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Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

ABSTRACT: Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pain and an average neuropathic pain score ?4/10. Duloxetine/placebo dose was 30 mg/day for 7 days, then 60 mg/day for 4 weeks. The Brief Pain Inventory-Short Form and the EORTC QLQ-C30 were used to assess pain and quality of life, respectively. Univariate and multiple logistic regression analyses were performed to identify demographic, physiologic and psychological predictors of duloxetine response. Higher baseline emotional functioning predicted duloxetine response (?30% reduction in pain; OR 4.036; 95% CI 0.999-16.308; p = 0.050). Based on the results from a multiple logistic regression using patient data from both the duloxetine and placebo treatment arms, duloxetine-treated patients with high emotional functioning are more likely to experience pain reduction (p = 0.026). In patients with painful, oxaliplatin-induced CIPN, emotional functioning may also predict duloxetine response. ClinicalTrials.gov, Identifier NCT00489411.

SUBMITTER: Smith EM

PROVIDER: S-EPMC4879099 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

Smith E M L EM Pang H H Ye C C Cirrincione C C Fleishman S S Paskett E D ED Ahles T T Bressler L R LR Le-Lindqwister N N Fadul C E CE Loprinzi C C Shapiro C L CL

European journal of cancer care 20151125 2

Duloxetine is an effective treatment for oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN). However, predictors of duloxetine response have not been adequately explored. The objective of this secondary and exploratory analysis was to identify predictors of duloxetine response in patients with painful oxaliplatin-induced CIPN. Patients (N = 106) with oxaliplatin-induced painful CIPN were randomised to receive duloxetine or placebo. Eligible patients had chronic CIPN pa ...[more]

PMID: 26603828

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Project description:PurposeWe 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.MethodsWe 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.ResultsPatients 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.ConclusionLower 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.

Project description:Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin.SignificanceWe found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.

Dataset Information

Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

Publications

Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601.

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