Neuronal Protection for Chemotherapy Neuropathy Prevention?

Substantial data have been generated over decades to try to find ways to prevent and/or treat chemotherapy-induced peripheral neuropathy (CIPN), a major clinical problem for many patients receiving a variety of neurotoxic chemotherapy drugs. The 2014 American Society of Clinical Oncology guideline publication regarding the prevention and management of CIPN in adults reported results on 48 randomized trials (1). None of the 42 clinical trials that evaluated strategies to prevent CIPN resulted in a clinical treatment recommendation; however, one trial resulted in evidence against its use due to increased toxicity (2). Of the six CIPN treatment trials, only one trial, evaluating the use of duloxetine, resulted in a positive recommendation (3). The guidelines strongly endorsed this treatment for painful CIPN, acknowledging that the benefit was modest.

An article in the current issue of the Journal by Su et al. (4) reveals promising data that suggest intravenous delivery of ganglioside-monosialic acid (GM-1) may effectively protect against taxane-induced neuropathy. GM-1 is in the family of gangliosides, which are present primarily within the plasma membrane of neurons, where they exert complex signaling functions. GM-1 has been implicated in a variety of neurobiological processes, including neuronal differentiation, plasticity, and survival (5). Notably, autoantibodies to GM-1 lead to multifocal motor neuropathy, and there are reports of a rare association between ganglioside treatment and Guillain-Barré syndrome (6,7). Promising data from in vitro and in vivo laboratory studies suggested that GM-1 may have neuroprotective properties (8), including in the setting of chemotherapy exposure (9). However, a previously published clinical trial, which evaluated 120 patients receiving oxaliplatin-based chemotherapy, found only a modest benefit in preventing high-grade neuropathy (10). The prior trial did not assess patient-reported outcomes and had an unblinded control group; therefore, the results from this report were difficult to interpret.

The report from Su et al. presents the results of a randomized, double-blind, placebo-controlled trial involving more than 200 patients who concurrently received four cycles of adjuvant taxane therapy (docetaxel or paclitaxel) administered every 2 to 3 weeks for breast cancer. The primary outcome of the trial was the validated Functional Assessment of Cancer Treatment Neurotoxicity instrument, an outcome measure that has been used in several prior trials. It should be noted that the GM-1 was intravenously administered for 3 consecutive days with each cycle. The baseline scores in both groups showed no symptoms of neuropathy (score of 44). The scores, 2 weeks following the last chemotherapy dose, were 43.3 for the intervention (drop of only 0.7) and 34 for the placebo (drop of 10 points). Similarly, in the intervention group, 73.6% reported grade 0 and 26.4% reported grade 1 sensory neuropathy, compared with 59.8% reporting grade 2 and 9.7% reporting grade 3 sensory neuropathy in the placebo arm. Similar benefits (ie, less CIPN symptom development in the GM-1 group) were seen for other neuropathy outcome measures.

The neuropathy prevention properties of GM-1 are supported by two additional findings from this report. The first of these is that patients receiving GM-1 had a lower incidence of chemotherapy dose reductions or delays, noting that taxane dose reductions or delays are frequently caused by neuropathy problems. This result should have a direct positive impact on breast cancer outcomes. The second finding is that the GM-1 group had a decreased incidence of the taxane-associated acute pain syndrome. As opposed to this syndrome routinely being known in the past as taxane-induced arthralgias-myalgias (11), in 2007 it was proposed that this syndrome is not related to joint and/or muscle pathology (12); rather, it appears to be a form of acute neuropathy that occurs within days of each dose of a taxane and then tends to improve over a few days. The time-frame pattern of this pain syndrome is similar to the acute neuropathy syndrome associated with oxaliplatin, understanding that the features of the pain syndromes between paclitaxel and oxaliplatin are quite distinct (13–15).

In the current trial, 91.0% of the patients received docetaxel, as opposed to paclitaxel, understanding that paclitaxel is more neuropathic than is docetaxel (16). Although the authors reported a subset analysis that suggested similar GM-1–associated CIPN reductions with both drugs, it would be nice to see the efficacy of this drug in a larger group of patients receiving paclitaxel.

One very peculiar aspect of this current trial report is that the taxane-associated neuropathy was virtually totally resolved 3 months following the completion of taxane therapy. Previous publications have supported that CIPN can be a persistent problem for months to years following completion of taxane therapy for a substantial percentage of patients (17–19). In one trial, using the same patient-reported outcome instrument as was used in the present trial (Functional Assessment of Cancer Treatment Neurotoxicity), neuropathy scores were statistically significantly worse at 2 years than they were before taxane initiation, with 34.4% of patients having at least a five-point decrease from baseline at 2 years (17). Another trial conveyed that 41.9% of patients reported neuropathy 2 years after finishing paclitaxel (18). A third trial, which also noted substantial neuropathy in patients 24 months after adjuvant taxane therapy initiation, did report less neuropathy at 24 months if the patient had received docetaxel as opposed to paclitaxel (18,19). One potential explanation for this discrepancy, related to neuropathy resolution following taxane completion, might be that resolution of neuropathy is more complete in patients of Chinese ethnicity as opposed to individuals from Western nationalities. It is also possible that other patient selection factors may have influenced the results.

In total, we congratulate the authors of this article. Given the exciting data they provide for oncology clinicians and patients, what questions might best be addressed to facilitate this drug becoming an established, guideline-directed therapy? One point the authors note at the end of their article is the need to replicate the study in a different ethnic population. Ideally, this would include patients receiving more neurotoxic chemotherapy than docetaxel, such as paclitaxel or oxaliplatin. Additionally, evaluation of the best dose schedule may be useful, because the protocol-required 3 days of intravenous injections are less than ideal.

Notes

Dr Loprinzi has received consulting fees from Asahi Kasei Pharma Corp; Disarm Therapeutics, Inc; Metys Pharmaceuticals AG; and PledPharma AB. Dr Staff has received grant funding R01 CA 211887. Dr Hershman has no disclosures.