We reviewed the evidence about the effect of treatments to prevent or reduce damage to nerves from the anticancer (chemotherapy) drug cisplatin or other platinum-containing drugs.
Cisplatin and other related platinum-containing drugs that are used to treat solid tumours are toxic to the peripheral nervous system. Most people who complete a full course of cisplatin chemotherapy develop a sensory neuropathy (damage to nerves that carry sensation). Symptoms can include tingling in the extremities and numbness. The neuropathy may only partially recover or not recover at all when the chemotherapy is stopped. To try to reduce the toxicity of platinum drugs, researchers have looked for therapies to protect the nerves.
We carried out a wide search for studies of treatments to prevent this type of nerve damage. We identified a total of 29 clinical trials, which involved almost 3000 participants who were receiving platinum-containing anticancer drugs (mostly cisplatin, oxaliplatin and carboplatin) for various types of cancer (mainly colon, ovary, and lung cancers). The nine treatments studied were: amifostine (seven trials), calcium and magnesium (four trials), glutathione (seven trials), Org 2766 (four trials) and vitamin E (three trials). There was one trial each of acetylcysteine, diethyldithiocarbamate (DDTC), oxcarbazepine, and retinoic acid. We chose an objective clinical test of sensation to report as our preferred measure of the effects of treatment. Only seven of the studies used this measure. Nine reported the results of nerve conduction studies which are another objective measure of nerve function. Most of the studies used a subjective assessment of neuropathy, such as the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy grading scale.
Key results and quality of the evidence
Most of the included studies were fairly well performed, where it was possible to obtain this information.
Based on the combined results that generally described secondary and non-quantitative measures such as the NCI-CTC neuropathy grading scale, modest but promising (borderline statistically significant) results favoured the use of amifostine, calcium and magnesium, and glutathione to reduce the neurotoxicity of cisplatin and related chemotherapies. Three studies of vitamin E could only be studied individually but the results of each imply some mild subjective benefits. Nevertheless, given the limitations of the studies, such as small numbers of participants, lack of objective measures of neuropathy, and differing results among similar trials, the data remain insufficient to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs. Most of the treatments were not associated with adverse events. Amifostine infusions were associated with temporary low blood pressure in a significant number of cases, and retinoic acid with low levels of calcium in the blood. About one-fifth of people treated with DDTC stopped taking it because of harmful effects.
Amifostine, calcium and magnesium, vitamin E, and glutathione require further well designed trials to clarify if they are effective or not.
This is an updated review. The evidence is current to 4 March 2013.
At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results were negative and did not support the positive findings based on the qualitative measures. In summary, the present studies are limited by the small number of participants receiving any particular agent, a lack of objective measures of neuropathy, and differing results among similar trials, which make it impossible to conclude that any of the neuroprotective agents tested prevent or limit the neurotoxicity of platinum drugs.
Cisplatin and several related antineoplastic drugs used to treat many types of solid tumours are neurotoxic, and most patients completing a full course of cisplatin chemotherapy develop a clinically detectable sensory neuropathy. Effective neuroprotective therapies have been sought.
To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs.
On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and CINAHL Plus for randomised trials designed to evaluate neuroprotective agents used to prevent or limit neurotoxicity of cisplatin and related drugs among human patients.
We included randomised controlled trials (RCTs) or quasi-RCTs in which the participants received chemotherapy with cisplatin or related compounds, with a potential chemoprotectant (acetylcysteine, amifostine, adrenocorticotrophic hormone (ACTH), BNP7787, calcium and magnesium (Ca/Mg), diethyldithiocarbamate (DDTC), glutathione, Org 2766, oxcarbazepine, or vitamin E) compared to placebo, no treatment, or other treatments. We considered trials in which participants underwent evaluation zero to six months after completing chemotherapy using quantitative sensory testing (the primary outcome) or other measures including nerve conduction studies or neurological impairment rating using validated scales (secondary outcomes).
Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology.
As of 2013, the review includes 29 studies describing nine possible chemoprotective agents, as well as description of two published meta-analyses. Among these trials, there were sufficient data in some instances to combine the results from different studies, most often using data from secondary non-quantitative measures. Nine of the studies were newly included at this update. Few of the included studies were at a high risk of bias overall, although often there was too little information to make an assessment. At least two review authors performed a formal review of an additional 44 articles but we did not include them in the final review for a variety of reasons.
Of seven eligible amifostine trials (743 participants in total), one used quantitative sensory testing (vibration perception threshold) and demonstrated a favourable outcome in terms of amifostine neuroprotection, but the vibration perception threshold result was based on data from only 14 participants receiving amifostine who completed the post-treatment evaluation and should be regarded with caution. Furthermore the change measured was subclinical. None of the three eligible Ca/Mg trials (or four trials if a single retrospective study was included) described our primary outcome measures. The four Ca/Mg trials included a total of 886 participants. Of the seven eligible glutathione trials (387 participants), one used quantitative sensory testing but reported only qualitative analyses. Four eligible Org 2766 trials (311 participants) employed quantitative sensory testing but reported disparate results; meta-analyses of three of these trials using comparable measures showed no significant vibration perception threshold neuroprotection. The remaining trial reported only descriptive analyses. Similarly, none of the three eligible vitamin E trials (246 participants) reported quantitative sensory testing. The eligible single trials involving acetylcysteine (14 participants), diethyldithiocarbamate (195 participants), oxcarbazepine (32 participants), and retinoic acid (92 participants) did not perform quantitative sensory testing. In all, this review includes data from 2906 participants. However, only seven trials reported data for the primary outcome measure of this review, (quantitative sensory testing) and only nine trials reported our objective secondary measure, nerve conduction test results. Additionally, methodological heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766).
Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity.