Impact of Lean Body Mass-Based Oxaliplatin Dose Calculation on Neurotoxicity in Adjuvant Treatment of Stage III Colon Cancer: Results of the Phase II Randomized LEANOX Trial

Abstract

Purpose: Oxaliplatin-based adjuvant chemotherapy is used for stage III colon cancer, but may induce disabling neurotoxicity. We previously showed that the incidence of oxaliplatin-induced peripheral neurotoxicity (OIPN) is higher for oxaliplatin doses >3.09 mg per kg of lean body mass (LBM). This proof-of-concept, multicenter, randomized trial assessed whether LBM-based oxaliplatin dose adjustment reduces OIPN (ClinicalTrials.gov identifier: NCT03255434).

Methods: Among the patients with resected stage III colon cancer eligible for adjuvant leucovorin, fluorouracil, and oxaliplatin chemotherapy, those without LBM reduction received body surface area (BSA)-based oxaliplatin doses (85 mg/m², arm 1). Patients with reduced LBM were randomly assigned (1:1) to receive BSA-based (arm 2) or LBM-based oxaliplatin doses (3.09 mg/kg LBM, arm 3). The primary end point was the percentage of patients without grade ≥2 OIPN in the first six cycles.

Results: In all, 33, 64, and 63 patients were enrolled in arms 1, 2, and 3, respectively (median age, 63 years; 52.5% of men; 89.3% Eastern Cooperative Oncology Group 0; 57.5% pT3; 60.6% pN1). The primary end point was achieved by 67.2% of patients in arm 3 versus 42.1% in arm 2 (P = .01). Longer grade ≥2 OIPN-free survival (hazard ratio [HR], 0.53 [95% CI, 0.34 to 0.84]; P = .01), longer time to grade ≥2 OIPN onset (P = .006), higher cumulative oxaliplatin doses without grade ≥2 OIPN (P = .044), and fewer oxaliplatin dose reductions (P < .001) were reported in arm 3. Relapse-free survival (HR, 1.05 [95% CI, 0.54 to 2.06]) and overall survival (OS; HR, 1.20 [95% CI, 0.36 to 3.92]) were similar in arms 2 and 3 (median follow-up of 38.6 months). Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 scores were better in arm 3.

Conclusion: In adjuvant settings for stage III colon cancer, using an LBM-based oxaliplatin dose significantly reduces OIPN and improves quality of life without affecting relapse-free survival and OS.

FIG 1.

Study flow chart. ^aTo quantify the skeletal muscle area, the total muscle cross-sectional area was measured using CT images taken at the third lumbar vertebra level (L3) and the Slice-O-Matic software. The muscle area was then normalized to the square of the height (m²) and reported as the lumbar skeletal muscle index. LBM in kg was calculated using the following formula: (L3 muscle area measured by CT [cm²] × 0.3) + 6.06. ^bAccording to center, age (≤65 years v >65 years), and weight loss (≤5% v >5%). BSA, body surface area; CT, computed tomography; LBM, lean body mass; NA, not appropriate; PP, per protocol.

FIG 2.

Kaplan-Meir estimates of grade ≥2 OIPN-free survival. Kaplan-Meier estimates of grade ≥2 OIPN-free survival in arm 2 (BSA-based dose) and arm 3 (LBM-based dose). The shaded regions represent the 95% CIs. HRs were calculated using the Cox proportional hazards model, with 95% CI based on log transformation and exponentiation for CI estimation, and P values determined with the log-rank test. BSA, body surface area; HR, hazard ratios; LBM, lean body mass; OIPN, oxaliplatin-induced peripheral neuropathy.

FIG 3.

Kaplan-Meir estimates of relapse-free survival and OS. Kaplan-Meier estimates of (A) relapse-free survival and (B) OS in arm 2 (BSA-based oxaliplatin dose) and arm 3 (LBM-based oxaliplatin dose). HRs were calculated using the Cox proportional hazards model, with 95% CI based on log transformation and exponentiation for CI estimation, and P values determined with the log-rank test. BSA, body surface area; HR, hazard ratios; LBM, lean body mass; OS, overall survival.

FIG 4.

EORTC QLQ-CIPN20 scores. Longitudinal analysis of the (A) total, (B) autonomy, (C) motor, and (D) sensory subscale scores of the EORTC QLQ-CIPN20 questionnaire in arm 2 (BSA-based dose) and arm 3 (LBM-based dose) at baseline, from C1D1 to C12D1, at the EOT, and during the follow-up visits (FUP3, FUP6, and FUP12, corresponding to 3, 6, and 12 months after treatment). Box plots display the median, and 25th and 75th percentiles; whiskers denote extreme values; and outliers are shown as circles. BSA, body surface area; C12D1, cycle 12 day 1; C1D1, cycle 1 day 1; EORTC QLQ-CIPN20, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20; EOT, end of treatment; FUP, follow-up; LBM, lean body mass.

FIG A1.

Example of LBM determination and oxaliplatin dose adaptation in function of the LBM using the Myrian software (Intrasense SA, Montpellier, France). CT, computed tomography; LBM, lean body mass.

FIG A2.

Changes in the relative dose intensity of oxaliplatin according to the treatment arm. Patients in arm 1, without significant LBM reduction, received a BSA-based oxaliplatin dose. Patients with reduced LBM were randomly assigned (1:1) to receive a BSA-based dose (arm 2) or LBM-based dose (arm 3) of oxaliplatin. Box plots show the median, and 25th and 75th percentiles; whiskers indicate extreme values; and outliers are represented as circles. BSA, body surface area; LBM, lean body mass.

FIG A3.

Kaplan-Meir survival curves. (A) Grade ≥2 OIPN-free survival, (B) relapse-free survival, and (C) OS stratified by treatment arm. Arm 1 includes patients without LBM reduction receiving a BSA-based oxaliplatin dose, whereas arms 2 and 3 include patients with LBM reduction, randomly assigned to BSA-based or LBM-based oxaliplatin dose, respectively. BSA, body surface area; LBM, lean body mass; OIPN, oxaliplatin-induced peripheral neuropathy; OS, overall survival.

FIG A4.

EORTC EQ5D scores. Longitudinal analysis of the total scores of the EORTC EQ5D questionnaire in arm 2 (BSA-based dose) and arm 3 (LBM-based dose) at baseline, at the EOT, and during the follow-up visits (FUP3, FUP6, corresponding to 3 and 6 months after treatment). Box plots display the median, and 25th and 75th percentiles; whiskers indicate extreme values; and outliers are shown as circles. BSA, body surface area; EORTC EQ5D, European Organization for Research and Treatment of Cancer European Quality of Life 5 Dimensions; EOT, end of treatment; FUP, follow-up; LBM, lean body mass.