Potential Mediators of Oxaliplatin-Induced Peripheral Neuropathy From Adjuvant Therapy in Stage III Colon Cancer: Findings From CALGB (Alliance)/SWOG 80702

Abstract

Purpose: We sought to evaluate the independent and interactive associations of planned treatment duration, celecoxib use, physical activity, body mass index (BMI), diabetes mellitus, and vitamin B6 with oxaliplatin-induced peripheral neuropathy (OIPN) among patients with stage III colon cancer enrolled in a clinical trial.

Methods: We conducted a prospective, observational study of 2,450 patients with stage III colon cancer enrolled in the CALGB/SWOG 80702 trial, randomly assigned to 6 versus 12 cycles of adjuvant fluorouracil, leucovorin, and oxaliplatin chemotherapy with or without 3 years of celecoxib. OIPN was reported using the Common Terminology Criteria for Adverse Events (CTCAE) during and following completion of chemotherapy and the FACT/GOG-NTX-13 15-17 months after random assignment. Multivariate analyses were adjusted for baseline sociodemographic and clinical factors.

Results: Patients assigned to 12 treatment cycles, relative to 6, were significantly more likely to experience higher-grade CTCAE- and FACT/GOG-NTX-13-reported neuropathy and longer times to resolution, while neither celecoxib nor vitamin B6 intake attenuated OIPN. Exercising ≥ 9 MET-hours per week after treatment relative to < 9 was associated with improvements in FACT/GOG-NTX-13-reported OIPN (adjusted difference in means, 1.47; 95% CI, 0.49 to 2.45; P = .003). Compared with patients with baseline BMIs < 25, those with BMIs ≥ 25 were at significantly greater risk of developing higher-grade CTCAE-reported OIPN during (adjusted odds ratio, 1.18; 95% CI, 1.00 to 1.40; P = .05) and following completion (adjusted odds ratio, 1.23; 95% CI, 1.01 to 1.50; P = .04) of oxaliplatin treatment. Patients with diabetes were significantly more likely to experience worse FACT/GOG-NTX-13-reported neuropathy relative to those without (adjusted difference in means, -2.0; 95% CI, -3.3 to -0.73; P = .002). There were no significant interactions between oxaliplatin treatment duration and any of these potentially modifiable exposures.

Conclusion: Lower physical activity, higher BMI, diabetes, and longer planned treatment duration, but not celecoxib use or vitamin B6 intake, may be associated with significantly increased OIPN severity.

Trial registration: ClinicalTrials.gov NCT01150045.

FIG 1.

Derivation of the study cohort for (A) CTCAE-reported neuropathy and (B) FACT/GOG-NTX-13–reported neuropathy. CTCAE, Common Terminology Criteria for Adverse Events.

FIG 2.

FACT/GOG-NTX-13 total score at median 12 months (IQR, 10-13 months) from last oxaliplatin dose by (A) planned treatment duration, (B) celecoxib use, (C) physical activity, (D) BMI, (E) comorbid diabetes, and (F) vitamin B6 intake. The bottom and top edges of the box indicate the IQR, the marker inside the box indicates the mean value, and the line inside the box indicates the median value. The upper and lower fences are maximum and minimum values, respectively, and points beyond the upper and lower fences are outliers. BMI, body mass index; IQR, interquartile range.

FIG 3.

CTCAE-reported neuropathy by (A) planned treatment duration and (B) celecoxib use. The maximum grade of neuropathy during the follow-up period is presented. x-axis represents follow-up time points (eg, 6m represents the period from end of chemotherapy to 6 months after chemotherapy), and y-axis represents the proportion of evaluated patients. Numbers within each bar are the percentage of patients in each category; numbers on top of each bar are the total number of patients. Normal (grade 0) patients are not shown. CTCAE, Common Terminology Criteria for Adverse Events.