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.

The association of clinical and patient factors with chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer: secondary analysis of the SCOT trial

“…Obesity was previously shown to be a significant predictor of CIPN severity. 46 , 47 However, in our study we did not find BMI-related differences in CIPN.…”

Oxaliplatin-associated shock in stage III colorectal cancer patients: real-world evidence in Taiwan

“…DM, hyperglycemia, and other metabolic complications might also lead to cardiovascular disorders and chronic peripheral neuropathy. 12 – 14 , 16 However, we did not find any difference in our analysis ( Figure 3 ). In the current study, the patients with DM and other metabolic syndromes, such as hyperuricemia and hyperlipidemia, were not associated with higher risks of oxaliplatin-associated severe shock.…”

“… 8 , 11 , 27 Cumulative dose of oxaliplatin enhances chronic OIPN. 9 , 16 , 28 , 29 The mechanisms of OIPN include neuron-cell nucleotide damage, mitochondrial breakdown with oxidative stress overload, glial activation, and neuroinflammation. 8 Previous studies showed that oxaliplatin accumulated in the DRG and destroyed neuronal mitochondria by forming platinum–mitochondria DNA adducts.…”

“… 8 – 11 In addition, although debatable, diabetes mellitus (DM) and other metabolic complications, such as hyperlipidemia and hyperuricemia, might also affect the severity of peripheral neuropathy. 12 – 16 Therefore, the current study aimed to investigate the incident rate and risk factors using real-world data.…”

Neurological adverse events associated with oxaliplatin: A pharmacovigilance analysis based on FDA adverse event reporting system

“…Previous reports have shown that acute sensory symptoms and chronic sensory neuropathy caused by oxaliplatin usually occurred after cumulative doses of 550 mg/m 2 , which was equivalent to six to seven cycles (3 months) at a dose of 85 mg/m 2 every 2 weeks ( Park et al, 2013 ). In a clinical trial of 2,450 patients with stage III colon cancer recruited from the United States and Canada, patients accepted 12 cycles (6 months) of adjuvant oxaliplatin, fluorouracil, and leucovorin, relative to 6 cycles (3 months), were more likely to experience higher-grade neuropathy and longer times to resolution ( Lee et al, 2023 ). Moreover, similar results have also been obtained in another randomized phase III trial conducted in Japan.…”