulative incidence of breast cancer death associated with low RDI (B). Multivariable models were adjusted for age at diagnosis, race/ethnicity, total adiposity, Charlson comorbidity index score, stage of cancer, and estrogen and progesterone receptor and ERBB2 (formerly HER2) status. Compared with women who received higher RDI, women with low RDI less than 0.85 had a 30% higher risk of dying from any cause (hazard ratio [HR], 1.30; 95% CI, 1.02-1.65) and a 38% higher risk of dying from breast cancer (HR, 1.38; 95% CI, 1.02-1.85).