Residual Platinum-Induced Neuropathy and the Feasibility of Second-Line Paclitaxel–Ramucirumab Therapy in Advanced Gastric Cancer: Prospective Multicenter Evidence from Japan

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Abstract
Background: Platinum-based doublets are standard first-line therapy for advanced gastric cancer (GC) in the Western Pacific region, but oxaliplatin frequently induces persistent peripheral sensory neuropathy (PSN). Whether residual PSN compromises the feasibility and efficacy of subsequent paclitaxel (PTX)-based therapy remains unclear. Methods: The IVY study was a prospective, multicenter observational trial conducted across 16 Japanese institutions. Patients with advanced GC progressing after fluoropyrimidine–platinum therapy received second-line PTX ± ramucirumab. Baseline PSN was assessed by CTCAE, PNQ, and FACT/GOG-Ntx. The primary endpoint was the incidence of grade ≥ 3 PSN during second-line therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), time to treatment failure (TTF), tumor response, and patient-reported outcomes. Results: Among 156 patients (90 PSN-positive, 66 PSN-negative), grade ≥ 3 PSN occurred more frequently in the PSN-positive group (16.7% vs. 4.5%; p = 0.02). Median PFS was 4.0 vs. 3.9 months (p = 0.20), and median OS was 10.3 vs. 8.1 months (p = 0.04). In multivariable analysis, residual PSN was not an independent predictor of OS (HR = 0.68 for PSN-positive vs. PSN-negative, 95% CI [0.46–1.01]; p = 0.06). Patient-reported instruments captured greater and earlier QoL impairment in PSN-positive patients, though trajectories stabilized by 12 weeks. Conclusions: Residual PSN increases the risk of clinically relevant neurotoxicity—particularly in patients with baseline grade ≥ 2—but, in this cohort, did not appear to preclude paclitaxel-based second-line therapy when monitoring and dose modification were available. The apparent survival difference was exploratory and, after adjustment for baseline imbalance, should not be interpreted as a benefit attributable to residual PSN. Residual neuropathy should therefore prompt structured baseline assessment and early-cycle monitoring rather than routine reassurance.
Funding Information
  • Department of Advanced Oncology, Kawasaki Medical School

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