Long-term neuropathy after oxaliplatin treatment: challenging the dictum of reversibility

Abstract

Objectives: Oxaliplatin-induced neuropathy is a significant and dose-limiting toxicity that adversely affects quality of life. However, the long-term neurological sequelae have not been adequately described. The present study aimed to describe the natural history of oxaliplatin-induced neuropathy, using subjective and objective assessments.

Methods: From a population of 108 oxaliplatin-treated patients referred for neurological assessment in 2002-2008, 52.2% of the surviving patient cohort (n = 24) was available for follow-up at a median of 25 months post-oxaliplatin. Patients underwent a protocol that incorporated clinical assessment scales, patient questionnaires, standard electrodiagnostic assessments, and novel nerve excitability studies to precisely assess nerve function.

Results: At follow-up, 79.2% of patients reported residual neuropathic symptoms, with distal loss of pin-prick sensibility in 58.3% of patients and loss of vibration sensibility in 83.3% of patients. Symptom severity scores were significantly correlated with cumulative dose. There was no recovery of sensory action potential amplitudes in upper and lower limbs, consistent with persistent axonal sensory neuropathy. Sensory excitability parameters had not returned to baseline levels, suggesting persisting abnormalities in nerve function. The extent of excitability abnormalities during treatment was significantly correlated with clinical outcomes at follow-up.

Conclusions: These findings establish the persistence of subjective and objective deficits in oxaliplatin-treated patients post-oxaliplatin, suggesting that sensory neuropathy is a long-term outcome, thereby challenging the literature on the reversibility of oxaliplatin-induced neuropathy.

Figure 1.

Flow diagram of patient inclusion in the study. From a total cohort of 108 oxaliplatin-treated patients referred for nerve studies, 46 patients were alive at the time of follow-up. Of these, 24 patients were available for follow-up and assessed at a mean of 2.5 years after oxaliplatin treatment.

Figure 2.

Persistence of neuropathy at long-term follow-up. (A): NCI neuropathy severity grade displayed post-oxaliplatin and at the time of follow-up, depicting the percentage of patients characterized with NCI grade 0 (post-oxaliplatin, 0%; follow-up, 20.8%), NCI grade 1 (post-oxaliplatin, 29.2%; follow-up, 37.5%), NCI grade 2 (post-oxaliplatin, 41.6%; follow-up, 29.2%), and NCI grade 3 (post-oxaliplatin, 29.2%: follow-up, 12.5%). (B): TNS at the time of follow-up (TNS clinical version, blue; TNS reduced version, yellow). (C): Plot of the association of oxaliplatin cumulative dose (mg/m²) with neuropathic severity as assessed by the TNS (reduced) (correlation coefficient, 0.704; p = .0005). Abbreviations: NCI, National Cancer Institute; TNS, Total Neuropathy Scale.

Figure 3.

Nerve conduction findings across oxaliplatin treatment. (A): Change in compound sensory action potential (CSAP) peak amplitude immediately following oxaliplatin treatment and at follow-up, normalized to baseline recordings, for median (triangle), radial (square), and sural (diamond) sensory nerves. (B): Relationship of lower limb sural and upper limb radial amplitudes at follow-up, demonstrating symmetrical upper and lower limb presentation (correlation coefficient, .617; p = .001).

Figure 4.

Sensory excitability values pre-oxaliplatin treatment (blue), post-oxaliplatin treatment (yellow), and at follow-up (orange). (A): Superexcitability at pre-oxaliplatin, post-oxaliplatin (pre-oxaliplatin versus post-oxaliplatin, p = .028), and follow-up (pre-oxaliplatin versus follow-up, p = .05). (B): Refractoriness at pre-oxaliplatin, post-oxaliplatin (pre-oxaliplatin versus post-oxaliplatin, p =.036), and follow-up (pre-oxaliplatin versus follow-up, p = .05). (C): Summed excitability change during treatment correlated with final clinical neurological outcome (Total Neuropathy Scale reduced [TNSr]) at long-term follow-up (correlation coefficient, −0.779; p = .003).