Clinical Course of Oxaliplatin-Induced Neuropathy: Results From the Randomized Phase III Trial N08CB (Alliance)

Abstract

Purpose: Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation.

Methods: Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy.

Results: Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001).

Conclusion: Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Trial registration: ClinicalTrials.gov NCT00316914.

Fig 1.

Mean scores associated with the four acute neuropathy symptoms during treatment. Higher values indicate more severe symptoms.

Fig 2.

Acute neuropathy symptom scores during the 12 cycles of oxaliplatin treatment, segregated by the worst mean maximum acute cycle 1 score (none v mild v moderate-severe) for (A) sensitivity to touching cold items, (B) discomfort swallowing cold liquids, (C) throat discomfort, and (D) muscle cramps. Higher values indicate more severe symptoms.

Fig 3.

Mean sensory, motor, and autonomic subscores from the 20-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy (CIPN-20), during the treatment period and for 18 months of follow-up, in terms of percent of baseline score over time. Higher values indicate less severity of symptoms.

Fig 4.

Mean tingling, numbness, and pain scores for toes/feet and fingers/hands from the 20-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy (CIPN-20) during 12 cycles of oxaliplatin therapy and after chemotherapy completion. Graphs showing (A) CIPN-20 subscale scores for the patients who completed all 12 cycles of treatment, and (B) the percent of end-of-treatment scores for these same items from the end of treatment through 18 months of follow-up for all patients, regardless of whether the patient stopped chemotherapy after all 12 planned cycles or earlier. Higher values indicate less severity of symptoms.

Fig 5.

Total sensory neuropathy scores from the 20-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy (CIPN-20), segregated by the worst acute neuropathy scores (for any of the four acute neuropathy symptoms) during cycle 1. Higher values indicate less severity of symptoms.

Fig A1.

Mean functional subscores from the 20-item European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for patients with chemotherapy-induced peripheral neuropathy during 12 cycles of oxaliplatin therapy and follow-up. Graphs show results for (A) “Difficulty manipulating small objects with your fingers,” (B) “Difficulty opening a jar or bottle because of weakness in your hands,” (C) “Problems holding a pen,” (D) “Problems standing or walking because of difficulty feeling ground,” (E) Difficulty walking because your feet dropped downward,” (F) “Difficulty climbing stairs or getting up out of a chair because of weakness in your legs,” (G) “Difficulty using car pedals,” and (H) “Difficulty distinguishing between hot and cold water.”

Fig A2.

Changes in chemotherapy-induced peripheral neuropathy sensory scores for individual patients in the time following the last dose of chemotherapy. Higher values indicate lower severity of symptoms.