Long-term neurotoxicity effects of oxaliplatin added to fluorouracil and leucovorin as adjuvant therapy for colon cancer: results from National Surgical Adjuvant Breast and Bowel Project trials C-07 and LTS-01

Abstract

Background: Neurotoxicity from adjuvant treatment with oxaliplatin has been studied in patients with colorectal carcinoma in short-term studies, but, to the authors' knowledge, the current article is the first long-term assessment which reports the National Surgical Adjuvant Breast and Bowel Project (NSABP) investigation of whether excess neurotoxicity persists beyond 4 years.

Methods: As part of a colorectal cancer long-term survivor study (LTS-01), long-term neurotoxicity was assessed in 353 patients on NSABP Protocol C-07 (cross-sectional sample). Ninety-two of these patients from LTS-01 also had longitudinal data and were reassessed 5 to 8 years (median, 7 years) after random assignment (longitudinal sample). Contingency tables compared cohorts, a mixed model compared neurotoxicity between treatments over time, and a Wilcoxon rank-sum test compared neurotoxicity between treatments (cross-sectional sample).

Results: In the cross-sectional sample, the increase in mean total neurotoxicity scores of 1.8 with oxaliplatin was statistically significant (P = .005), but not clinically significant (a minimally important difference of 4 was reported at the long-term assessment). Patients who received oxaliplatin had increased odds of numbness and tingling in hands (odds ratio, 2.00; P = .015) and feet (odds ratio, 2.78; P < .001) versus patients who did not receive oxaliplatin. The magnitude of the oxaliplatin effect varied with time (P < .001) in the longitudinal sample, such that the oxaliplatin-treated group did not have significantly greater total neurotoxicity scores by 7 years.

Conclusions: At the long-term endpoint, there was no clinically significant increase in total neurotoxicity scores for patients who received oxaliplatin, but the specific neurotoxicities of numbness and tingling of the hands and feet remained significantly elevated for oxaliplatin-treated patients.

Figure 1

Patient Flow from the National Surgical Adjuvant Breast and Bowel Project C-07 trial to the Patient-Reported Outcomes (PRO) substudy and Long-Term Survivors study (LTS-01) to the overlapping subset available for long-term neurotoxicity analysis. FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin.

Figure 2

Forest plot depicting odds ratio for each neurotoxicity question for the 353 C-07 and Long-Term Survivors, LTS-01, patients; Odds of reporting the symptom (with severity of “somewhat,” “quite a bit,” or “very much” vs. “not at all” or a “little bit”) for FLOX divided by the odds for FULV; FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin.

Figure 3

Panel A: Distribution of severity of numbness or tingling in hands, for 353 NSABP C-07 patients participating in the Long-Term Survivors, LTS-01, long-term assessment of neurotoxicity; P-value compares distributions by treatment across the 5 levels of severity; FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin. Panel B: Distribution of severity of numbness or tingling in feet, for 353 NSABP C-07 patients participating in the Long-Term Survivors, LTS-01, long-term assessment of neurotoxicity; P-value compares distributions by treatment across the 5 levels of severity; FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin.

Figure 3

Panel A: Distribution of severity of numbness or tingling in hands, for 353 NSABP C-07 patients participating in the Long-Term Survivors, LTS-01, long-term assessment of neurotoxicity; P-value compares distributions by treatment across the 5 levels of severity; FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin. Panel B: Distribution of severity of numbness or tingling in feet, for 353 NSABP C-07 patients participating in the Long-Term Survivors, LTS-01, long-term assessment of neurotoxicity; P-value compares distributions by treatment across the 5 levels of severity; FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin.

Figure 4

In the longitudinal sample, mean and median changes from baseline of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Oxaliplatin-Specific Neurotoxicity Scale total score (NTX-12-score). FULV, fluorouracil and leucovorin; FLOX, FULV plus oxaliplatin.