Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

Abstract

Background: Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy.

Methods: We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy.

Results: A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy.

Conclusion: We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Fig 1.

Grade 2 to 4 (A) and grade 3 to 4 (B) neuropathy rates by comorbid disease category. Each bar represents the proportion with neuropathy for patients with the specified condition (blue) or without the specified condition (gold). The P values shown above each set of bars show the statistical significance for the covariate representing whether a patient had the specified condition (ie, with v without condition) from the multivariable logistic regression analyses. The comorbid disease categories are sorted in descending order of the odds ratio for having grade 2 to 4 neuropathy, derived from multivariable regression analyses. P values were derived from multivariable logistic regression models adjusting for age, race (black/white/other), sex, cancer stage/risk, date of initial enrollment, and planned treatment time according to the protocol (at or above v below the median), and stratified by treatment type (docetaxel v paclitaxel) and platinum treatment (yes/no). For the analysis of diabetes with chronic complications, the comparison is between patients with diabetes plus complications versus patients with no diabetes. Patients with diabetes without complications are excluded from this analysis. Autoimmune diseases include Sjögren’s syndrome, lupus, rheumatoid arthritis, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, vasculitis, and giant cell arteritis. VD, vascular disease.

Fig 2.

Forest plot of the association of neuropathy grade with each comorbid condition, controlling for demographic, clinical, and treatment characteristics. Each box represents the odds ratio, and each line represents the 95% CI around the estimated odds ratio. The vertical line shows the line of equal odds. Odds ratios to the right of the vertical line indicate that patients with the specified condition had higher odds of grade 2 to 4 or grade 3 to 4 neuropathy, and odds ratios to the left of the vertical line indicate that patients with the specified condition had lower odds of grade 2 to 4 or grade 3 to 4 neuropathy. The comorbid disease categories are sorted in descending order of the odds ratio for having grade 2 to 4 neuropathy in multivariable regression. Odds ratios and P values were derived from multivariable logistic regression models, adjusting for age, race (black/white/other), sex, cancer stage and risk, date of initial enrollment, and planned treatment time according to the protocol (at or above v below the median), and stratified by treatment type (docetaxel v paclitaxel) and platinum treatment (yes/no). For the analysis of diabetes with chronic complications, the comparison is between patients with diabetes plus complications versus patients with no diabetes. Patients with diabetes without complications were excluded from this analysis. Autoimmune diseases include Sjögren’s syndrome, lupus, rheumatoid arthritis, scleroderma, mixed connective tissue disease, dermatomyositis, polymyositis, vasculitis, and giant cell arteritis. Each square represents an odds ratio, and each horizontal line is the 95% CI. The vertical line is the line of equal odds.