Quantitative Sensory Testing at Baseline and During Cycle 1 Oxaliplatin Infusion Detects Subclinical Peripheral Neuropathy and Predicts Clinically Overt Chronic Neuropathy in Gastrointestinal Malignancies

Abstract

Purpose

Oxaliplatin neurotoxicity has a spectrum of manifestations from an often reversible acute neurotoxicity to a more irreversible “stocking and glove” chronic neuropathy that is associated with high morbidity. Quantitative sensory testing (QST) is a noninvasive psychometric testing method that can potentially be used in the clinic setting to measure subclinical neurologic changes early on to identify patients that will experience chronic oxaliplatin-induced peripheral neuropathy at 1 year.

Patients and Methods

Thirty patients with gastrointestinal malignancies who were receiving oxaliplatin were recruited. QST and patient-reported outcomes were assessed at baseline; during infusion cycles 1, 2, 4, and 6; and at 1 year. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0, chronic neuropathy scores were assessed at the 1-year time point. The variables at each time point were evaluated for prediction of 1-year chronic neuropathy scores.

Results

We found that patients with preexisting subclinical neuropathy were more likely to experience grades 2 and 3 chronic neuropathy than were those who did not have this condition (heat detection threshold, Spearman correlation coefficient (r_s) = 0.39; P = .037; pellet retrieval time, r_s = 0.47; P = .024). Patients in whom thermal and cutaneous sensory deficits developed with cycle 1 infusion were also more likely to experience grades 2 and 3 neuropathy at 1 year (cold detection threshold, r_s = 0.50; P = .007; heat detection threshold, r_s = 0.39; P = .042; cutaneous detection threshold, r_s = 0.42; P = .043).

Conclusion

QST provides a noninvasive, commercially available, and feasible clinical test to select patients, even before oxaliplatin treatment, who are likely to experience moderate to severe chronic peripheral neuropathy.

Introduction

Oxaliplatin is a third-generation platinum-based chemotherapeutic agent with a unique acute neurotoxicity as well as the more classic chronic neurotoxicity.1, 2, 3, 4 Acute oxaliplatin neurotoxicity occurs in 65% to 98% of patients,5, 6 often beginning during the infusion and peaking hours to days later.⁷ It is characterized by symptoms including cold-induced dysesthesias and parasthesias of the upper extremities and face, cold “hypersensitivity,” jaw tightness, pharyngolaryngeal dysesthesia (loss of sensation of breathing without any objective evidence of respiratory distress), muscle spasms, fasciculations, voice changes, and ocular pain.3, 5, 8, 9, 10, 11, 12 Interestingly, this acute neurotoxicity is thought to be essentially reversible.

In contrast, chronic neurotoxicity occurs in a peripheral “stocking and glove” pattern and is an axonal sensory neuropathy that occurs with cumulative dosing of oxaliplatin, similar to other platinum-based chemotherapies.3, 7 It is often irreversible, with high morbidity and decreased quality of life many years after treatment completion.¹³ Using the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE), the incidence of grades 2 and 3 chronic chemotherapy-induced peripheral neuropathy (CIPN) was shown to be 43% to 46% in a recent large phase III trial.¹⁴

Therefore, early identification of patients at risk for chronic oxaliplatin CIPN would be ideal to allow for preventive measures such as dose reductions or the development of prophylactic agents.¹⁵ To this end, nerve excitability studies (NESs), which primarily measure large nerve fiber function, demonstrate that patients exhibiting changes immediately after initial oxaliplatin doses—presumably indicative of acute neurotoxicity—are at greater risk for the development of chronic CIPN.10, 16 Unfortunately, this testing can be laborious and requires specialized expertise to perform and interpret the findings, making it less feasible to implement for widespread use in the oncology clinic. Although simpler noninvasive measurements have been shown to be predictive, they have either not been shown to be predictive at time points earlier than cycle 4 when it would be most clinically useful5, 17, 18 or have not assessed clinically significant CIPN interfering with function.¹⁹

Quantitative sensory testing (QST) paradigms are noninvasive psychophysiological tests that quantify neurologic function of both small- and large-fiber nerves.20, 21 Unlike NESs, they test small-fiber function as well to better capture symptoms such as pain.22, 23 Given that previous studies using NESs reported findings predictive of chronic CIPN immediately after oxaliplatin dosing, our aim was to find early predictors using simpler measures that might be used in the oncology clinic before and during the early part of an oxaliplatin course to better predict those at risk for clinically significant chronic oxaliplatin-induced peripheral neuropathy.