Interventions for preventing neuropathy caused by cisplatin and related compounds

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Authors


Abstract

Background

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.

Objectives

To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs.

Search methods

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.

Selection criteria

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).

Data collection and analysis

Two review authors assessed each study, extracted the data and reached consensus, according to standard Cochrane methodology.

Main results

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.

Authors' conclusions

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.

Résumé scientifique

Interventions visant à prévenir la neuropathie causée par le cisplatine et les composés de même nature

Contexte

Le cisplatine et plusieurs médicaments antinéoplasiques de même nature utilisés dans le traitement de nombreux types de tumeurs solides sont neurotoxiques, et la plupart des patients suivant un cycle complet de chimiothérapie à base de cisplatine développent une neuropathie sensorielle cliniquement détectable. Des traitements neuroprotecteurs efficaces ont été recherchés.

Objectifs

Examiner l'efficacité et l'innocuité des agents potentiellement chimioprotecteurs pour prévenir ou limiter la neurotoxicité du cisplatine et des médicaments de même nature.

Stratégie de recherche documentaire

Le 4 mars 2013, nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur les affections neuromusculaires, CENTRAL, MEDLINE, EMBASE, LILACS et CINAHL Plus pour des essais randomisés conçus pour évaluer des agents neuroprotecteurs utilisés pour prévenir ou limiter la neurotoxicité du cisplatine et des médicaments apparentés chez les patients humains.

Critères de sélection

Nous avons inclus les essais contrôlés randomisés (ECR) ou quasi-ECR dans lesquels les participants recevaient une chimiothérapie au cisplatine ou aux composés apparentés, avec un chimioprotecteur potentiel (acétylcystéine, amifostine, hormone adrénocorticotrope (ACTH), BNP7787, calcium et magnésium (Ca/Mg), diéthyldithiocarbamate (DDTC), glutathion, ORG 2766, oxcarbazépine ou vitamine E) comparé à un placebo, à l'absence de traitement ou à d'autres traitements. Nous avons pris en compte les essais dans lesquels les participants avaient subi zéro à six mois après la fin de la chimiothérapie une évaluation faisant appel à un examen sensoriel quantitatif (critère de jugement principal) ou à d'autres mesures, y compris les études de conduction nerveuse ou l'évaluation des troubles neurologiques à l'aide d'échelles homologuées (critères de jugement secondaires).

Recueil et analyse des données

Deux auteurs de la revue ont évalué chaque étude, extrait les données et atteint un consensus, selon la méthodologie Cochrane standard.

Résultats principaux

En 2013, la revue inclut 29 études décrivant neuf agents chimioprotecteurs potentiels, ainsi que la description de deux méta-analyses publiées. Parmi ces essais, des données suffisantes étaient disponibles dans certains cas pour combiner les résultats de différentes études, le plus souvent en utilisant des données de mesures secondaires non quantitatives. Neuf de ces études sont de nouveaux ajouts dans cette mise à jour. Peu d'études incluses présentaient un risque élevé de biais dans l'ensemble, bien que souvent il y ait eu trop peu d'informations pour effectuer une évaluation. Au moins deux auteurs ont effectué une revue formelle de 44 articles supplémentaires, mais nous ne les avons pas inclus dans la revue finale pour diverses raisons.

Sur les sept essais éligibles évaluant l'amifostine (743 participants au total), un utilisait un examen sensoriel quantitatif (seuil de perception des vibrations) et rapportait un résultat favorable en termes de la neuroprotection apportée par l'amifostine, mais le résultat du seuil de perception des vibrations reposait uniquement sur les données de 14 participants sous amifostine ayant achevé l'examen post-traitement, et devrait être traité avec prudence. En outre, le changement mesuré était subclinique. Aucun des trois essais éligibles sur Ca/Mg (ou quatre, en incluant une étude rétrospective unique) ne décrivait nos principaux mesures de résultats. Les quatre essais sur Ca/Mg incluaient un total de 886 participants. Sur les sept essais éligibles évaluant le glutathion (387 participants), un utilisait un examen sensoriel quantitatif mais documentait uniquement les analyses qualitatives. Les quatre essais éligibles évaluant l'ORG 2766 (311 participants) utilisaient un examen sensoriel quantitatif mais rapportaient des résultats disparates ; les méta-analyses de trois de ces essais utilisant des mesures comparables ne révélaient aucune neuroprotection significative en termes de seuil de perception des vibrations. L'essai restant documentait uniquement des analyses descriptives. De même, aucun des trois essais éligibles sur la vitamine E (246 participants) ne rapportait un examen sensoriel quantitatif. Les essais éligibles uniques portant sur l'acétylcystéine (14 participants), le diéthyldithiocarbamate (195 participants), l'oxcarbazépine (32 participants) et l'acide rétinoïque (92 participants) n'ont pas réalisé d'examen sensoriel quantitatif. Dans l'ensemble, cette revue inclut des données de 2 906 participants. Cependant, seulement sept essais rapportaient des données pour le critère de jugement principal de cette revue (examen sensoriel quantitatif), et seulement neuf essais rendaient compte de notre mesure secondaire objective, les résultats de tests de conduction nerveuse. En outre, l'hétérogénéité méthodologique a empêché le regroupement des résultats dans la plupart des cas. Néanmoins, un plus grand nombre d'essais rapportaient les résultats de mesures secondaires (non quantitatives et subjectives) telles que les critères communs de toxicité pour la neuropathie du National Cancer Institute (NCI-CTC) (15 essais), et ces résultats ont été regroupés et rapportés sous forme de méta-analyse. L'amifostine a montré une réduction significative du risque de développer une neurotoxicité ≥ 2 sur l'échelle NCI-CTC (ou équivalent) par rapport à un placebo (RR 0,26, IC à 95 % 0,11 à 0,61). Le glutathion était également efficace avec un RR de 0,29 (IC à 95 % 0,10 à 0,85). Dans trois études sur la vitamine E, les mesures subjectives ne se prêtant pas au regroupement dans une méta-analyse étaient chacune favorables à la vitamine E. Pour d'autres interventions, les mesures qualitatives de toxicité étaient soit négatives (N-acétylcystéine, Ca/Mg, DDTC et acide rétinoïque) ou n'étaient pas évaluées (oxcarbazépine et ORG 2766).

Les événements indésirables étaient peu fréquents ou n'étaient pas rapportés pour la plupart des interventions. L'amifostine était associée à une hypotension transitoire chez 8 % à 62 % des participants, l'acide rétinoïque à l'hypocalcémie chez 11 %, et environ 20 % des participants ont arrêté le traitement par le DDTC en raison de la toxicité.

Conclusions des auteurs

À l'heure actuelle, les données sont insuffisantes pour conclure que l'un des agents chimioprotecteurs potentiels (acétylcystéine, amifostine, calcium et magnésium, diéthyldithiocarbamate, glutathion, ORG 2766, oxcarbazépine, acide rétinoïque ou vitamine E) prévient ou limite la neurotoxicité des médicaments à base de platine chez les patients humains, tel que cela a été déterminé à l'aide de mesures quantitatives objectives de la neuropathie. L'amifostine, le calcium et le magnésium, le glutathion et la vitamine E ont montré des résultats modestes mais prometteurs (à la limite de la signification statistique) en faveur de leur capacité à réduire la neurotoxicité du cisplatine et des traitements chimiothérapiques apparentés, tel que cela a été mesuré à l'aide de mesures secondaires non quantitatives et subjectives comme l'échelle de classification neuropathique NCI-CTC. Parmi ces interventions, l'efficacité de la seule vitamine E a été évaluée à l'aide d'études quantitatives de conduction nerveuse ; les résultats étaient négatifs et n'étayaient pas les résultats positifs basés sur les mesures qualitatives. En résumé, les études présentes sont limitées par le petit nombre de participants recevant un agent donné, le manque de mesures objectives de la neuropathie et les résultats divergents parmi des essais similaires, qui ne permettent pas de conclure que l'un des agents neuroprotecteurs évalués prévient ou limite la neurotoxicité des médicaments à base de platine.

Plain language summary

Interventions for preventing nerve damage caused by cisplatin and other tumour-inhibiting platinum drugs

Review question

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.

Background

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.

Study characteristics

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.

Résumé simplifié

Les interventions pour la prévention des lésions nerveuses causées par le cisplatine et d'autres médicaments anti-tumoraux à base de platine

Question de la revue

Nous avons examiné les preuves concernant les effets de traitements pour prévenir ou réduire les lésions nerveuses dues au médicament anticancéreux (chimiothérapie) cisplatine ou à d'autres médicaments contenant du platine.

Contexte

Le cisplatine et d'autres médicaments de même nature contenant du platine utilisés dans le traitement des tumeurs solides sont toxiques pour le système nerveux périphérique. La plupart des personnes qui achèvent une chimiothérapie complète à base de cisplatine développent une neuropathie sensorielle (lésions aux nerfs transmettant les sensations). Les symptômes peuvent inclure des picotements aux extrémités et un engourdissement. Les patients peuvent ne se rétablir que partiellement ou ne pas se rétablir du tout lorsque la chimiothérapie est arrêtée. Pour essayer de réduire la toxicité des médicaments à base de platine, les chercheurs ont recherché des traitements pour protéger les nerfs.

Caractéristiques des études

Nous avons réalisé une vaste recherche d'études portant sur des traitements pour prévenir ce type de lésions nerveuses. Nous avons identifié un total de 29 essais cliniques, qui portaient sur près de 3 000 participants recevant des médicaments anticancéreux contenant du platine (principalement le cisplatine, l'oxaliplatine et le carboplatine) pour différents types de cancers (principalement les cancers du côlon, de l'ovaire et du poumon). Les neuf traitements étudiés étaient : l'amifostine (sept essais), le calcium et le magnésium (quatre essais), le glutathion (sept essais), l'ORG 2766 (quatre essais) et la vitamine E (trois essais). Des essais individuels portaient sur l'acétylcystéine, le diéthyldithiocarbamate (DDTC), l'oxcarbazépine et l'acide rétinoïque. Nous avons choisi un test clinique objectif de sensation comme la mesure préférée pour rendre compte des effets du traitement. Sept études seulement utilisaient cette mesure. Neuf études rapportaient les résultats de tests de conduction nerveuse qui sont une autre mesure objective de la fonction nerveuse. La plupart des études utilisaient une évaluation subjective de la neuropathie, telle que l'échelle de classification neuropathique du National Cancer Institute-Common Toxicity Criteria (NCI-CTC).

Résultats principaux et qualité des preuves

La plupart des études incluses étaient relativement bien réalisées, d'après les informations disponibles.

Sur la base des résultats combinés qui décrivaient généralement des mesures secondaires et non quantitatives telles que l'échelle de classification neuropathique NCI-CTC, des résultats modestes mais prometteurs (à la limite de la signification statistique) étaient favorables à l'utilisation d'amifostine, de calcium et de magnésium, et de glutathion pour réduire la neurotoxicité du cisplatine et des traitements chimiothérapiques apparentés. Trois études sur la vitamine E ont dû être examinées individuellement, mais les résultats de chacune suggèrent de légers bénéfices subjectifs. Néanmoins, compte tenu des limitations des études, telles que le petit nombre de participants, le manque de mesures objectives de la neuropathie et les résultats divergents d'essais similaires, les données restent insuffisantes pour conclure que l'un des agents neuroprotecteurs évalués prévient ou limite la neurotoxicité des médicaments à base de platine. La plupart des traitements n'étaient pas associés à des événements indésirables. Les perfusions d'amifostine ont été associées à une pression artérielle basse passagère dans un nombre considérable de cas, et l'acide rétinoïque à de faibles niveaux de calcium dans le sang. Environ un cinquième des personnes traitées avec le DDTC ont arrêté de le prendre en raison d'effets nocifs.

L'amifostine, le calcium et le magnésium, la vitamine E et le glutathion nécessitent d'autres essais bien conçus afin de clarifier s'ils sont efficaces ou non.

Ceci est une revue mise à jour. Les preuves sont à jour au 4 mars 2013.

Notes de traduction

Traduit par: French Cochrane Centre 8th July, 2014
Traduction financée par: Financeurs pour le Canada : Instituts de Recherche en Santé du Canada, Ministère de la Santé et des Services Sociaux du Québec, Fonds de recherche du Québec-Santé et Institut National d'Excellence en Santé et en Services Sociaux; pour la France : Ministère en charge de la Santé

Laički sažetak

Intervencije za sprečavanje oštećenja živaca (neuropatije) uzrokovane cisplatinom i ostalim antitumorskim lijekovima koji sadrže platinu

Istraživačko pitanje

U ovom Cochrane sustavnom pregledu analizirani su dokazi o učinku terapija u prevenciji ili smanjenju oštećena živaca (neuropatije) uzrokovanog antitumorskim (kemoterapijskim) lijekom cisplatinom ili drugim lijekovima koji sadrže platinu.

Dosadašnje spoznaje

Cisplatin i drugi slični lijekovi koji sadrže platinu (platini) korišteni su u terapiji solidnih tumora toksični su za periferni živčani sustav. Većina osoba koje završe puni ciklus kemoterapije cisplatinom razvije osjetilnu neuropatiju (oštećenje živaca koji prenose osjete). Simptomi mogu uključivati trnce i gubitak osjeta u udovima. Neuropatija se može povući samo djelomično ili se ne povući uopće kada se kemoterapija obustavi. Kako bi pokušali smanjiti toksičnost platina, istraživači su analizirali terapije za očuvanje živaca.

Značajke studija

Napravljeno je opsežno pretraživanje literature kako bi se našle studije terapija koje bi spriječile taj tip oštećenja živaca. Pronađeno je 29 kliničkih studija koje su uključile gotovo 3000 sudionika koji su primali platine (uglavnom cisplatin, oksaliplatin i karboplatin) za različite tipove raka (pretežno debelog crijeva, jajnika i pluća). Devet terapijskih mogućnosti koje su ispitivane bili su: amifostin (devet studija), kalcij i magnezij (četiri studije), glutation (sedam studija), Org 2766 (četiri studije) i vitamin E (tri studije). Bila je po jedna studija za acetilcistein, dietilditiokarbamat (DDTC), okskarbazepin i retinoičnu kiselinu. Kao glavna mjera učinka terapije odabrano je objektivno kliničko ispitivanje osjeta. Samo sedam studija je koristilo takvo mjerenje. Devet studija objavilo je rezultate živčane provodnosti što je još jedna objektivna mjera funkcije živaca. Većina studija koristila je subjektivne procjene neuropatije, poput National Cancer Institute-Common Toxicity Criteria (NCI-CTC) ljestvice ocijenjivanja neuropatije.

Ključni rezultati i kvaliteta dokaza

Većina uključenih studija bile su poprilično dobro izvedene.

Temeljem kombiniranih rezultata koji su uglavnom opisivali sekundarna i nekvantitativna mjerenja poput NCI-CTC ljestvice ocijenjivanja neuropatije, skromni, ali obećavajući (granično statistički značajni) rezultati išli su u prilog korištenju amifostina, kalcija i magnezija te glutationa za smanjenje neurotoksičnosti cisplatina i sličnih kemoterapeutika. Tri studije vitamina E mogle su se proučavati jedino odvojeno, ali rezultati svake upućuju na neke blage subjektivne blagotvorne učinke. Unatoč tome, uzimajući u obzir ograničenja studija, poput malog broja sudionika, nedostatka objektivnih načina mjerenja neuropatije i različitim rezultatima među sličnim studijama, podatci ostaju nedovoljni kako bi se zaključilo da je bilo koji od ispitanih neuroprotektivnih lijekova sprečava ili smanjuje neurotoksičnost platina. Većina terapija nije bila povezana s nuspojavama. Infuzije amifostina povezane su s privremeno niskim krvnim tlakom u značajnom broju slučajeva, a retinoična kiselina s niskom razinom kalcija u krvi. Otprilike petina osoba koje su primale DDTC prestalo ga je uzimati zbog štetnih učinaka.

Za amifostin, kalcij i magnezij, vitamin E i glutation potrebno je provesti dodatne dobro osmišljene studije kako bi se utvrdilo jesu li učinkoviti ili ne.

Ovo je obnovljena verzija Cochrane sustavnog pregleda. Dokazi su zadnji put pretraženi 4. ožujka 2013.

Bilješke prijevoda

Hrvatski Cochrane
Preveo: Adam Galkovski
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Background

Cisplatin (cis-diaminodichloroplatinum) was the first heavy metal used as an antineoplastic agent. It has been used since the early 1970s to treat several kinds of solid tumours, including lung, ovary, testis, bladder, head and neck, and endometrium (Mollman 1990; Prestayko 1979). Typical dosage regimes vary from 50 to 100 mg/m² given intravenously every three to four weeks, usually for about six cycles, based on clinical response and toxicity. Alternative schedules include 20 mg/m² daily for five days, or 20 mg/m² given weekly for about six weeks. Cisplatin is known to be toxic to the nervous system (Cavaletti 2004; Mollman 1990; van der Hoop 1990; Von Hoff 1979); it exhibits preferential uptake in the dorsal root ganglia and produces a dose-related large fibre sensory neuropathy (neuronopathy). The sensory neuropathy most often becomes evident after a cumulative cisplatin dose of at least 300 mg/m², but occasional patients, especially those with risk factors, those with pre-existing neuropathy, and those who are receiving combination chemotherapy, may develop symptoms after lower cumulative doses (Roelofs 1984; Windebank 1994). Most people completing a full course of cisplatin chemotherapy develop a symptomatic and clinically detectable sensory neuropathy. Symptoms, including unpleasant distal paraesthesias (tingling in the extremities) and numbness, may appear as soon as one month after initiating treatment. Lhermitte's symptom (an electric shock-like sensation on bending the neck), likely caused by centripetal degeneration of posterior columns, has also been described. Associated signs include evidence of large fibre sensory loss (reduced vibration and joint position sensations) and diminished or absent muscle stretch reflexes (Roelofs 1984; Thompson 1984). Sensory ataxia (inco-ordination) may be disabling in those who have severe neuropathy. Small fibre sensation is spared or mildly diminished (decreased pin-pain sensation). Strength is generally normal. Symptoms and signs are symmetric and usually worse distally. Despite the high frequency of neuropathy among people treated with cisplatin, relatively few people develop functional impairment sufficient to interfere with activities of daily living (ADL). Nevertheless, neurotoxicity is a major reason that cisplatin is discontinued and the cumulative dosage limited, potentially reducing its chemotherapeutic efficacy. In an attempt to reduce the toxicity of platinum drugs, second and third generation tumour-inhibiting platinum compounds including carboplatin, oxaliplatin, nedaplatin, and lobaplatin have emerged. Carboplatin lacks the nephrotoxicity of cisplatin, and neurotoxicity also is thought to be considerably less than that associated with cisplatin. Carboplatin is used to treat ovarian, small cell lung, and refractory testicular cancers. Oxaliplatin is now FDA and European Union approved for use in the treatment of metastatic colon cancer; neurotoxicity is the major dose-limiting adverse-event (Grothey 2003; Grothey 2004).

Quantitative measures of vibration perception threshold (VPT) and sensory nerve action potential (SNAP) amplitude are complementary means of evaluating large sensory fibres. Both measures have been used to document the development and progression of cisplatin-induced neuropathy (Wald 1994). Sequential nerve conduction studies among people receiving cisplatin chemotherapy demonstrate progressive reduction of SNAP amplitudes, with little or no change in motor nerve conduction studies and needle electromyography (EMG). Reduction of the SNAP amplitude is thought to be a relatively sensitive indication of early cisplatin-induced neurotoxicity. This objective change occurs early in the course of cisplatin neuropathy, often before development of symptoms or signs of sensory neuropathy. It is generally believed that most patients receiving cisplatin show a sequential decline in SNAP amplitude relative to baseline (Wald 1994; Wald 1995). A decline which exceeds 40% from baseline is used by some as the physiological criterion for sensory neuropathy associated with chemotherapy toxicity (Molloy 2001). Sural nerve biopsy shows evidence of Wallerian-like axonal degeneration affecting the large myelinated fibres, with scant evidence of regeneration, consistent with damage at the level of the dorsal root ganglia. Unmyelinated fibres are spared (Krarup-Hansen 1993). Cisplatin-induced neuropathy stabilises or improves after discontinuing cisplatin (Elderson 1989), but clinical and electrodiagnostic deterioration often progresses for a few weeks after completing cisplatin treatment (called 'coasting'). With higher cumulative dosages, however, residual nerve damage may persist for long periods of time.

Experimental models of cisplatin neurotoxicity confirm that the neuronal cell body within the dorsal root ganglion is the site of injury. Cultured rat embryo dorsal root ganglion models have been used to study the mechanisms of cisplatin neurotoxicity (Windebank 1994). Cisplatin reproducibly inhibits axonal growth in a dose-dependent manner that includes concentrations similar to those known to produce human toxicity. The mechanism of action is thought to be related to platinum binding to DNA and interfering with DNA synthesis. Cisplatin produced abnormalities in the nucleoli of spinal root ganglion cells of large and small neurons (Tomiwa 1986). The hypothesis that cisplatin-induced neuropathy may result from nuclear and nucleolar changes in the sensory ganglion cell body was confirmed in the rat (Cavaletti 1992). After chronic cisplatin administration, the spinal ganglia and peripheral nerves showed severe damage of the spinal ganglia neurons with predominant involvement of the nucleus and nucleolus associated with a decrease in the cell size after chronic cisplatin administration. Changes also occurred in the sciatic and peroneal nerves with the features of axonopathy (Cavaletti 1992). These changes described in rats also have been confirmed in mice (Carozzi 2010). In addition, Schmidt 1995 showed in a mouse model that nerve growth factor (NGF) exerts a major effect on the metabolism of transmitters associated with nociception, pain and sensation in cervical dorsal root ganglia in various models of toxic neuropathy, including the neuropathy produced by cisplatin. Cisplatin specifically induced a significant decrease in the number of large- and medium-sized neurons in the dorsal root ganglia, indicating neuronal atrophy, a finding that correlated with a highly significant loss of neuropeptides in cervical dorsal root ganglia in mice (Schmidt 1995).

Prevention of cisplatin neurotoxicity

In most instances of cisplatin-induced neuropathy, the nerves only partially recover or do not recover at all. For this reason, effective neuroprotective therapies have been sought. As therapeutic strategies were developed to maximise cisplatin effectiveness, such as minimising renal insufficiency, cumulative dose-related neuropathy emerged as a major dose-limiting toxicity (Gandara 1991). Attempts to modulate cisplatin dose schedules did not influence the intensity of the resultant neurotoxicity (Hilkens 1995). Additional means of optimising the therapeutic index of cisplatin were sought, such as coadministration of chemoprotective or rescue therapies to reduce adverse side effects without reversing antitumour activity. An ACTH (4-9) analogue Org 2766, glutathione (GSH), amifostine, and various neurotrophic growth factors have all been tried in clinical and experimental models to prevent cisplatin-induced neurotoxicity, and reviews exist of the clinical pharmacology and therapeutic efficacy of several chemoprotectants (e.g. Links 1999). Acetyl-L-carnitine has recently been reported to have a neuroprotective effect in cisplatin and paclitaxel models (Pisano 2003). Both GSH and vitamin E have been tested in human trials with platinum drugs (Cascinu 1995; Cascinu 2002; Pace 2003; Smyth 1997). Although the precise mechanism of cisplatin-induced neurotoxicity is unknown, various agents have been proposed to protect the peripheral nervous system from such neurotoxicity. For example, amifostine, an organic thiophosphate that acts as a scavenger of oxygen free-radicals, shows selective protection of normal tissues (cytoprotective) against toxicities induced by radiation, alkylating agents, and platinum compounds without influencing the antitumour effects of these treatments (Planting 1999). Diethyldithiocarbamate (DDTC) is a chelating agent thought to bind and remove tissue-bound platinum without interfering with the antitumour activity of cisplatin (Gandara 1995). Glutathione (GSH) is a nucleophilic sulphur-containing tripeptide thiol thought to permit delivery of higher doses of cisplatin without producing the expected neurotoxicity, perhaps by preventing the initial accumulation of platinum adducts in the dorsal root ganglia (Cascinu 1995; Cascinu 2002). The neuropeptide Org 2766 is thought to potentially ameliorate cisplatin neuropathy by exerting trophic effects and enhancing endogenous nerve repair mechanisms (as opposed to directly protecting against cisplatin neurotoxicity) (van Gerven 1994). Vitamin E is an antioxidant thought to protect against cisplatin-induced oto- and nephro-toxicities and potentially to protect against neurotoxicity (Pace 2003). Acetylcysteine (N-acetylcysteine, NAC) is a nutritional supplement thought to increase whole blood concentrations of glutathione, a useful agent for preventing the initial accumulation of platinum adducts and clinical oxaliplatin-induced neurotoxicity (Lin 2006). BNP7787 (disodium 2, 2' dithio-bisethane sulfonate) was developed as a putative chemoprotective agent (Miller 2008). Calcium and magnesium infusions were proposed to act as chelators of oxalate, thereby reducing the effect of oxalate on voltage-gated sodium channels (Gamelin 2004). Oxcarbazepine resembles the antiepileptic drug carbamazepine and also blocks voltage-sensitive sodium channels and certain calcium channels.  Oxcarbazepine was developed as a neuroprotective against oxaliplatin-induced neuropathy, which is thought to reflect the alteration of voltage-gated sodium channels by oxalate, a metabolite of oxaliplatin (Argyriou 2006a).

Description of the intervention

Several different interventions have been described as being effective in preventing platinum-induced neuropathy. A complex description of each intervention is beyond the scope of this review.

  • Acetylcysteine (NAC) is a nutritional supplement thought to increase whole blood concentrations of glutathione, a useful agent for preventing the initial accumulation of platinum adducts and clinical oxaliplatin-induced neurotoxicity (Lin 2006).

  • Amifostine is an organic thiophosphate described as a broad-spectrum cytoprotective agent potentially able to protect normal tissues from cytotoxic effects of chemotherapeutic agents (Kanat 2003).

  • Calcium and magnesium infusions may chelate oxalate (a metabolite of oxaliplatin), thereby reducing the effect of oxalate on voltage-gated sodium channels (Ishibashi 2010).

  • Diethyldithiocarbamate (DDTC) is a heavy metal chelating agent and has been reported to reduce the incidence and severity of cisplatin-induced neuropathy (Gandara 1995).

  • Glutathione (GSH). The mechanism of neurotoxicity from platinum drugs is thought to be the accumulation of platinum within the dorsal root ganglia. The thio nucleophilic region of reduced GSH has high affinity for heavy metals and may be able to prevent the accumulation of platinum in the dorsal root ganglia.

  • Org 2766 is an ACTH (4-9) analogue which has been reported to reduce the incidence and severity of cisplatin-induced polyneuropathy (van der Hoop 1990).

  • Oxcarbazepine resembles the antiepileptic drug carbamazepine and also blocks voltage-sensitive sodium channels and certain calcium channels. It was developed as a neuroprotective against oxaliplatin-induced neuropathy, which is thought to reflect the alteration of voltage-gated sodium channels by oxalate, a metabolite of oxaliplatin (Argyriou 2006).

  • Retinoic acid. Retinoids play a role in a variety of biological functions; all-trans retinoic acid (ATRA) binds and activates subtypes of retinoid acid receptors and stimulates nerve growth factor (NGF) and the expression of its receptor. ATRA prevents and reverses neuropathy-associated morphological changes in diabetic animals (Arrieta 2011).

  • Vitamin E, an antioxidant protecting against free-radical injury, may be protective against cisplatin-induced polyneuropathy. Based on the observation that deficiency of vitamin E produces a pattern of peripheral neuropathy similar to cisplatin-induced toxic neuropathy and the fact that decreased plasma vitamin E levels are observed in patients with cisplatin neuropathy, trials of vitamin E for prevention of toxic neuropathy have been done (Pace 2003).

Why it is important to do this review

Whilst platinum-containing chemotherapy can be highly effective for the treatment of a number of cancers, its use and dosing is not infrequently limited by neurotoxicity. As well as limiting choice and efficacy of chemotherapy agents the disability caused by the neuropathy can be devastating and irreversible. Agents that limit or prevent toxicity from platinum containing chemotherapy could be very important adjuncts to oncology regimens.

Objectives

To examine the efficacy and safety of purported chemoprotective agents to prevent or limit the neurotoxicity of cisplatin and related drugs.

Methods

Criteria for considering studies for this review

Types of studies

We included all randomised or quasi-randomised controlled human trials in which the efficacy of any form of chemoprotective treatment used to prevent or limit the neurotoxicity of cisplatin (or related oncologic platinum compounds including oxaliplatin or carboplatin) was compared with placebo, no treatment, or other treatments.

Types of participants

Adult participants of either sex undergoing chemotherapy with cisplatin (or related oncologic platinum compounds including oxaliplatin or carboplatin) as an antineoplastic medication.

Types of interventions

We included in the review any form of chemoprotective treatment, such as acetyl-L-carnitine, acetylcysteine (NAC), adrenocorticotrophic hormone (ACTH), amifostine, BNP7787, calcium and magnesium, Org 2766, glutathione, oxcarbazepine, vitamin E, and growth factors, used to prevent or limit cisplatin-induced neurotoxicity.

Types of outcome measures

Primary and secondary outcomes were evaluated in the zero to six month period after completing or discontinuing chemotherapy. When more than one evaluation occurred during this interval, we selected the one closest to three months after completing chemotherapy treatment.

Primary outcomes

The primary outcome measure was the change in quantitative sensory testing (QST) results (e.g., vibration perception threshold (VPT). Measures of VPT have been used in several studies of cisplatin toxicity. Although VPT does not have the specificity of nerve conduction study results, the sensitivity of QST is likely similar to nerve conduction study results.

Secondary outcomes

Secondary outcome measures included nerve conduction study results (SNAP amplitude) and measures of neurological impairment. Any other available measure of impairment was considered, but priority was given to those clinical, functional, or electrodiagnostic measures that used a validated scale. Examples of secondary outcome measures included the following.

  1. SNAP amplitude.

  2. Clinical impairment measured by neurological examination, using a validated scale.

  3. Functional measures of activities of daily living (ADL).

  4. Information from toxicity rating scales.

  5. Serious adverse events of chemoprotective treatment, which were fatal, life threatening, or require prolonged hospital admission.

The National Cancer Institute-Common Toxicity Criteria for Peripheral Sensory Neuropathy (NCI-CTC for neuropathy) is an example of a neurotoxicity scale commonly used in clinical practice and frequently used in the studies we reviewed. Despite the wide use of the NCI-CTC, it is not a validated scale, which is a major limitation (Cavaletti 2010a; Cavaletti 2013). The NCI-CTC as used in many of the studies we reviewed exists in slightly different forms. One form has the following grades: 1) Asymptomatic: loss of deep tendon reflexes or paraesthesias; 2) Moderate symptoms: limiting instrumental ADL; 3) Severe symptoms: limiting self care ADL; 4) Life-threatening consequences: urgent intervention indicated; and 5) Death. The second form uses grades as follows: 1) Asymptomatic: loss of deep tendon reflexes or paraesthesias (including tingling), but not interfering with function; 2) Sensory alteration or paraesthesias (including tingling) interfering with function, but not ADL; 3) Sensory alteration or paraesthesias interfering with ADL; and 4) Disabling. In the studies we reviewed, few participants developed grade 4 neuropathy, using either scale, and we elected to emphasise neuropathy based on participants showing grades ≥2 from either scale. In our opinion, such grading likely represents similar degrees of neuropathy, and separation based on which of the scales used limited the analyses we could perform (which was already severely limited by the few studies using our prespecified end points).

Search methods for identification of studies

Electronic searches

On 4 March 2013, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL (2013, Issue 2 in The Cochrane Library), MEDLINE (January 1966 to February 2013), EMBASE (January 1980 to February 2013), LILACS (January 1982 to February 2013), and CINAHL Plus (January 1937 to February 2013).

Our search strategy was not restricted by language. In the initial and updated review, we did not approach pharmaceutical companies, but, in a few instances, we did contact the authors of the trials for additional information. We did not formally screen the references of the selected papers.

The detailed search strategies are in the appendices: Appendix 1 (CENTRAL); Appendix 2 (MEDLINE); Appendix 3 (EMBASE); Appendix 4 (CINAHL Plus); and Appendix 5 (LILACS).

Data collection and analysis

Selection of studies

Both for the original review and updates, two review authors (JA and VC or GC) independently screened the titles and abstracts of references to select potential studies for inclusion The review authors obtained the full text of all potentially relevant studies for independent assessment by two authors for each article (among JA, GC, VC, and RD). The authors decided which studies fitted the inclusion criteria and graded their risk of bias. The two authors assessing each article resolved any disagreements about inclusion by communication, resulting in consensus.

Data extraction and management

Two review authors performed data extraction for each article and a third author (JA) checked the data extraction to identify differences of opinion. We began by separating the studies into treatment categories: for example, amifostine, glutathione, Ca/Mg, DDTC (diethyldithiocarbamate), Org 2766, oxcarbazepine, ATRA and vitamin E. We assigned two authors to each of the categories (combining categories with few studies, such as DDTC and vitamin E). We next tabulated whether or not individual studies showed dose-response efficacy (if more than one dose was studied). We summarised the types of outcomes reported (QST, nerve conduction studies, clinical, functional measure). We included consideration of serious adverse events and determined if information on cost benefits was available.

Assessment of risk of bias in included studies

We assessed risk of bias in included studies using the Cochrane Collaboration 'Risk of bias' tool, described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008, updated Higgins 2011). We considered the adequacy of studies in the following domains: sequence generation, allocation concealment, blinding (subject, observer and assessor), incomplete outcome data addressed, selective reporting, and other sources of bias. Assessments were 'low risk of bias', 'high risk of bias', and 'unclear risk of bias' (where there was insufficient information to make a judgment or when the criterion did not apply to the study). At least two review authors evaluated each study and consensus agreement was reached.

Data synthesis

For studies using a common outcome measure, we calculated a treatment effect across trials and expressed the results as risk ratios (RR). For continuous outcomes, where meta-analysis was possible, we calculated a mean difference and expressed the results with confidence intervals.

When the results indicated unexplained heterogeneity, we undertook these tests using a random-effects model; if not, we used a fixed-effect model. When there was unexplained heterogeneity, we investigated its source by repeating the analysis after elimination of trials that were at high or unclear risk of bias on each of the risk of bias domains, paying particular attention to allocation concealment. We investigated heterogeneity beginning with visual inspection of forest plots to determine if the confidence intervals (CIs) were not overlapping or there were outliers to suggest statistical heterogeneity. As a general guideline, we used a Chi-squared statistic greater than the degrees of freedom to indicate heterogeneity, recognising that a non-significant result does not necessarily mean the absence of heterogeneity when the studies are small/few. As a rule of thumb, we used I2, describing heterogeneity as moderate for 30% to 60%, substantial for I2 of 50% to 90% and considerable for I2 of 75% to 100%. When there was unexplained heterogeneity, we repeated the analyses using a random-effects model to see whether the results differed. The possible outcomes were: 1. effect estimate is the same, 2. Effect estimate is similar, with different CIs (we used the random-effects model), or 3. Effect estimate is different, in which case we performed sensitivity analyses repeating the analyses excluding studies at high risk of bias (e.g. on allocation concealment), large studies, unpublished studies, or other studies, depending on any suspected source of heterogeneity.

Results

Description of studies

The initial search identified 135 articles. From these, we selected 39 articles for complete review. We identified 15 articles fulfilling inclusion criteria. The 2010 search identified 275 articles (including many duplications and previously identified), from which we selected 11 new studies for complete review, of which we included five (a total of 20 included studies).

The 2013 search produced the following results: Cochrane Neuromuscular Disease Group Specialized Register 76 papers (19 new), CENTRAL 79 papers, MEDLINE 263 papers (34 new), EMBASE 193 papers (41 new), CINAHL Plus 50 papers (14 new), and LILACS 1 paper. The 2013 search resulted in selection of 21 articles for complete review, from which eight trials fulfilled inclusion criteria. One additional retrospective article was included (for reasons described below) and two articles describing the results of meta-analyses were excluded but selected for the Discussion, for comparison to our interpretation of the data. We documented reasons for excluding studies (see Characteristics of excluded studies). A total of 29 studies (2906 participants) are included in the review. The combined articles involved the following potential chemoprotectant treatments:

  • acetylcysteine (NAC) (one study);

  • amifostine (seven studies);

  • calcium and magnesium (four studies);

  • diethyldithiocarbamate (DDTC) (one study);

  • glutathione (GSH) (seven studies);

  • Org 2766 (four studies);

  • oxcarbazepine (one study);

  • retinoic acid (one study); and

  • vitamin E (three studies).

The characteristics of the individual studies, including the 'Risk of bias' assessments, are summarised in the table Characteristics of included studies.

Acetylcysteine (N-acetylcysteine, NAC)

Our 2010 update identified one article fulfilling the selection criteria and reporting the results of a randomised controlled trial (RCT) designed to evaluate the protective effects of NAC against oxaliplatin-induced neurotoxicity (Lin 2006). This study, described as a "pilot study" involved only a small number of participants. Oxaliplatin dose was discontinued or dose reduced to 75% of previous dose if the participants developed NCI-CRC grade 3 or 4 neuropathy or had National Cancer Institute (NCI) grade 1 neuropathy respectively. Additionally, calculation of the score was arbitrarily modified (sum of worst neurological toxicity divided by number of assessable participants at each dose level). Trial participants received:   

  • oxaliplatin for colorectal cancer (five NAC-treated and nine placebo control participants) (Lin 2006).

Participants received oral NAC (1200 mg) one and one half hours before each oxaliplatin administration, occurring every two weeks for up to 12 treatment cycles.

Amifostine

Our search identified nine articles describing a total of eight studies fulfilling the selection criteria and reporting the results of RCTs designed to evaluate the protective effects of amifostine against chemotherapy neurotoxicity. Two articles with different first authors (Kemp 1996; Rose 1996), described the same trial and were considered together for this review (Kemp 1996). One of the studies identified in the 2013 review (DeVos 2005), described a meta-analysis of studies involving amifostine infusions for the prevention of neurotoxicity related to carboplatin (with paclitaxel); we included a review of that meta-analysis in the Discussion. The seven eligible trials included 372 amifostine-treated participants and 371 control participants. These trials included participants being treated with:

  • cisplatin for advanced head and neck cancer (37 amifostine-treated participants and 37 control participants) (Planting 1999);

  • paclitaxel and carboplatin for non-small cell lung cancer (19 amifostine-treated and 19 control participants) (Kanat 2003);

  • paclitaxel and carboplatin for ovarian cancer (93 amifostine-treated and 94 control participants) (Lorusso 2003);

  • cisplatin and cyclophosphamide for advanced ovarian cancer (122 amifostine-treated and 120 control participants) (Kemp 1996);

  • oxaliplatin (FOLFOX-4) for advanced or relapsed colorectal or gastric cancer with variable metastatic disease to liver, lung, and other sites (46 amifostine-treated and 46 control participants) (Lu 2008);

  • carboplatin with paclitaxel for advanced ovarian carcinoma (45 amifostine-treated and 45 control participants (DeVos 2005); and

  • radiotherapy and cisplatin for cervical cancer (10 amifostine-treated participants and 10 control participants) (Gallardo 1999)

The amifostine regimens varied only slightly among trials, and all participants randomised to the amifostine groups received intravenous amifostine immediately before chemotherapy at doses of 740 mg/m² (DeVos 2005; Planting 1999), 910 mg/m² (Kanat 2003; Kemp 1996; Lorusso 2003), or 500 mg/m² ( Lu 2008). All trials involved scheduled treatments of up to six cycles of chemotherapy, either weekly (Planting 1999), at three-week intervals (DeVos 2005; Kanat 2003; Kemp 1996), or in two- or four-week cycles ( Lu 2008).

Calcium and magnesium (Ca/Mg)

The 2010 and 2013 updates identified three articles fulfilling the selection criteria and reporting the results of an RCT to evaluate the protective effects of calcium and magnesium infusions against oxaliplatin neurotoxicity (Chay 2010; Grothey 2011; Ishibashi 2010). Grothey 2011 and Ishibashi 2010 included participants being treated with six cycles of FOLFOX, which includes oxaliplatin (85 mg/m²) every two weeks. The Chay 2010 trial included participants being treated with up to eight cycles of either XELOX, which includes oxaliplatin 130 mg/m² on day one every three weeks (received by 22 or 27 participants) or FOLFOX-4, which includes oxaliplatin (85 mg/m²) every two weeks. This study was terminated prematurely because of negative results from the CONcePT trial. The initial three eligible trials included 76 Ca/Mg-treated participants and 78 control participants. One additional article describing a retrospective, non-randomised study of Ca/Mg used at the discretion of treating physicians (as part of a large multicentre RCT of different chemotherapy drugs) was included because neither the participants nor the investigators appeared aware that Ca/Mg was being (or was going to be) investigated (Knijn 2011). When data from this retrospective study were included, there were 627 Ca/Mg-treated participants and 259 control participants. The 2013 review also identified two papers that described meta-analysis of studies involving Ca/Mg infusions for the prevention of oxaliplatin-related neurotoxicity (Ao 2012; Wen 2013); we included these studies in the Discussion.

  • oxaliplatin for colorectal cancer (9 Ca/Mg-treated and 10 control participants) (Chay 2010);

  • oxaliplatin for colon cancer (50 Ca/Mg-treated and 52 control participants) (Grothey 2011);

  • oxaliplatin for metastatic colorectal cancer (17 Ca/Mg-treated and 16 control participants) (Ishibashi 2010); and

  • oxaliplatin plus capecitabine, and bevacizumab with or without cetuximab for previously untreated colorectal cancer (551 Ca/Mg-treated and 181 control, at the discretion of the treating physician) (pseudo-random and retrospective) (Knijn 2011).

In two studies, investigators administered calcium gluconate 1 g (10 mL of 10% calcium gluconate) + 15% magnesium sulfate 1 g diluted into 100 mL of normal saline infused over 15 minutes before and after oxaliplatin infusion (Chay 2010; Grothey 2011). In addition to oxaliplatin FOLFOX chemotherapy includes administration of 5-fluorouracil and l-leucovorin with each of six, two-week treatment cycles. Knijn 2011 infused 2.25 mmol calcium glubionate plus 4 mmol magnesium chloride in 100 mL glucose over 15 minutes, before and after oxaliplatin infusion (retrospective analyses). Ishibashi 2010 administered Ca/Mg (850 mg/720 mg, respectively) before and after infusion of oxaliplatin or placebo.

Diethyldithiocarbamate (DDTC)

Our search identified only one article fulfilling the selection criteria and reporting the results of an RCT designed to evaluate the protective effects of DDTC against cisplatin neurotoxicity (Gandara 1995). The trial included participants being treated with six courses of 100 mg/m² cisplatin every four weeks at 1.6 g/m²:

  • cisplatin for ovarian, small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC) (data available for 96 DDTC-treated participants and 99 control (placebo-treated) participants (Gandara 1995).

DDTC, at 1.6 g/m², was administered 15 minutes before the start of cisplatin. In addition to cisplatin, other chemotherapies used were etoposide 100 mg/m² on days 1, 2, and 3 for SCLC and NSCLC, and cyclophosphamide 750 mg/m² for ovarian carcinoma as six courses every four weeks.

Gluthathione (GSH)

Our search identified seven articles fulfilling the selection criteria that reported the results of RCTs designed to evaluate the protective effects of GSH against platinum drugs (cisplatin and oxaliplatin) neurotoxicity. The seven prospective, randomised, and placebo-controlled studies included 193 GSH-treated participants and 194 control participants. The two platinum drugs used were cisplatin (153 and 155 respectively in each group and oxaliplatin (40 in the GSH group and 39 in the control group). The dose of cisplatin was variable (from 40 to 100 mg/m²) and oxaliplatin 100 mg/m² for every one to two weeks for three to nine weeks.

These trials included participants being treated with:

  • cisplatin for ovarian cancer (27 GSH-treated participants and 27 control participants) (Bogliun 1996);

  • cisplatin for ovarian cancer (25 GSH-treated participants and 25 control participants) (Cascinu 1995);

  • oxaliplatin for colorectal cancer (26 GSH-treated participants and 26 control participants) (Cascinu 2002);

  • cisplatin for relapsing ovarian cancer (16 GSH-treated participants and 17 control participants) (Colombo 1995);

  • oxaliplatin for colorectal cancer (14 GSH-treated participants and 13 control participants) (Milla 2009);

  • cisplatin for non-small cell lug cancer (NSCLC) and head and neck cancer (11 GSH-treated participants and 9 control participants) (Schmidinger 2000); and

  • cisplatin for ovarian cancer (74 GSH-treated participants and 77 control participants) (Smyth 1997).

The GSH dose was variable from 1.5 g/m² to 5 g before chemotherapy. The end points used were a toxicity score NCI/World Health Organization (WHO)) in all participants; functional scales (Hospital Anxiety and Depression (HAD) and Rotterdam scales) in 151 participants; Neuropathy Impairment Scale/Neuropathy Symptom Scale (NIS/NSS) in 54 participants; sensory nerve conduction studies (sural, median, or ulnar) in 156 participants; motor nerve conduction studies in 20 participants; and vibration perception threshold (VPT) testing in 54 participants.

Org 2766

Our search identified four articles fulfilling the selection criteria and reporting the results of RCTs designed to evaluate the protective effects of Org 2766 against cisplatin neurotoxicity. The four trials included 188 Org 2766-treated participants and 123 control participants. These trials included participants being treated with:

  • cisplatin and cyclophosphamide for epithelial ovarian cancer (33 Org 2766-treated participants and 22 control participants) (van der Hoop 1990);

  • cisplatin and cyclophosphamide for epithelial ovarian cancer (7 Org 2766-treated and 11 control participants) (Hovestadt 1992);

  • cisplatin and different combinations of etoposide, bleomicin and ifosphamide for testicular and adenocarcinoma of unknown primary (19 Org 2766-treated and 23 control participants) (van Gerven 1994); and

  • cisplatin and cyclophosphamide for epithelial ovarian cancer (129 Org 2766-treated and 67 control participants) (Roberts 1997).

The Org 2766 regimens largely varied among trials in the range 0.25 to 4.0 mg/kg. All participants randomised to the Org 2766 groups received subcutaneous Org 2766 before and one hour after cisplatin in one trial (Roberts 1997), before and 24 hours after cisplatin in two trials (Hovestadt 1992; van der Hoop 1990) and during the daily course of cisplatin administration in one trial (van Gerven 1994). All trials involved scheduled treatments of up to nine cycles of chemotherapy, at three (Hovestadt 1992; van der Hoop 1990; van Gerven 1994) or three-to-four week intervals (Roberts 1997). Cisplatin was administered at different doses/cycle: 75 mg/m² (Hovestadt 1992; van der Hoop 1990), 75 to 100 mg/m² (Roberts 1997) or 100 mg/m² (van Gerven 1994).

Oxcarbazepine (OXC)

Our search identified one article fulfilling the selection criteria and designed to evaluate the protective effects of OXC against cisplatin neurotoxicity (Argyriou 2006a). Argyriou 2006a was prospective and randomised but without a placebo control arm (that is, control participants were untreated). The trial participants received:

  • cisplatin for colon cancer (1782 mg cumulative OXC-treated participants and 1750 mg cumulative control participants) (Argyriou 2006a).

Argyriou 2006a included 40 patients being treated with cisplatin for colon cancer, of whom 20 were randomised to receive OXC, 600 mg twice a day, and 20 were randomised to receive no treatment. The cumulative oxaliplatin dose after 12 courses was similar in both groups (1782 mg OXC versus 1750 mg control). Ultimately, 16 participants in each group completed the trial, and data from the 32 participants were available for analysis. Neurological symptoms and neurophysiological testing (sural, superficial peroneal, and ulnar sensory nerve action potential (SNAP) and peroneal motor responses) were recorded at baseline and after 4, 8, and 12 courses of chemotherapy (that is, the last neurophysiological tests were performed at completion of 24 weeks of treatment).

Retinoic acid, all-trans (ATRA)

Our search identified one article fulfilling the selection criteria and designed to evaluate the protective effects of ATRA against cisplatin neurotoxicity (Arrieta 2011). Arrieta 2011 was a prospective, randomised, placebo-controlled study that included 92 participants being treated with cisplatin and paclitaxel for stage IIIB/IV NSCLC cancer, of whom 45 were randomised to receive ATRA, 20 mg/m²/day one week prior to chemotherapy until completion of two courses. The length of follow-up was only until immediately after the second course of therapy (three weeks). Motor and sensory response amplitudes were recorded, but the electrophysiological results were summarised as "grade of damage," ranked from zero to three for latency and amplitude measures. In addition, clinical examination results and NCI-CTC version 3.0 were recorded for each participant. The trial participants received:

  • cisplatin and paclitaxel for stage IIIB/IV NSCLC cancer (45 ATRA-treated participants and 47 control participants) (Arrieta 2011).

Vitamin E

Our original search identified only one article fulfilling the selection criteria of RCT to assess the protective effect of vitamin E against cisplatin neurotoxicity (Pace 2003). In that study, the cumulative cisplatin dose was > 300 mg/m² (Pace 2003). Alpha tocopherol (vitamin E) was used at a dose of 300 mg/day starting before cisplatin and continuing up to three months after cisplatin treatment. Unmasked neurologists recorded neurological symptoms and signs and investigators performed neurophysiological testing (sural and median sensory nerves) at baseline, after three cycles, and after completion of chemotherapy. A cumulative toxicity score was assigned. The 2010 update identified a second trial of similar design (Argyriou 2006). Argyriou 2006 included six courses of cisplatin chemotherapy in various doses. The treatment protocols in both studies were specific for the individual cancers, and all included chemotherapy drugs in addition to cisplatin. Of note, five participants with gastric cancer also received docetaxel, another potential neurotoxicant (two participants in the vitamin E group and three control participants). Thirty-five participants were enrolled; of whom 30 completed the trial. Of these, 14 participants received vitamin E (600 mg/day) starting before cisplatin and continuing up to three months after cisplatin treatment. Unmasked neurologists recorded neurological symptoms and signs and investigators performed neurophysiological testing (sural and median sensory nerves) at baseline, after three cycles, and after completion of chemotherapy. Both trials were prospective and randomised studies without a placebo control arm (control group participants were untreated). Both studies included participants being treated with cisplatin for various solid tumours (lung, ovarian, rhinopharynx, gastric, testicular, oesophagus, ethmoid, and tongue cancer). The 2010 update identified a third RCT involving the use of vitamin E (Pace 2010), but the substantial participant dropout rate prevented intention-to-treat analyses. The 2013 update identified one additional study, a randomised, double-blind, placebo-controlled trial investigating use of vitamin E among 189 evaluable participants with breast, lung, and other cancers being treated with cisplatin (8), carboplatin (2), oxaliplatin (50), taxanes (109), or combinations of each (20), with the inclusion of a large number of participants receiving taxanes confounding (Kottschade 2011). In this study, participants were randomly assigned to vitamin E (dl-alpha-tocopherol) 300 mg by mouth twice daily or matching placebo twice daily, initiated within four days of the first chemotherapy treatment and continued throughout and for one month beyond the last chemotherapy treatment (Kottschade 2011). The three trials included 130 vitamin E-treated participants and 134 control participants. These trials included participants being treated with:

  • cisplatin for various solid tumours (lung, ovarian, rhinopharyngeal, gastric, testicular, oesophagus, ethmoid, and tongue) (13 vitamin E-treated participants and 14 control participants) (Pace 2003);

  • cisplatin chemotherapy for various solid tumours (lung, ovarian, rhinopharyngeal, gastric, testicular, oesophagus, ethmoid, and tongue) (14 vitamin E-treated participants and 16 control participants) (Argyriou 2006); and

  • cisplatin (8), carboplatin (2), oxaliplatin (50), taxanes (109), or combinations of each (20) for the treatment of breast, lung, and other cancers (96 vitamin E-treated participants and 93 control participants) (Kottschade 2011).

Risk of bias in included studies

The 'Risk of bias' information for each study is summarised in Figure 1.

Figure 1.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Red (-) = high risk of bias; yellow (?) = unclear risk of bias; green (+) = low risk of bias.

Acetylcysteine (N-acetylcysteine, NAC)

The single trial of NAC had adequate baseline and follow-up NCI neurotoxicity assessment; although electrophysiological assessment, the nerve conduction study data, was only described qualitatively (Lin 2006), indicating no electrophysiological change in the NAC group without available data for the control group. The method of randomisation and of allocation concealment was unclear. It also was unclear whether the study was blinded to participants, investigators, or outcome assessors.

Amifostine

All seven trials had adequate baseline and follow-up assessments that occurred after completing chemotherapy within the intended zero to six-month window. All trials also included assessment following the last treatment cycle, with adequate follow-up to that point. Two trials included additional assessments up to three months after the last treatment cycle (Kemp 1996; Planting 1999). The method of randomisation was deemed secure and allocation concealment at low risk of bias for two trials (Lorusso 2003; Lu 2008), but unclear for four trials. DeVos 2005 performed a phase II evaluation, with a control group that did not receive placebo, and participants received both carboplatin and taxanes. One additional trial was an open pilot study in which the participants were randomised and blinded but the control group did not receive placebo an the investigators were not blinded (Gallardo 1999). None of the trials clearly masked the participant or the observer, and only one study stated that the outcome assessor was blinded to the treatment group or to adverse events reported by the participant (Kemp 1996). The adequacy of analyses was deemed at low risk of bias for four studies but unclear for one (Planting 1999).

Calcium and magnesium (Ca/Mg)

The three trials had adequate baseline and follow-up assessments that occurred after completing chemotherapy within the intended zero to six month window, with assessment occurring immediately after the sixth treatment cycle (10 weeks). The method of randomisation was deemed secure, and allocation of concealment and subject, observer, and outcome assessor blinding appeared at low risk of bias. An unavoidable limitation of the Ishibashi 2010 study was that enrolment was discontinued after 33 participants were entered into the study because the interim analyses showed poorer results in the Ca/Mg group (early termination of enrolment). Similarly, the Chay 2010 study was terminated prematurely because of reports of negative results from the CONcePT trial, and the Grothey 2011 study was terminated prematurely because of reports from another trial suggesting that Ca/Mg decreased treatment efficacy, data subsequently found to be incorrect.

Diethyldithiocarabamate (DDTC)

In the single DDTC study (Gandara 1995), the methods of randomisation and allocation concealment were unclear, although we judged the participant blinding to be at low risk of bias. Observer and outcome assessor blinding were considered at low risk of bias. A large number of withdrawals for progressive disease or toxicity (40 in the intervention arm and 71 in the control arm) were noted.

Glutathione (GSH)

All seven trials had adequate baseline and follow-up assessments that occurred after completing chemotherapy within the intended zero to six- month window. The method of randomisation was deemed secure, allocation concealment was also at low risk of bias, and blinding was done for participants and observers in three trials (Cascinu 1995; Cascinu 2002; Smyth 1997), but not for the remaining three trials (Bogliun 1996; Colombo 1995; Milla 2009; Schmidinger 2000). Outcome blinding was at low risk of bias for four trials (Bogliun 1996; Cascinu 1995; Cascinu 2002; Smyth 1997), and unclear in the other three (Colombo 1995; Milla 2009; Schmidinger 2000). The adequacy of analyses was deemed adequate for five studies (Bogliun 1996; Cascinu 1995; Cascinu 2002; Milla 2009; Smyth 1997), and inadequate for two (Colombo 1995; Schmidinger 2000).

Org 2766

All four trials had adequate baseline and follow-up assessments that occurred after completing chemotherapy within the intended zero to six-month window. One trial (Hovestadt 1992) included additional assessments up to 24 months after the last treatment cycle. The method of randomisation was deemed secure and allocation concealment at low risk of bias for one trial (van der Hoop 1990), but unclear for the remaining three trials. Participant and outcome assessor blinding was at low risk of bias in three trials (Hovestadt 1992; Roberts 1997; van der Hoop 1990), and unclear in one (van Gerven 1994), while observer blinding was at low risk of bias in two trials (Roberts 1997; van der Hoop 1990) and unclear in two (Hovestadt 1992; van Gerven 1994). The adequacy of analyses was deemed adequate for one study (Roberts 1997), but unclear for two trials (Hovestadt 1992; van Gerven 1994), and inadequate for one (van der Hoop 1990).

Oxcarbazepine (OXC)

Out of 40 participants enrolled in the single OXC study (Argyriou 2006a), eight dropped out (four in each arm), mainly for disease progression plus two for adverse symptoms related to OXC treatment. The specific method of randomisation was unclear, but the details were known only to the randomisation coordinator and concealed from the data analysts. Participants were not blinded, as this was an open label study. The dropout rate was not considered excessive, and the analyses were performed both on an intention-to-treat and completion-of-trial basis.

Retinoic acid, all-trans (ATRA)

There were no withdrawals and no participants were lost to follow-up. We deemed the risk for bias for all measures to be low.

Vitamin E

Out of 47 participants enrolled in the initial vitamin E study (Pace 2003), 20 participants dropped out, mainly for disease progression. Twenty-seven participants, all of whom completed six cycles of cisplatin chemotherapy and received a cumulative dose of cisplatin greater than 300 mg/m², were available for analysis. Individual doses and combinations of chemotherapy varied. Methods of randomisation, allocation concealment, and blinding were unclear. Insufficient details were provided on withdrawals, dropouts, and losses to follow-up and we thought the analysis at unclear risk of bias in this respect. A modified total neuropathy scale was used, but this modified version is not a validated measure. In the second study (Argyriou 2006). Five of the 37 enrolled participants dropped out because of death or disease progression. Thirty participants completed the chemotherapy protocol; the mean total cisplatin dose was comparable in the vitamin E and control groups (120.6 ± 5.2 mg and 121.9 ± 3.4 mg, respectively). The precise randomisation method was not described but the allocation concealment appeared to be at low risk of bias, with details of the randomisations known only to the randomisation co-ordinator. In this open label study, the subjects were not blinded but those performing the evaluations were blinded, as were the outcome assessors. Out of 207 initial enrollees, there were 18 cancellations (7 ineligible and 11 withdrawals, mainly due to refusal of further treatment) (Kottschade 2011). One hundred and twenty-seven participants completed the study treatment protocol but a total of 189 participants completed a sufficient portion of the protocol to be available for the end point analyses. The study was a randomised, double-blind, placebo-controlled trial. Allocation concealment was not specifically described but there was no indication that it was inadequate. The inclusion of a large number of participants receiving taxanes was confounding.

Effects of interventions

The results of the review for each potential chemoprotective agent follow.

Acetylcysteine (N-acetylcysteine, NAC)

Primary outcome measure

No primary outcome measure was available in the single NAC study (Lin 2006).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

Sensory (sural SNAP) amplitude, distal latency, and conduction velocity, and motor (median compound muscle action potential (CMAP)) amplitude, distal latency, conduction velocity, and F wave latency were measured at baseline and after 4, 8, and 12 cycles of chemotherapy. However, the data were only reported for the NAC group, indicating no significant deterioration over the full trial (something the authors attributed to NAC), without reporting similar data for the control group.

(2) Clinical impairment on neurological examination using a validated scale

A neurologist performed a complete neurological examination but the report does not provide the data, aside from noting (in the Discussion) that oxaliplatin-induced neurotoxicity is characterised by a rapid-onset acute sensory neuropathy.

(3) Functional activities of daily living

Not an outcome

(4) Information from toxicity rating scales

Toxicity due to possible sensory neuropathy was assessed every two weeks using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC). After 12 cycles of treatment, the incidence of ≥ Grade 1, 2, and 3 neurotoxicity was 80%, 20%, and 0% among the five participants in the NAC group, respectively, and 100%, 89%, and 33% in the nine participants in the control group (P = 0.01).

Adverse effects attributed to the study intervention

No adverse neurotoxicity was attributed to the NAC intervention.

Details of other outcomes not specified in the protocol

None described

Amifostine

Primary outcome measure

Quantitative sensory testing (QST) was used as an outcome measure in a single amifostine trial (Planting 1999), although only mean baseline and post-treatment values and non-parametric analyses were reported. This trial involved 74 participants with advanced neck cancer who were treated with six cycles of weekly cisplatin (70 mg/m²). Cisplatin neurotoxicity was measured by VPT recordings made from the second metatarsal bone of each hand (test of large sensory axons and receptors). An increased threshold indicates worsening sensory performance. Three measurements of the VPT (in μm of skin displacement) were recorded for each hand and the mean taken as the VPT for each side. Participants receiving pretreatment with amifostine (740 mg/m²) prior to cisplatin administration (37 participants) showed significantly less subclinical neurotoxicity as measured by the VPT relative to control participants receiving cisplatin only (37 participants). Although the groups were similar in terms of most measures, a slightly smaller number of participants (borderline significant) in the amifostine group relative to the control group completed six cycles of cisplatin (20 versus 28; P = 0.07). The VPT analyses, which were based on participants in whom a three-month post-treatment VPT value was available, included 14 participants in the amifostine group and 20 participants in the control group. The mean VPT increased at three months compared to baseline values for both groups, but the increase was smaller for the amifostine group compared to the control group (left hand, 0.15 μm versus 0.48 μm, mean difference (MD) 0.33 μm (95% CI -0.01 μm to 0.67 μm); right hand 0.18 μm versus 0.40 μm, MD 0.12 μm (95% CI -0.03 μm to 0.27 μm). The authors explained that the borderline significant group difference for the right hand VPT reflected an imbalance at baseline for the groups and limited data.

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

This secondary outcome measure was used in a single trial evaluating the protective effect of amifostine against neurotoxicity of carboplatin (area under the curve according to the Calvert formula) and paclitaxel (175 mg/m²) among participants with non-small cell lung cancer (Kanat 2003). Chemotherapy-induced neurotoxicity was assessed by serial SNAPs recorded from the right sural, left ulnar, and right median sensory nerves. Evaluations were performed at baseline and immediately after the sixth cycle of treatment. Participants who received pretreatment with amifostine (910 mg/m²) prior to chemotherapy (19 participants) were compared to control participants who received chemotherapy only (19 participants). The mean SNAP amplitudes for both groups were comparable at baseline and also after six cycles of chemotherapy. There was no significant decline in the mean amplitudes for either group after treatment.

(2) Clinical impairment on neurological examination using a validated scale

There was no use of a uniform or standardised neurological examination scale among the studies, but several clinical scales were used that were based on descriptions of conventional neurological symptoms or signs. For example, in Planting 1999, clinical neurotoxicity "grade 1" developed in 4 of 37 participants in the cisplatin plus amifostine group and 5 of 37 participants in the cisplatin only group (risk ratio (RR) 0.80, 95% CI 0.23 to 2.75) (see Analysis 1.1). Conversely, paraesthesias "grade 2" (reflecting an adverse sensory symptom outcome) developed in 8 of 19 participants in the carboplatin and paclitaxel plus amifostine group compared to 18 of 19 in the carboplatin and paclitaxel only group (RR 0.59, 95% CI 0.36 to 0.98) in Kanat 2003. Neurotoxicity as evaluated by a clinical examination and scored as "grade 3-4" (not further described) was reported among 93 participants receiving carboplatin and paclitaxel plus amifostine at any of the scheduled evaluations in 19 of 508 evaluations (3.7%) versus in 37 of 514 evaluations (7.2%) among participants receiving carboplatin and paclitaxel only (Lorusso 2003). Our review protocol was interested in results after treatment was completed. Data recorded after the last treatment cycle were not available in the Lorusso et al. article (Lorusso 2003), but, despite there being a similar proportion of subjects in each group who continued to show an adverse effect, the neurotoxicity comparisons for the last three cycles of chemotherapy no longer showed a substantial group difference (10 of 244 evaluations (4%) in the amifostine group and 23 of 245 evaluations (9%) in the control group). Furthermore, the paper reports the data as adverse neurotoxicity occurring during any of the treatment cycles and therefore includes multiple observations from individual participants, not independent observations, precluding further evaluation.

(3) Functional activities of daily living

Based on a sensorimotor neurotoxicity score, Kanat 2003 reported a minor ("grade 2") decrease in the activities of daily living (ADL) score in 2 of 19 participants in the carboplatin and paclitaxel plus amifostine group compared to 9 of 19 participants in the carboplatin and paclitaxel only group (RR of 0.22, 95% CI 0.06 to 0.90) (see Analysis 2.1).

(4) Information from toxicity rating scales

Kemp 1996 reported that the incidence of neurotoxicity, defined as symptoms of peripheral neuropathy or as a decrease in the neurological function daily activity score, was related to the cumulative dose of cisplatin among participants with ovarian cancer who were treated with cisplatin and cyclophosphamide. By treatment cycle five, there was a significant difference between the groups, favouring the amifostine group (P = 0.015). Following the last treatment cycle, the NCI-CTC neurologic toxicity rating (grades 0, 1, 2, or 3) was significantly reduced (P = 0.029) by pretreatment with amifostine (122 participants pre-treated with amifostine, 120 control participants). The risk of developing any level of neurotoxicity (grade 1, 2, or 3) was almost significantly reduced by pretreatment with amifostine relative to no treatment (RR of 0.81, 95% CI 0.66 to 1.00) (see data for Kemp 1996, Analysis 3.1). None of the participants in the amifostine group but two of the participants in the control group discontinued cisplatin because of neurotoxicity. Lu 2008 used the NCI-CTC (2.0) scale to evaluate neurotoxicity. The occurrence rate of an acute neurotoxicity during treatment was significantly lower in the amifostine group relative to the control (glutamine) group: 6.5% versus 95.7% (P < 0.001). The occurrence rates of grade I–II and grade III–IV peripheral neurotoxicity after chemotherapy were significantly lower in amifostine group than in control group (10.9% versus 73.9%, P < 0.001; 2.2% versus 19.6%, P = 0.007). The results at trial end were combined by grades 0, 1-2, and 3-4 and could not be evaluated using the more frequently used definition of neuropathy based on a ≥ grade 2 rating. Nevertheless, after treatment cycle 6, the occurrence rates of all grades of neuropathy were significantly lower in the amifostine group relative to the control (glutamine) group: grade 0 (no neuropathy), 38 of 44 versus 6 of 43; grades 1-2, 6 of 44 versus 30 of 43; grade 3-4, 0 of 44 versus 7 of 43 (P < 0.001) (See Lu 2008 data in Analysis 3.1). The incidence of acute cold paraesthesias was also lower in the intervention group than the control group. The frequency of regimen change because of chemotherapy-related neurotoxicity was significantly lower in the amifostine group than in the control group (4.3% versus 23.9%, P = 0.007). The overall response rates of evaluable participants were 44.4% in the amifostine group and 38.5% in the control group (P = 0.66). DeVos 2005 performed evaluations at the end of six cycles of chemotherapy using a subjective neuropathy-related symptom score (for which none of the items reached statistical significance) and the NCI-CTC neurotoxicity rating. Participants who experienced an NCI-CTC rating of ≥ grade 2 at the end of six cycles (plus those terminated early because of neurotoxicity) included 7 of 45 participants in the amifostine group and 17 of 45 in the control group. Those who had a NCI-CTC grade 3 included 4 of 45 participants in the amifostine group and 5 of 45 control participants. Gallardo 1999 used a neurotoxicity scale, presumably the NCI-CTC grading scale for neuropathy. That study included 20 participants with locally advanced, histologically diagnosed, cervical cancer to investigate the feasibility of five-day scheduling of amifostine with radiotherapy and cisplatin, randomised to receive amifostine (10 participants) or no amifostine (10 participants) before infusion of cisplatin.

A pooled analysis of the available data from four studies (DeVos 2005; Kanat 2003; Kemp 1996; Lu 2008) was possible for the equivalent of NCI-CTC grades ≥1 (all grades of neuropathy). The pooled analysis showed a significantly reduced risk of developing any level of neurotoxicity favouring the amifostine group relative to the placebo group, with an RR of 0.66 (95% CI 0.57 to 0.76) (random-effects model because of substantial heterogeneity) (Analysis 3.1). A pooled analysis of the available data from three studies (DeVos 2005; Gallardo 1999; Kanat 2003) was possible for NCI-CTC grades ≥2. Despite use of slightly different versions of the NCI-CTC, inclusion of taxanes by DeVos 2005, and slightly different evaluation times (e.g., end of the treatment cycle versus three months later), there was a significantly reduced risk favouring the amifostine group relative to the placebo group, showing an RR of 0.26 (95% CI 0.11 to 0.61) (random-effects model because of substantial heterogeneity) (Analysis 3.2, Figure 2). This analysis included a small number of participants (74 received amifostine) and included data from an open pilot study (Gallardo 1999), although similar results were found after exclusion of the Gallardo et al. study results. An additional pooled analysis of the available data from three studies was possible for the equivalent of NCI-CTC grades ≥3 (Kemp 1996; Lu 2008; DeVos 2005). Despite use of slightly different versions of the NCI-CTC and slightly different evaluation times (e.g., end of treatment cycle versus three months later), there was a non-significant reduced risk favouring the amifostine group relative to the placebo group, showing an RR of 0.54 (95% CI 0.2 to 1.29) (random-effects model because of substantial heterogeneity) (Analysis 3.3, Figure 3).

Figure 2.

Forest plot of comparison: 2 Amifostine - neurotoxicity rating, outcome: 2.2 Neurotoxicity rating ≥ 2.

Figure 3.

Forest plot of comparison: 2 Amifostine - neurotoxicity rating, outcome: 2.3 Neurotoxicity rating ≥ 3.

Adverse effects attributed to the study intervention

Hypotension occurred during 133 of 508 amifostine infusions (26%, 95% CI 23.5 to 23.8%) in Lorusso 2003. However, the degree of hypotension was generally mild and well tolerated and led to a reduction of the amifostine dose from 910 mg/m² to 740 mg/m² in subsequent cycles after only 18 of the 133 occurrences (14%). Similarly, Kanat 2003 reported that hypotension occurred in 5 of 19 participants (26%) during the first or second administration of amifostine; lowering the subsequent dose from 910 mg/m² to 740 mg/m² for these participants again eliminated the problem. In Planting 1999, hypotension was observed during amifostine infusion in 17 of 36 participants (47%) and in 45 out of 184 cycles (24%), despite use of a lower dose of amifostine (740 mg/m²) compared to the other three trials. The hypotension was described as grade 3 in two participants (three cycles) and grade 4 in three participants (four cycles), but considered to be of clinical relevance in only one participant. In Kemp 1996, amifostine was well tolerated; the principal adverse side effect was a transient decrease in blood pressure observed in 75 of 122 (62%) of participants during amifostine administration. In addition, emesis occurred in 96% of participants in the amifostine group relative to 88% of participants in the control group. Lu 2008 reported that the incidence of leucopenia, thrombocytopenia, and anaemia were all less in the amifostine group relative to the placebo group, but not significantly so. For grade 3-4 haemotoxicity, the occurrence rates of hypoleukaemia were 8.7% versus 17.4% in the amifostine versus placebo groups, respectively (P = 0.216). The incidence of transient hypotension was higher in the amifostine group (occurring in 4 of 46 participants during infusion). DeVos 2005 reported that nausea and vomiting occurred more frequently in participants receiving amifostine than in those not receiving amifostine (moderate nausea 21% versus 29%, and severe nausea 2% versus 6%, P = 0.007). Amifostine infusion was temporarily halted in five participants for 10 cycles due to hypotension (DeVos 2005). Gallardo et al. reported that 1 of 10 amifostine-treated participants needed temporary interruption of amifostine due to hypotension, and 8 of 10 participants receiving amifostine developed hypocalcaemia during treatment (Gallardo 1999).

Details of other outcomes not specified in the protocol

Progression of disease (ovarian cancer) was similar in the amifostine and control groups after an average of 24 months of follow-up (Lorusso 2003). Amifostine did not compromise the antitumour effect of cisplatin in the treatment of ovarian cancer (Kemp 1996). However, amifostine also did not result in a higher dose intensity of cisplatin (Kemp 1996; Planting 1999). Similarly, amifostine did not affect the response to oxaliplatin chemotherapy for digestive tract tumours (Lu 2008).

Calcium and magnesium (Ca/Mg)

Primary outcome measure

No primary outcome measure was available in the any of the Ca/Mg studies (Chay 2010; Grothey 2011; Ishibashi 2010; Knijn 2011).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

SNAP amplitudes were measured in the Chay 2010 study, but the results were reported as "abnormal" if each of the nerve conduction study measures was outside the normal values for their laboratory controls. At the end of treatment, six of seven participants receiving Ca/Mg compared to zero of nine participants receiving placebo experienced neuropathy, indicating that the treatment group had worse objective scores relative to the placebo group (RR 16.25, 95% CI 1.07 to 247.19) (Analysis 4.1).

(2) Clinical impairment on neurological examination using a validated scale

Not reported, aside from mention by Grothey 2011 that acute muscle spasms associated with oxaliplatin were significantly reduced (P < 0.01)

(3) Functional activities of daily living

Not reported

(4) Information from toxicity rating scales

The NCI-CTC and Debiopharm Neurotoxicity Scale (DEB-NTS) were used to asses the development and severity of neurotoxicity in the Ishibashi 2010 study. According to the NCI-CTC criteria after six cycles of treatment, the incidence of ≥ Grade 1, 2, and 3 neurotoxicity were 100%, 6%, and 6% in the Ca/Mg group, respectively, and 94%, 6%, and 0% in the control group, there being no significant difference between groups. Similarly, according to the DEB-NTS criteria after six cycles of treatment, the incidence of ≥ Grade 1, 2, and 3 neurotoxicity was 100%, 71%, and 6% in the Ca/Mg group, respectively, and 94%, 56%, and 0% in the control group, there being no significant difference between groups. The authors did not comment on the acute neuropathy symptoms. Chay 2010 included an acute subjective sensory neuropathy rating using the NCI-CTC (grades 0, 1, 2, or 3) during and at the end of treatment. Overall, the subjective neuropathy rate was 77% in the Ca/Mg group and 86% in the placebo group (P = 0.6). At the end of treatment, three participants receiving Ca/Mg and none receiving placebo reported grade 3 numbness (P = 0.02). Assessment of grade 3 toxicity favoured the placebo group but not significantly (P = 0.09), with no significant treatment group difference for dysaesthesias or time to onset of neuropathy. Grothey 2011 included a subjective cumulative sensory neurotoxicity (sNT) rating (grade ≥2 endpoint), the oxaliplatin-specific sNT. In the 102 participants available for analysis, Ca/Mg decreased the incidence of sNT ≥ grade 2 on the oxaliplatin-specific sNT scale (RR 0.56, 95% CI 0.33 to 0.94) (Analysis 5.1), representing a significant minor effect. No effect on acute, cold-induced sNT was found.

The pooled results from the three available studies reporting NCI-CTC neuropathy ≥ grade 2 neurotoxicity at the end of chemotherapy showed no significant risk reduction associated with the use of Ca/Mg (Chay 2010; Grothey 2011; Ishibashi 2010), RR 0.84 (95% CI 0.44 to 1.60, random-effects model) (Analysis 5.2, Figure 4).

Figure 4.

Forest plot of comparison: 5 Ca/Mg - sensory neuropathy (SNP), outcome: 5.1 Chronic NCI-CTC ≥ grade 2.

Adverse effects attributed to the study intervention

No adverse neurotoxicity was attributed to the Ca/Mg intervention (Chay 2010; Grothey 2011; Ishibashi 2010).

Details of other outcomes not specified in the protocol

The authors in Ishibashi 2010 reported in their final analyses that Ca/Mg infusions did not influence antitumour activity among participants. However, their interim analyses had indicated that "the results of treatment were poor" in the Ca/Mg group relative to the control group, resulting in discontinuation of subsequent enrolment. The authors of Chay 2010 concluded that Ca/Mg infusions failed to reduce the rate of oxaliplatin-induced acute and cumulative sensory neuropathy, although there appeared to be a trend toward a benefit in the patient’s perception of numbness during chemotherapy, a perception that was not supported by the authors' nerve conduction findings.

Diethyldithiocarabamate (DDTC)

Primary outcome measure

No primary outcome measure was available in the single DDTC study (Gandara 1995).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

SNAP amplitudes were not measured.

(2) Clinical impairment on neurological examination using a validated scale

Not reported

(3) Functional activities of daily living

Not reported

(4) Information from toxicity rating scales

NCI toxicity rating scale showed 13 of 96 participants (13%) in the DDTC arm and 12 of 99 participants (12%) in the control group developed neuropathy (RR 1.12, 95% CI 0.54 to 2.32) (see Analysis 6.1).

Adverse effects attributed to the study intervention

Adverse effects were reported in all study participants, with severe adverse events in 27 control group participants and 30 participants in the DDTC group. Twenty-two participants in the DDTC group and nine in control group withdrew because of toxicity.

Details of other outcomes not specified in the protocol

None described

Glutathione (GSH)

Primary outcome measure

QST was used as an outcome measure in only one study (Bogliun 1996). Although the manuscript does not state the site of recording the VPT, a two- to three-fold increase in vibratory threshold occurred in the GSH group versus a seven- to 10-fold increase in the control group three months after chemotherapy. One of the Cochrane authors (GC) who is a co-author on this paper was able to retrieve the original information as follows. QST, measured at cisplatin doses of 50 mg/m² and 75 mg/m², changed from baseline to end of induction to end of consolidation from approximately 1.5 to 1.6 and 4.1 respectively in the GSH group, and changed from approximately 1.6 to 8.3 and 9.4 respectively in the control group. No additional information was available.

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

Sural SNAP amplitude decreased by a greater amount in the control arm than in the GSH arm (58% to 68% controls versus 12% to 35% GSH) among participants receiving < 150 mg/m² or > 150 mg/m², respectively (Bogliun 1996). Similarly, Cascinu 1995 documented a significant reduction of sural, median, and ulnar SNAP amplitudes in the control group versus the GSH arm. At week 15, the sural SNAP decreased from 13.3 ± 4.1 µv to 8.0 ± 1.68 µv in the control arm (n = 18) and from 10.8 ± 5.84 µv to 9.0 ± 6.48 µv in the GSH arm (n = 24). Median and ulnar SNAP amplitudes also reduced by significant amounts only in the control groups. In the oxaliplatin trial, the sural amplitude decreased in the placebo group (n = 8) from 11.0 ± 6.92 µv to 7.20 ± 5.05 µv in the placebo arm (P = 0.05) but did not change in the GSH group (n = 10) (9.1 ± 6.34 µv to 8.7 ± 5.50 µv; P = non-significant) after eight cycles of therapy (Cascinu 2002). Colombo 1995 recorded sensory responses at baseline and at examination end, after nine weeks of weekly chemotherapy. The sural SNAP amplitude changed from 13.2 ± 8.5 µv to 7.6 ± 3.3 µv in the placebo group (n = 16) and from 13.1 ± 8.2 µv to 9.7 ± 5.9 µv in the GSH group (n = 15). A combined group analysis of post-treatment scores produced a MD in favour of GSH, with 95% CIs that allowed the possibility of no effect (Analysis 7.1).

No SNAP amplitudes were measures in the other studies (Bogliun 1996; Cascinu 2002; Milla 2009; Schmidinger 2000).

(2) Clinical impairment on neurological examination using a validated scale

At three months post chemotherapy, 5 of 19 participants in the GSH group and 8 of 16 in the control group changed in their neurological disability score (NDS) by more than 12 points (RR 0.53, 95% CI 0.21 to 1.29) (see Analysis 8.1) (Bogliun 1996). In the same study, the neuropathy symptom score (NSS) developed in 14 of 19 participants in the GSH arm and all 16 participants in the control group (RR 0.75, 95% CI 0.56 to 0.99) (see Analysis 9.1). After nine weeks of chemotherapy, at study end, Colombo 1995 reported that 2 of 16 GSH participants and 4 of 15 placebo participants became symptomatic for sensory neuropathy (Analysis 9.1). The pooled results from the Bogliun 1996 and Colombo 1995 data showed a borderline significant decreased risk of developing neuropathy based on the NSS favouring the GSH group relative to the control group (RR 0.69, 95% CI 0.50 to 0.97) (Analysis 9.1). Colombo 1995 performed clinical neurological examinations but did not use a validated scale; Schmidinger 2000 also performed clinical neurological examinations and, although the investigators did not use a validated scale, they found no cases of peripheral neuropathy in either the GSH or the control group.

(3) Functional activities of daily living

Participants who received GSH reported an improvement in their quality of life. They also reported significantly less tingling in hands and feet and GSH allowed more cycles of cisplatin to be administered because of less toxicity (Smyth 1997).

(4) Information from toxicity rating scales

Bogliun 1996 assessed the NSS (symptoms) and NDS (signs) neuropathy scores, indicating a trend toward less severe neurotoxicity after cotreatment with GSH, although neuroprotection was not complete. Four of 24 participants in the GSH group developed neurotoxicity (3 grade I and 1 grade II by WHO criteria) and 16 of 18 in the control group (3 grade I; 10 grade II; 2 grade III and 1 grade IV) developed neuropathy by WHO neurotoxicity grade criteria (RR 0.19, 95% CI 0.08 to 0.47) (see Analysis 10.1) (Cascinu 1995). Grade 3 or 4 neurotoxicity by NCI-CTC grading was seen in 0 of 21 participants at 8 weeks and 1 of 10 participants at 12 weeks in the GSH group and in 5 of 18 participants at 8 weeks and 6 of 8 participants at 12 weeks in the control group (RR 0.13, 95% CI 0.02 to 0.89) (see Analysis 11.1) (Cascinu 2002). In Schmidinger 2000, no change in WHO toxicity was noted in either the GSH or the control group, although the authors noted that no finding of peripheral neuropathy was observed in any of their participants. In Smyth 1997 after six cycles, neuropathy (NCI-CTC) was seen in 39% of participants (24 grade 1, and 5 grade 2) in the GSH group and 49% of participants in the control group (32 grade 1, 4 grade 2, and 2 grade 3). Mean increase in Hospital Anxiety and Depression functional score was 0.8 in the GSH arm and 2.5 in the control arm. In addition, 45 of 47 had better Rotterdam scores in the GSH group. In Milla 2009, neurologic adverse effects were assessed using the neurosensory section of the NCI-CTC, version 3. At the end of treatment, only moderate neurotoxicity was reported in the GSH arm (50% grade 1 and 50% grade 2), whereas in the placebo arm the neurotoxicity was more severe (69% grade 2 and 31% grade 3), a difference considered statistically significant (Mann-Whitney test; P = 0.0037).

Three trials utilised WHO or NCI-CTC grade ≥2 neurotoxicity at end of treatment (the most frequently used subjective measure of neuropathy in available studies) after 12 cycles of oxaliplatin (Cascinu 1995; Cascinu 2002; Milla 2009). The pooled data significantly favoured the GSH group relative to the placebo group and showing a protective RR of 0.29 (95% CI 0.10 to 0.85, random-effects model) (see Analysis 12.1, Figure 5). Although all three studies showed a favourable effect using this subjective rating, the data showed substantial heterogeneity (I2 = 73%) and the studies that contributed data to the combined analysis involved a small number of participants (11 of 48 participants receiving GSH showing ≥2 neurotoxicity relative to 34 of 39 control participants showing a similar grade of neurotoxicity).

Figure 5.

Forest plot of comparison: 11 GSH - NCI NT rating 2-4 at treatment end, outcome: 11.1 Chronic NCI ≥ grade 2.

Details of other outcomes not specified in the protocol

Oliguria occurred in 21 of 27 participants in cisplatin alone and 10 of 27 participants in the cisplatin with GSH group (RR 0.48, 95% CI 0.28 to 0.81) (see Analysis 13.1) (Bogliun 1996). Participants in the GSH group also required fewer haemotransfusions and showed fewer incidences of thrombocytopenia and anaemia than did participants in the control group (Cascinu 1995).

Adverse effects attributed to the study intervention

None described

Details of other outcomes not specified in the protocol

None described

Org 2766

Primary outcome measure

QST was used as an outcome measure in all four trials. Cisplatin neurotoxicity was measured by VPT recordings made from the second metacarpal bone of each hand (Hovestadt 1992; van der Hoop 1990; van Gerven 1994), or from the index finger and great toe (Roberts 1997). An increased threshold indicates worsening sensory performance. Three measurements of the VPT (in μm of skin displacement) were recorded for each hand and the mean taken as the VPT for each side in one study (van der Hoop 1990). Two trials (Hovestadt 1992; van Gerven 1994) referred to van der Hoop 1990 in describing their methodology, but that study did not provide a clear description of the method actually used. The final study did not report details of the QST methodology used (Roberts 1997).

Participants receiving treatment with Org 2766 1 mg/m² (n = 16) before and 24 hours after cisplatin administration showed significantly less increase in the VPT than did the 22 placebo-treated participants (mean value after 4th cycle 0.50 μm versus 1.61 μm, P < 0.005; mean value after 6th cycle 0.88 μm versus 5.87 μm, P < 0.005) in van der Hoop 1990. In the same study, the administration of Org 2766 at the dose of 0.25 mg/kg had no effect. In Hovestadt 1992, only an exploratory, descriptive statistical analysis without formal tests for significance was performed, due to the low number of participants enrolled in the study (seven in the placebo group, five treated with Org 2766 at the dose of 0.25 mg/kg and six at the dose of 1 mg/kg). Mean values in placebo-treated participants were higher than in the low- and high-dose Org 2766-treated participants one month after cisplatin treatment (mean 3.7 versus 2.9 versus 1.1 μm, respectively), intermediate one to four months after treatment (8.1 versus 14.6 versus 2.5 μm), and higher again after 4 to 12 and 12 to 24 months (4.8 versus 3.6 versus 2.0 μm, and 2.9 versus 0.6 versus 0.8 μm). However, the number of evaluable participants decreased markedly during the study and the final evaluation included only nine participants (for whom no indication about treatment is available). van Gerven 1994 reported VPT changes after the fourth cycle and three to five months later. Mean values obtained after the fourth cycle (0.95 μm in the placebo group versus 0.45 μm in the Org 2766-treated group, number of participants nine versus six respectively) and three to five months later (4.03 versus 1.85 μm, number of participants 12 versus eight) were statistically compared with two different methods: the difference in slopes between Org 2766 and placebo-treated groups was significant by ANOVA (P value = 0.04), but not by Wilcoxon's rank sum test (P = 0.06). In that study, VPTs became abnormal three to five months after treatment in nine out of 12 placebo-treated participants and in four of the eight participants treated with Org 2766 (RR 0.67, 95% CI 0.31 to 1.43) (see Analysis 14.1). In Roberts 1997, VPT was assessed separately for the index finger and for the great toe. After the blind was broken, 174 participants (59 in the placebo group, 52 in the 2 mg/kg Org 2766 group, and 57 in the 4 mg/kg Org 2766 group) were evaluable. At each time point (i.e., at each cisplatin cycle up to six courses and monthly for three months after treatment withdrawal) no difference was observed between groups. The four Org 2799 studies all performed QST and evaluated our primary outcome measure, VPT. Three of the trials (Roberts 1997; van der Hoop 1990; van Gerven 1994), measured VPT at the index finger or hand, and evaluated comparable doses of Org 2766 (1 mg or 2 mg). Based on comparison of the Org 2766 treatment and placebo groups at three to five months, the combined data from the three trials showed no significant group difference at the follow-up QST examination (MD -1.77 μm, 95% CI -4.78 to 1.23 μm, random-effects model) (see Analysis 15.1).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

This secondary outcome measure was not used in any of the selected trials.

(2) Clinical impairment on neurological examination using a validated scale

There was no use of a uniform or standardised neurological examination scale among the studies, but clinical scales were used that were based on descriptions of conventional neurological symptoms or signs. In one trial (van der Hoop 1990) neurological examination was based on a series of signs and symptoms evaluated after four and six chemotherapy courses, resulting in a "sum score." Using this score a difference was observed only for the high dose Org 2766 treatment at the evaluation performed after the 6th course versus the placebo-treated participants (P = 0.03). Two other trials used non-validated neurological scales and the authors performed no statistical comparison (Hovestadt 1992; van Gerven 1994). Roberts 1997 stated that neurological evaluation was used to assess inclusion/exclusion criteria, but provided no data about the severity of the neuropathy. In this trial, repeated neurological examinations failed to demonstrate any significant difference between Org 2766- and placebo-treated participants up to three months after cisplatin treatment withdrawal.

(3) Functional activities of daily living

This secondary outcome measure was not used in any of the selected trials.

(4) Information from toxicity rating scales

In one study (van Gerven 1994), authors reported that two participants in the placebo group and one in the Org 2766 group discontinued cisplatin treatment because of peripheral neurotoxicity (P = not significant). The other three trials reported no details about neurotoxicity-induced treatment withdrawal.

Adverse effects attributed to the study intervention

No adverse effects were attributed to Org 2766 in any trial.

Details of other outcomes not specified in the protocol

Progression of disease (ovarian cancer) was similar in the Org 2766 and control groups after an average of 24 months of follow-up (Roberts 1997). Org 2766 did not compromise the antitumour effect of cisplatin in the treatment of ovarian cancer (van der Hoop 1990).

Oxcarbazepine (OXC)

Primary outcome measure

QST was not used as a primary outcome measure in the single OXC study available (Argyriou 2006a).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

This secondary outcome measure was reported for sural, superficial peroneal, and ulnar SNAP amplitudes. A modest but significant decline in SNAP amplitude pre- to post- treatment was reported for the control group relative to the OXC group for the sural nerve (14.5 ± 6.1 to 8.3 ± 6.1 µv versus 13 ± 6.8 to 11.5 ± 7.1 µv) and superficial peroneal nerve (9.2 ± 3.2 to 6.8 ± 4.8 µv versus 9.3 ± 4.0 to 8.8 ± 4.4 µv) but not for the ulnar nerve (9.9 ± 3.4 to 7.0 ± 4.3 µv versus 9.5 ± 4.2 to 8.2 ± 4.3 µv ) (or for ulnar or peroneal motor amplitudes; motor nerves not thought to be affected by oxaliplatin) (Argyriou 2006a). However, group comparisons of SNAP amplitudes at post-treatment (at six months, after 24 cycles) showed no significant differences (Analysis 16.1, Analysis 16.2, Analysis 16.3).

(2) Clinical impairment on neurological examination using a validated scale

Based on a NSS and the NDS, the incidence of oxaliplatin-induced neuropathy was decreased among those who completed the trial in the OXC group relative to the control group (five of 16 versus 12 of 16) (RR 0.42, 95% CI 0.19 to 0.91) (see Analysis 17.1), and the between-group comparisons of the NSS (0.6 ± 0.9 versus 1.5 ± 1.3) and NDS (5 ± 8.2 versus 20.0 ± 23.1) differed significantly, both favouring the OXC group. Also, the severity of oxaliplatin-induced neuropathy was significantly lower in the OXC group versus controls, based on the total neuropathy scores (MD -7.10, 95% CI -11.98 to -2.22) (see Analysis 17.2). None of the participants receiving OXC reported negative sensory symptoms versus three controls; five participants receiving OXC reported positive sensory symptoms versus 12 controls.

(3) Functional activities of daily living

This secondary outcome measure was not used in the selected trial.

(4) Information from toxicity rating scales

None described

Adverse effects attributed to the study intervention

Adverse chemotherapy effects were described but none was attributed to OXC (there was a similar frequency in both groups).

Details of other outcomes not specified in the protocol

None reported

Retinoic acid

Primary outcome measure

QST was not performed in Arrieta 2011.

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

Arrieta 2011 utilised nerve conduction study results summarised by converting the quantitative results to a non-parametric zero to three ranking of "damage," summated for latency and amplitude measures. These electrophysiological results were not separated into their motor and sensory components, something physiologically nonsensical. Significant deterioration was reported for the summated sensory response amplitude only for the placebo group, but this group demonstrated worse function relative to the intervention group at baseline. Baseline differences between the intervention and control groups are troublesome and not explained. Also, the period of evaluation (i.e. six weeks to the end of the second course of chemotherapy) was likely to have been inadequate.

(2) Clinical impairment on neurological examination using a validated scale

No validated scale of clinical impairment on neurological examination was measured (Arrieta 2011).

(3) Functional activities of daily living

Arrieta 2011 did not measure any functional ADL.

(4) Information from toxicity rating scales

Arrieta 2011 utilised the NCI-CTC rating scale for assessment of neuropathy. NCI-CTC neuropathy grades ≥2 were present in 23 of 45 ATRA participants and in 37 of 47 placebo participants (RR 0.75, 95% CI 0.55 to 1.02) (Analysis 18.1). As noted previously, the period of evaluation (i.e., six weeks to the end of second course of chemotherapy) was likely to have been inadequate.

Adverse effects attributed to the study intervention

Five of 45 participants in the intervention group but no participants in the control group developed hypertriglyceridaemia grade 3 and 4 (Arrieta 2011).

Details of other outcomes not specified in the protocol

None described

Vitamin E

Primary outcome measure

QST was not performed in any of the vitamin E studies (Argyriou 2006; Kottschade 2011; Pace 2003).

Secondary outcome measures
(1) Nerve conduction measures of sensory response amplitudes

In Pace 2003, after six cycles of treatment, four of 13 participants in the vitamin E group had at least one abnormal finding among the median sensory or sural sensory amplitude, whereas 11 of 14 participants in the control group had at least one abnormal amplitude (RR 0.39, 95% CI 0.17 to 0.93) (see Analysis 19.1). Nerve conduction measures of sensory response amplitudes showed that the median SNAP amplitudes were reduced by a lesser degree in those taking vitamin E relative to control participants (vitamin E group: baseline 15.1 ± 9.2 µv, six months later 12.0 ± 0.6 [sic] µv; control group: baseline 15.0 ± 9.2 µv, six months later 8.7 ± 5.3 µv (P < 0.01)). By comparison, the sural amplitudes showed little effect of vitamin E (vitamin E group: baseline 15.5 ± 6.3 µv, six months later 13.7 ± 5.5 µv; control group: baseline 14.5 ± 8.5 µv, six months later 13.6 ± 9.2 µv, P = not significant). In the second vitamin E trial (Argyriou 2006), after six cycles of treatment and three months after treatment ended, all SNAP amplitudes (sural, superficial peroneal, and ulnar) had deteriorated, although the change from baseline was significantly less in the vitamin E group relative to controls. In contrast, the peroneal and ulnar motor amplitudes and conduction velocities showed no significant group differences in terms of change from baseline as reported in the trial report. However, group comparisons of the SNAP amplitudes at post-treatment (at end of treatment and three months later) showed no significant differences, although the comparison of the superficial peroneal SNAP amplitude for the vitamin E and control groups showed slightly better performance for the vitamin E group at the end of treatment (8.5 ± 6.6 versus 4.9 ± 3.6 µv; P = 0.07; MD 3.60 µv, 95% CI -0.35 to 7.55 µv), although the CIs just allowed the possibility of no effect (Analysis 20.1). There was little difference between vitamin E and control groups in post-treatment ulnar SNAP amplitude (Analysis 20.2). When the sural nerve results at end of treatment were combined for the two studies, no significant treatment effect existed (MD 2.01 µv, 95% CI -1.60 to 5.61 µv) (see Analysis 20.3, Figure 6). Kottschade 2011 did not perform nerve conduction studies.

Figure 6.

Forest plot of comparison: 20 Vitamin E - SNAP amplitude, outcome: 20.1 Sural amplitude uv after 6 cycles.

(2) Clinical impairment on neurological examination using a validated scale

Although both selected trials measured clinical impairment on neurological examination (Argyriou 2006; Pace 2003), neither trial used a validated scale. Argyriou 2006 reported that the incidence of clinical neuropathy was lower in the vitamin E group than in the control group among participants completing the study (3 of 14 versus 11 of 16, RR 0.31, 95% CI 0.11 to 0.90) (see Analysis 21.1). Similar results were reported for the intention-to-treat analysis (5 of 16 versus 13 of 19, RR 0.46, 95% CI 0.21 to 1.00) (see Analysis 21.2). The severity of clinical neuropathy, as judged by the mean score on a modified peripheral neuropathy scale at trial end, also showed a significant difference favouring the vitamin E group (4.99 ± 1.33 versus 10.47 ± 10.62, P = 0.04) (MD -5.48, 95% CI -10.73 to -0.23) (see Analysis 22.1).

(3) Functional activities of daily living

The vitamin E studies (Argyriou 2006; Kottschade 2011; Pace 2003), did not measure any functional ADL and did not provide any information on standardised toxicity rating scales.

(4) Information from toxicity rating scales

In Pace 2003, the incidence of neurotoxicity, measured by a modified version of the total neuropathy score, was significantly lower in the group with vitamin E supplementation (4 of 13 participants) compared to the group without vitamin E (12 of 14 participants; RR of developing symptoms or signs of neurotoxicity was 0.36, 95% CI 0.15 to 0.83) (see Analysis 23.1). In addition, the severity of neuropathy, measured with neurotoxicity scores, was higher (worse) in participants without vitamin E supplementation compared to those who received vitamin E (4.7 versus 2.0, P < 0.01).

Argyriou 2006, using a measure presumably derived from a modified Peripheral Neuropathy (PNP) score, reported results similar to those of Pace 2003, including mean PNP scores in the vitamin E group versus the control group of 4.99 ± 1.33 and 10.47 ± 10.62, respectively (P = 0.023). The pooled results from these two studies identified neurotoxicity after completion of chemotherapy in 9 of 29 participants receiving vitamin E versus 25 of 33 controls (P = 0.002); with an RR of 0.41 (95% CI 0.23 to 0.73, fixed-effect model) (see Analysis 23.1, Figure 7).

Figure 7.

Forest plot of comparison: 24 Vitamin E - Clinical impairment, outcome: 24.1 Total neuropathy score after 6 cycles.

Kottschade 2011 reported the incidence of neuropathy using the NCI-CTC adverse event (NCI-CTCAE) score for neuropathy (a scale of one to four), as well as by a neuropathy-specific questionnaire developed by the North Central Cancer Treatment Group (NCCTG). The primary endpoint was a ≥2 grade sensory neuropathy using the NCI-CTC 3.0 criteria, with the percentage of grade 2+ sensory neuropathic toxicity. Although this endpoint produced a negative result, the inclusion of a large number of participants (109, 58% of the total) treated with taxanes versus those treated with cisplatin, oxaliplatin, or carboplatin made it impossible to combine the results of this study with other studies using similar measures because it was impossible to separate out those subjects who did not receive taxanes.

Adverse effects attributed to the study intervention

No information was provided pertaining to the adverse effects attributed to the study interventions in Pace 2003. Overall adverse effects experienced were judged unlikely to be due to vitamin E supplementation in Argyriou 2006. Similar results were report for the Kottschade 2011 study; namely, no adverse effects were attributed to vitamin E.

Details of other outcomes not specified in the protocol

None described.

Discussion

Summary of main results

Acetylcysteine (N-acetylcysteine, NAC)

The single eligible study evaluating the use of N-acetylcysteine (NAC) against the neurotoxicity of oxaliplatin was described as a pilot study and included only a small number of participants (five receiving NAC and nine controls) (Lin 2006). In addition, uncertainty about the randomisation methods and presence of blinding (participants or investigators), report only of subjective toxicity scales, and inclusion of nerve conduction results from the NAC group but not the control group are issues that limit interpretation of the preliminary study results.

Amifostine

The eligible studies evaluating the use of amifostine as a neuroprotective agent against the neurotoxicity of cisplatin and other chemotherapy agents are inconclusive in demonstrating efficacy, primarily because few studies utilised quantitative measures of neurotoxicity. Although the studies were generally well done, participant masking was unclear, perhaps because amifostine was given intravenously in conjunction with interval chemotherapy and felt to be of little interest to the recipient. The authors of one study acknowledged that the trial was not conceived as a double-blind study, but that the physicians assessing non-haematological toxicity usually were not the same physicians involved in administering treatment and they therefore could not be influenced by the evaluation of symptoms and signs associated with chemotherapy (Lorusso 2003). It is unknown whether this belief about the low likelihood of inadvertent influence on judgment is correct. Paclitaxel was used together with carboplatin in two of the amifostine trials that were included (Kanat 2003; Lorusso 2003).

Planting 1999 was the single study that included quantitative sensory testing (QST), our primary outcome measure, among their assessment instruments. That trial showed a favourable outcome in terms of amifostine neuroprotection, but the subclinical result was based on only 14 participants in the amifostine group and 20 participants in the control group and the results were not particularly robust, showing statistical but unclear clinical significance. Among the secondary outcome measures we selected, the only other quantitative measure used in any of the four studies was related to evaluation of peripheral nerve electrophysiology. A single study utilised electrophysiological measures, recording sensory nerve action potential (SNAP) amplitudes from two upper extremity sensory nerves and one lower extremity sensory nerve at baseline and after completing chemotherapy (Kanat 2003). This study, which also included a relatively small number of participants (19 participants in each study arm), found that the quantitative measures of large fibre sensory axons failed to identify evidence of significant amifostine neuroprotection. Unfortunately, the study also showed an unexpected and almost implausible low level of neurotoxicity among the control participants who received carboplatin and paclitaxel but not amifostine, rendering the amifostine efficacy result uninterpretable.

Despite the lack of quantitative measures showing amifostine efficacy, the authors of all seven trials concluded that pretreatment with amifostine reduced, prevented, or at least exerted some protection from the cumulative neurotoxicity associated with cisplatin or carboplatin and paclitaxel. This conclusion reflected the results obtained from the various neurological examination scales or neurotoxicity scales, most often the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) neuropathy rating. The neurotoxicity rating scale was not specified by Gallardo 1999, but presumably represented the NCI-CTC scale. For the most part, the other scales utilised were of unknown sensitivity or specificity, and the clinical relevance of the results uncertain. For example, it is unclear whether any of the sensory symptoms or signs resulted in substantial functional impairment or persisted. Some of the neurotoxicity results were reported in terms of each evaluation, rather than for each participant, suggesting fluctuation during the trial. Such fluctuation suggests inclusion of non-specific symptoms, as opposed to the persistent distal predominant and symmetrical sensory symptoms and signs characteristic of most toxic neuropathies. One exception is the functional activities of daily living (ADL) scale reported by Kanat 2003. Although based on a small number of participants (19 participants in each study arm), the results of this sensorimotor neurotoxicity score suggested a small but statistically significant decrease in the ADL in 2 of 19 participants in the amifostine group compared to 9 of 19 participants in the control group (risk ratio (RR) 0.22, 95% confidence interval (CI) 0.6 to 0.90). Another exception reflected the use of the NCI neurological toxicity rating among 242 participants with ovarian cancer treated with cisplatin and cyclophosphamide (Kemp 1996). The significant decrease in the NCI rating among participants pre-treated with amifostine compare to control participants was an impressive finding, despite the lack of QST or electrophysiological evaluations. The limited availability of clinical trials utilising conventional QST and nerve conduction study measures of peripheral nerve function is disappointing, at least in part because of the relative simplicity of the peripheral nervous system evaluation relative to other neurological functions, such as behavior. Similarly, De Vos 2005 concluded that amifostine showed minor but significant activity in diminishing neurotoxicity (but not in preventing paclitaxel plus carboplatin-induced bone marrow toxicity) without interfering with chemotherapy efficacy.

The largely positive results based on subjective neuropathy ratings generally led to conclusions that amifostine could reduce the incidence and severity of peripheral neurotoxicity caused by cisplatin or oxaliplatin chemotherapy (e.g., Kemp 1996; and Lu 2008). These conclusions were supported by the pooled data involving secondary neurotoxicity rating scales, most often based on the NCI-CTC neuropathy scale. Although the additional studies identified in the 2013 update permitted pooling of data, there still were only a small number of studies that could be included, and those studies involved a relatively small number of participants. For example, the pooled data from three studies involving the equivalent of NCI-CTC grades ≥2 neurotoxicity included only 148 participants, of which 10 of 74 receiving amifostine showed ≥ grade 2 neurotoxicity relative to 39 of 74 control participants showed a similar grade of neurotoxicity (DeVos 2005; Gallardo 1999; Kanat 2003). In this analysis, the Kanat 2003 results represented outlying (positive) values relative to the other studies. That the pooled data showed substantial heterogeneity is perhaps not surprising considering the different cancers and primary treatment protocols described in these studies. Similar results were obtained from pooled analysis of the available data from three other studies using the equivalent of NCI-CTC grades ≥3 although the results were no longer statistically significant (De Vos 2005; Kemp 1996; Lu 2008), demonstrating how sensitive the results are to inclusion of data from different trials. In this analysis, the Lu 2008 results represent very outlying (positive) values relative to the other studies.

In terms of direct relevance to chemotherapy, the expectation that reduced neurotoxicity would result in increased dosing was not clearly realised in any of the trials reviewed, although Lu 2008 reported that the proportion of chemotherapy schedule adjustment because of chemotherapy-induced neurotoxicity was significantly lower in the amifostine group relative to the placebo group (4.3% versus 23.9%, P = 0.007).The expectation of the beneficial result of increased dosing is based on recognition that neurotoxicity is the primary dose-limiting adverse effect attributed to cisplatin.

De Vos 2005 conducted a randomised phase II study of paclitaxel and carboplatin with and without amifostine and, as part of their discussion, pooled the results of three studies, all involving chemotherapy with paclitaxel and carboplatin (De Vos 2005; Kanat 2003; Leong 2003). We had excluded from our review the data from the Leong et al. study because participants received only two doses of carboplatin. We included the data from the De Vos et al. study, but noted that we were unable to separate the effects of carboplatin versus paclitaxel. The pooled results reported by De Vos et al. identified an odds ratio (OR) for developing ≥ grade 2 neurotoxicity of 0.30 (95% CI 0.15, 0.63; P < 0.05, random-effects model. This compared to our pooled results (after change the RR to an OR), which showed an OR of 0.08 (95% CI 0.01to 0.79, random-effects model, P = 0.03) for developing ≥ grade 2 neurotoxicity. Notwithstanding the different studies included, the two analyses based on pooled data (our analysis and the one reported by De Vos et al.) suggested potential amifostine protection against chemotherapy-induced neurotoxicity.

In conclusion, the results of the available trials suggest the possibility of potential amifostine neuroprotection against cisplatin and other chemotherapy drugs. However, data involved a relatively small number of trials and participants, did not include improvement of primary measures or objective quantitative secondary measures, and the neuroprotection appears to be of small magnitude. Given this, in our opinion the overall efficacy results, while promising, remain inconclusive.

Calcium and magnesium (Ca/Mg)

The studies of Ca/Mg infusions as a chemoprotective agent against oxaliplatin neurotoxicity included subjective NCI-CTC grading for neuropathy and Debiopharm Neurotoxicity Scale (DEB-NTS) or similar neurotoxicity grading criteria (Chay 2010; Grothey 2011; Ishibashi 2010). Enrolment in all three studies was terminated prematurely, owing to reports that treatment results were poorer in the Ca/Mg group than in the control group. in This was according to the authors' interim analysis in the Ishibashi 2010 study, results not confirmed in the final analyses and, in the Chay 2010 study, according to reports from other studies indicating negative results. Grothey 2011 was terminated early because of reports of treatment interference by the study medication (Grothey 2011).The early discontinuations resulted in a small sample size and limited the data available to determine if Ca/Mg infusions had neuroprotective potential. The NCI-CTC rating of Grothey 2011, the largest of the available studies, reported a borderline significant result favouring Ca/Mg infusions for preventing neuropathy, defined as an NCI-CTC grading ≥2 (OR 0.42; 95% CI 0.17 to 0.99). However, the combined available data using the same grading scale did not support a significant beneficial effect. In a non-randomised retrospective analyses, Knijn 2011 reported that early ≥ NCI-CTC grade 2 neurotoxicity (occurring during six cycles of oxaliplatin chemotherapy) occurred in 218 of 551 (40%) Ca/Mg-treated participants versus 81 of 181 (45%) non-Ca/Mg-treated participants. Similarly, late ≥ grade 2 neurotoxicity present at the last cycle before going off of study was present in 148 of 551 (27%) Ca/Mg-treated participants versus 62 of 181 (34%) non-Ca/Mg-treated participants. The retrospective Knijn 2011 described a decrease in the frequency of late ≥ grade 2 neurotoxicity present at the last cycle before going off of study in Ca/Mg-treated participants relative to those who did not receive Ca/Mg. When we pooled these positive results with the other studies reporting ≥ grade 2 neurotoxicity at the end of chemotherapy, we found a modest but statistically significant result favouring the use of Ca/Mg, OR 0.68 (95% CI 0.49 to 0.94) (Chay 2010; Grothey 2011; Ishibashi 2010; Knijn 2011).

Our limited pooled results showed a non-significant reduced risk of developing a NCI-CTC ≥ grade 2 favouring Ca/Mg (RR 0.84, 95% CI 0.62 to 1.05), results different from those two published meta-analysis involving the efficacy of Ca/Mg infusions (Ao 2012; Wen 2013). Ao 2012 analyses included one study requiring translation that we are waiting to review (Dong 2010), a double-blind study involving oxaliplatin-induced neuropathy in which 4 of 20 Ca/Mg-treated participants developed chronic neuropathy versus 11 of 27 control participants (a borderline significant difference). The pooled analyses performed in Ao 2012 reported an OR of 0.44 (95% CI 0.23 to 0.85, fixed-effect model), indicating a significant result favouring treatment with Ca/Mg. After converting our analyses to an OR and using a fixed effects analyses, we showed a non-significant OR of 0.58 (95% CI 0.27 to 1.21), results still different from those reported by Ao et al. Similarly, Wen 2013 reported the results of a second meta-analysis involving oxaliplatin-related neurotoxicity. Their analysis is potentially flawed because of the variability of the studies included, in which the study by Chay et al. was the only RCT included (it had a non-significant outcome for total cumulative subjective sensory neurotoxicity). Their analyses reached significance only after including the non-randomised trials of Knijn 2011 (discussed immediately above) and Gamelin 2004. We did not include data from either the Knijn et al. or the Gamelin et al. studies in our analyses because both represented retrospective non-randomised studies (and because it is a Cochrane Neuromuscular Disease Group policy to not include data from non-randomised studies in the results section). When we investigated the effect of pooling the retrospective data from Knijn et al. with the data we reported in the results section, we found a borderline significant RR of 0.80 (95% CI 0.62 to 1.05) favouring the use of Ca/Mg, a result qualitatively similar to the results of the two published meta-analyses. Regardless, the conclusion of Wen 2013a that Ca/Mg infusions tend to decrease the incidence of oxaliplatin-induced cumulative neurotoxicity and thus enhance patients' tolerance to oxaliplatin is based primarily on subjective data derived from retrospective studies, not RCTs.

In summary, the results of the best available trials selected for analyses are difficult to evaluate because of the small number of subjects, due primarily to early termination of several important studies (for reasons unrelated to the study intervention or treatment protocols). Based on the remaining data however, our results of the available RCT data do not show suggest statistically significant effect of Ca/Mg in preventing oxaliplatin-induced neurotoxicity. Inclusion of results from several retrospective non-randomised studies suggest more positive, borderline significant results favouring the use of Ca/Mg. At present, however, the limited data are not convincingly positive in favour of Ca/Mg neuroprotection and in our opinion, the overall efficacy results are promising but inconclusive.

Diethyldithiocarabamate (DDTC)

The single study of DDTC as a neuroprotective agent suffers from having no measures of neurotoxicity other than subjective reporting (NCI). To gain full appreciation of the magnitude of the difference between the two arms (DDTC and placebo), one should probably add those withdrawn for toxicity, to patient request, and adverse experience (Gandara 1995).

Glutathione (GSH)

Overall, six out of seven studies reported a significant protective effect of GSH. All measures of peripheral neuropathy favoured the GSH group, including the measure of VPT (one study), sural SNAP amplitudes (four studies) and improvement in functional measures or various neurotoxicity rating scales (six studies). Even though the overall effect of GSH appears to be beneficial and protective, the variable dosages used with different malignancies and different combinations of chemotherapy, high drop out rate, predominant reliance on subjective measures, limited statistical analyses, and lack of long-term follow-up, make the overall effect of GSH difficult to judge.

Org 2766

Overall, the few eligible studies evaluating the use of Org 2766 as a neuroprotective agent against the neurotoxicity of cisplatin are inconclusive in demonstrating efficacy. A major concern is that the total number of participants enrolled in the studies is rather low (188 Org 2766-treated and 123 control participants) and, moreover, participants are not homogenously distributed among the four trials, since one of them (Roberts 1997) included 68% of the Org 2766-treated and 54% of the control participants. All the trials included QST, our primary outcome measure, among their assessment instruments, while none of the studies reported an evaluation of peripheral nerve electrophysiology or effects on ADL. Neurological examination was based on non-validated scales in all the four trials.

The first study suggesting a protective effect of Org 2766 (van der Hoop 1990) is based on an inadequate statistical analysis. In fact, analysis was performed after six cycles of cisplatin on only 28 participants out of the 55 admitted to the study, while the others were not eligible or had not yet received the planned chemotherapy cycles. Intermediate analysis (i.e. after four cycles of cisplatin) was performed on 39 participants. The authors of the second study (Hovestadt 1992) admitted that the number of participants was too low to allow a reliable formal statistical analysis. The third study was the only one performed mostly on males (22 men versus 1 woman). The authors used two different methods of statistical analysis and the results were conflicting (van Gerven 1994). The largest study had adequate subject, outcome assessor and observer blinding and also the statistical analysis was adequate (Roberts 1997). Instead of providing evidence of protection induced by Org 2766, the authors suggested that high doses of the compound might even increase the rate of change and degree of neuropathy induced by cisplatin (P value > 0.05).

In conclusion, although the results of the first trial (van der Hoop 1990) suggested the possibility of potential Org 2766 neuroprotection, effects appear to be of small magnitude or not convincingly positive in favour of Org 2766 neuroprotection, particularly in view of the results reported in the most recent trial (Roberts 1997). Furthermore, the combined data from the three trials using the same measure showed no significant group difference at the follow-up QST examination (mean difference -1.77 95% CI -4.78 to 1.23). The overall efficacy results are negative.

Oxcarbazepine (OXC)

The only study evaluating the efficacy of OXY for prophylaxis against oxaliplatin-induced neuropathy reported a favourable effect (Argyriou 2006a). The results were based on an open label evaluation (randomised but not placebo-controlled), a small sample size, and without quantitative sensory testing as a primary outcome measure. However, validated clinical instruments (NSS and NDS) and appropriate neurophysiological measures were incorporated and showed several significant group differences, all favouring the OXC group. The significant nerve conduction results involved a change in the baseline to six month recordings for the lower extremity SNAP amplitude measures (sural and superficial peroneal), but not the ulnar sensory or peroneal motor measures, results consistent with those expected to represent the most sensitive indicators of an oxaliplatin-induced neuropathy. Comparisons of the mean SNAP amplitudes for the treatment versus control groups post treatment (six-month recordings after 24 cycles) showed no significant differences in any of the SNAP amplitudes, however. Although the significant neurophysiological group differences based on the change from baseline to six month records were modest and of uncertain clinical importance, the overall results support further investigation of OXC in a larger placebo-controlled randomised trial.

Retinoic acid

The results from the single study involving retinoic acid as a neuroprotective agent are limited by methodological issues resulting in uninterpretable nerve conduction study results, unbalanced and unexplained baseline group differences, use of the NCI-CTC grading as the only measure of neuropathy, and an inadequate follow-up interval (Arrieta 2011). The NCI-CTC assessment of neuropathy grades ≥2 were present in 23 of 45 ATRA participants and in 37 of 47 placebo participants, showing a borderline significant difference favouring the ATRA treatment group over the placebo group (RR 0.75 95% CI 0.55 to 1.02) (Analysis 18.1).

Vitamin E

Although the results involving vitamin E as a neuroprotective agent are encouraging, methodology issues, the small size of the study, the use of multiple chemotherapeutic regimens (including taxane in the largest available study), lack of blinding, and lack of primary outcome measures make the data less than convincing. This conclusion is despite the statistically significant results from the pooled data involving subjective measures of neuropathy (NCI-CTC neurotoxicity rating). The changes noted in median SNAP but not the in sural SNAP amplitudes and the use of a non-validated toxicity measure suggest that additional more definitive studies are needed. In our opinion the overall efficacy results, while promising, remain inconclusive.

Comment

The quality and characteristics of the trials reviewed were quite variable, and included different measures of neuropathy (qualitative and subjective), different durations of follow-up, and different analyses. The duration of follow-up must be sufficient to identity cisplatin-induced sensory nerve deterioration, and therefore should extend beyond the last cisplatin treatment. How long after the last treatment is open to debate, as all toxic neuropathies demonstrate some progression after exposure ceases, and patients with cisplatin-induced neuropathy can show improvement (depending on the initial severity) after cisplatin is discontinued. We included all evaluations performed zero to six months after the last treatment, selecting the evaluation closest to three months after treatment to the extent possible. We believe that a two to three month interval after treatment is completed is biologically reasonable. In all, 15 trials were included in our initial review, a further five trials in our 2010 review, and an additional 9 trials in our 2013 update. The combined trials involved nine separate, unrelated potential neuroprotective agents and included many disparate measures of neuropathy, resulting in sufficient data to combine the results for only a few measures, most of which were secondary measures such as the NCI-CTC neurotoxicity rating. Based on our review, we feel that the evaluation of agents intended to prevent cisplatin-induced sensory neuropathy should include validated measures, and not necessarily be limited to the primary measures we initially identified (tests of QST at the index finger and great toe and nerve conduction study evaluation of SNAP amplitudes in the median sensory and sural nerves). Before performing our review, considerable consideration was given to two measures (QST or nerve conduction studies) competing for the primary endpoint. We selected QST as the primary endpoint, in part, because it had been used in several prominent trials. While QST is an excellent quantitative measure of the endpoint of interest (sensation), the SNAP amplitude has the advantage of providing information about the actual cisplatin target, the peripheral sensory nerve, independent of patient co-operation or motivation. Sufficient information exists about both measures to perform power calculations to determine the number of subjects required to detect a meaningful group difference. A difficulty we experienced in performing our review related to the limited data available, even when QST or SNAP amplitude recordings were performed. Most studies provided only descriptive statistics (e.g., mean, SD) reflecting the baseline examination and the follow-up examination for treatment and control groups, without information about change (mean, SD) between baseline and follow-up examinations. Inclusion of the latter facilitates comparisons with subsequent studies.

Authors' conclusions

Implications for practice

There is no high quality evidence that any agent has been demonstrated as neuroprotective against cisplatin-induced neuropathy, although the non-parametric available evidence, based primarily on grading of neurotoxicity using instruments such as the National Cancer Institute Common Toxicity Criteria neuropathy scale, suggests that amifostine, calcium and magnesium, glutathione, and vitamin E may have modest but potential use as neuroprotective agents.

Implications for research

There is a continued need for randomised controlled clinical trials, using objective measures of neuropathy, utilising appropriate masking of subjects and examiners, and including adequate numbers of participants to evaluated the efficacy of neuroprotective agents.

Acknowledgements

The authors acknowledge the helpful comments and assistance of RAC Hughes in preparing the protocol. The Cochrane Neuromuscular Disease Group Trials Search Co-ordinator ran the searches.

The editorial base of the Cochrane Neuromuscular Disease Group receives support from the MRC Centre for Neuromuscular Diseases.

Data and analyses

Download statistical data

Comparison 1. Amifostine - clinical impairment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Clinical impairment at 3 months174Risk Ratio (M-H, Fixed, 95% CI)0.8 [0.23, 2.75]
Analysis 1.1.

Comparison 1 Amifostine - clinical impairment, Outcome 1 Clinical impairment at 3 months.

Comparison 2. Amifostine - functional activities of daily living
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Functonal activities of daily living as measured at 3 months138Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.06, 0.90]
Analysis 2.1.

Comparison 2 Amifostine - functional activities of daily living, Outcome 1 Functonal activities of daily living as measured at 3 months.

Comparison 3. Amifostine - neurotoxicity rating
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Neurotoxicity rating ≥ 14457Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.57, 0.76]
2 Neurotoxicity rating ≥ 23148Risk Ratio (M-H, Random, 95% CI)0.26 [0.11, 0.61]
3 Neurotoxicity rating ≥ 33419Risk Ratio (M-H, Random, 95% CI)0.54 [0.22, 1.29]
Analysis 3.1.

Comparison 3 Amifostine - neurotoxicity rating, Outcome 1 Neurotoxicity rating ≥ 1.

Analysis 3.2.

Comparison 3 Amifostine - neurotoxicity rating, Outcome 2 Neurotoxicity rating ≥ 2.

Analysis 3.3.

Comparison 3 Amifostine - neurotoxicity rating, Outcome 3 Neurotoxicity rating ≥ 3.

Comparison 4. Calcium/magnesium - nerve conduction study (NCS) results
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Abnormal sensory nerve action potential116Risk Ratio (M-H, Fixed, 95% CI)16.25 [1.07, 247.19]
Analysis 4.1.

Comparison 4 Calcium/magnesium - nerve conduction study (NCS) results, Outcome 1 Abnormal sensory nerve action potential.

Comparison 5. Calcium/magnesium - sensory neuropathy (SNP)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Oxaliplatin specific sensory neurotoxicity ≥ grade 21102Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.33, 0.94]
2 Chronic NCI-CTC ≥ grade 23153Risk Ratio (M-H, Random, 95% CI)0.84 [0.44, 1.60]
3 SNP grade 3119Risk Ratio (M-H, Fixed, 95% CI)7.7 [0.45, 131.36]
Analysis 5.1.

Comparison 5 Calcium/magnesium - sensory neuropathy (SNP), Outcome 1 Oxaliplatin specific sensory neurotoxicity ≥ grade 2.

Analysis 5.2.

Comparison 5 Calcium/magnesium - sensory neuropathy (SNP), Outcome 2 Chronic NCI-CTC ≥ grade 2.

Analysis 5.3.

Comparison 5 Calcium/magnesium - sensory neuropathy (SNP), Outcome 3 SNP grade 3.

Comparison 6. Diethyldithiocarbamate - National Cancer Institute (NCI) neurotoxicity rating scale
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NCI toxicity for neuropathy1195Risk Ratio (M-H, Fixed, 95% CI)1.12 [0.54, 2.32]
Analysis 6.1.

Comparison 6 Diethyldithiocarbamate - National Cancer Institute (NCI) neurotoxicity rating scale, Outcome 1 NCI toxicity for neuropathy.

Comparison 7. Glutathione - nerve conduction study (NCS) results
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SSC amplitude273Mean Difference (IV, Fixed, 95% CI)1.79 [-0.53, 4.11]
Analysis 7.1.

Comparison 7 Glutathione - nerve conduction study (NCS) results, Outcome 1 SSC amplitude.

Comparison 8. Glutathione - clinical impairment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Impairment at 3 months135Risk Ratio (M-H, Random, 95% CI)0.53 [0.21, 1.29]
Analysis 8.1.

Comparison 8 Glutathione - clinical impairment, Outcome 1 Impairment at 3 months.

Comparison 9. Glutathione - Neuropathy Symptom Score (NSS)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NSS symptoms of neuropathy at 3 months266Risk Ratio (M-H, Fixed, 95% CI)0.69 [0.50, 0.97]
Analysis 9.1.

Comparison 9 Glutathione - Neuropathy Symptom Score (NSS), Outcome 1 NSS symptoms of neuropathy at 3 months.

Comparison 10. Glutathione - World Health Organization (WHO) evidence of neurotoxicity
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 WHO neurotoxicity during trial142Risk Ratio (M-H, Fixed, 95% CI)0.19 [0.08, 0.47]
Analysis 10.1.

Comparison 10 Glutathione - World Health Organization (WHO) evidence of neurotoxicity, Outcome 1 WHO neurotoxicity during trial.

Comparison 11. Glutathione - chronic National Cancer Institute (NCI) toxicity rating
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NCI toxicity at 12 weeks118Risk Ratio (M-H, Fixed, 95% CI)0.13 [0.02, 0.89]
Analysis 11.1.

Comparison 11 Glutathione - chronic National Cancer Institute (NCI) toxicity rating, Outcome 1 NCI toxicity at 12 weeks.

Comparison 12. Glutathione - National Cancer Institute (NCI) neurotoxicity rating 2-4 at treatment end
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Chronic NCI ≥ grade 2387Risk Ratio (M-H, Random, 95% CI)0.29 [0.10, 0.85]
Analysis 12.1.

Comparison 12 Glutathione - National Cancer Institute (NCI) neurotoxicity rating 2-4 at treatment end, Outcome 1 Chronic NCI ≥ grade 2.

Comparison 13. Glutathione - other outcomes
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Oliguria154Risk Ratio (M-H, Fixed, 95% CI)0.48 [0.28, 0.81]
Analysis 13.1.

Comparison 13 Glutathione - other outcomes, Outcome 1 Oliguria.

Comparison 14. Org 2766 - qualitative vibration position testing (VPT)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Abnormal VPT at 3 to 5 months120Risk Ratio (M-H, Fixed, 95% CI)0.67 [0.31, 1.43]
Analysis 14.1.

Comparison 14 Org 2766 - qualitative vibration position testing (VPT), Outcome 1 Abnormal VPT at 3 to 5 months.

Comparison 15. Org 2766 (1 or 2 mg)- vibration perception testing (VPT) finger or hand
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 VPT hand 3 to 5 months post treatment3175Mean Difference (IV, Random, 95% CI)-1.77 [-4.78, 1.23]
Analysis 15.1.

Comparison 15 Org 2766 (1 or 2 mg)- vibration perception testing (VPT) finger or hand, Outcome 1 VPT hand 3 to 5 months post treatment.

Comparison 16. Oxcarbazepine - sensory nerve action potential (SNAP) amplitude
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 SNAP amplitude: sural132Mean Difference (IV, Fixed, 95% CI)3.20 [-1.39, 7.79]
2 SNAP amplitude: superficial peroneal132Mean Difference (IV, Fixed, 95% CI)2.00 [-1.19, 5.19]
3 SNAP amplitude: ulnar132Mean Difference (IV, Fixed, 95% CI)1.20 [-1.78, 4.18]
Analysis 16.1.

Comparison 16 Oxcarbazepine - sensory nerve action potential (SNAP) amplitude, Outcome 1 SNAP amplitude: sural.

Analysis 16.2.

Comparison 16 Oxcarbazepine - sensory nerve action potential (SNAP) amplitude, Outcome 2 SNAP amplitude: superficial peroneal.

Analysis 16.3.

Comparison 16 Oxcarbazepine - sensory nerve action potential (SNAP) amplitude, Outcome 3 SNAP amplitude: ulnar.

Comparison 17. Oxcarbazepine - neurotoxicity rating
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Neuropathy after 12 cycles132Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.19, 0.91]
2 Severity of neuropathy (TNS)140Mean Difference (IV, Fixed, 95% CI)-7.1 [-11.98, -2.22]
Analysis 17.1.

Comparison 17 Oxcarbazepine - neurotoxicity rating, Outcome 1 Neuropathy after 12 cycles.

Analysis 17.2.

Comparison 17 Oxcarbazepine - neurotoxicity rating, Outcome 2 Severity of neuropathy (TNS).

Comparison 18. Retinoic acid - National Cancer Institute (NCI) neurotoxicity rating
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 NCI-CTC grade ≥ 2192Risk Ratio (M-H, Fixed, 95% CI)0.75 [0.55, 1.02]
Analysis 18.1.

Comparison 18 Retinoic acid - National Cancer Institute (NCI) neurotoxicity rating, Outcome 1 NCI-CTC grade ≥ 2.

Comparison 19. Vitamin E - qualitative sensory nerve conduction study (NCS) amplitudes
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Abnormal median or sural sensory amplitude127Risk Ratio (M-H, Fixed, 95% CI)0.39 [0.17, 0.93]
Analysis 19.1.

Comparison 19 Vitamin E - qualitative sensory nerve conduction study (NCS) amplitudes, Outcome 1 Abnormal median or sural sensory amplitude.

Comparison 20. Vitamin E - sensory nerve action potential amplitude
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Superficial peroneal amp 3 mos s/p treatment130Mean Difference (IV, Fixed, 95% CI)3.60 [-0.35, 7.55]
2 Ulnar SNAP amp 3 mos s/p treatment130Mean Difference (IV, Fixed, 95% CI)1.50 [-2.71, 5.71]
3 Sural amplitude uv after 6 cycles257Mean Difference (IV, Fixed, 95% CI)2.01 [-1.60, 5.61]
Analysis 20.1.

Comparison 20 Vitamin E - sensory nerve action potential amplitude, Outcome 1 Superficial peroneal amp 3 mos s/p treatment.

Analysis 20.2.

Comparison 20 Vitamin E - sensory nerve action potential amplitude, Outcome 2 Ulnar SNAP amp 3 mos s/p treatment.

Analysis 20.3.

Comparison 20 Vitamin E - sensory nerve action potential amplitude, Outcome 3 Sural amplitude uv after 6 cycles.

Comparison 21. Vitamin E - incidence of neuropathy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of peripheral neuropathy (completed trial)130Risk Ratio (M-H, Fixed, 95% CI)0.31 [0.11, 0.90]
2 Incidence of peripheral neuropathy (intention to treat)135Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.21, 1.00]
Analysis 21.1.

Comparison 21 Vitamin E - incidence of neuropathy, Outcome 1 Incidence of peripheral neuropathy (completed trial).

Analysis 21.2.

Comparison 21 Vitamin E - incidence of neuropathy, Outcome 2 Incidence of peripheral neuropathy (intention to treat).

Comparison 22. Vitamin E - modified peripheral neuropathy (PNP) score
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Modified peripheral neuropathy (PNP) score130Mean Difference (IV, Fixed, 95% CI)-5.48 [-10.73, -0.23]
Analysis 22.1.

Comparison 22 Vitamin E - modified peripheral neuropathy (PNP) score, Outcome 1 Modified peripheral neuropathy (PNP) score.

Comparison 23. Vitamin E - clinical impairment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Total neuropathy score after 6 cycles262Risk Ratio (M-H, Fixed, 95% CI)0.41 [0.23, 0.73]
Analysis 23.1.

Comparison 23 Vitamin E - clinical impairment, Outcome 1 Total neuropathy score after 6 cycles.

Appendices

Appendix 1. CENTRAL search strategy

#1 (cisplatin OR cis-diaminedichloroplatinum OR platinum OR organoplatinum OR oxaliplatin OR carboplatin)
#2 (therap* OR adverse OR toxic* OR neurotoxic*)
#3 (#1 AND #2)
#4 (neuroprotect* OR chemoprotect* OR protect* OR org2766 OR corticotrop* OR glutathione OR amifostine OR (growth NEXT factor*) OR neurotrophin3 OR neurotropin3 OR antidote* OR (vitamin NEXT E))
#5 MeSH descriptor Acetylcarnitine, this term only
#6 (acetyl l carnitine) or alc
#7 (#4 OR #5 OR #6)
#8 (neuropath* OR nerv* OR neurotox* OR neurol*)
#9 MeSH descriptor Peripheral Nervous System Diseases, this term only
#10 MeSH descriptor Peripheral Nerves, this term only
#11 (#8 OR #9 OR #10)
#12 (#3 AND #7 AND #11)

Appendix 2. MEDLINE (OvidSP) search strategy

Database: Ovid MEDLINE(R) <1946 to February Week 3 2013>
Search Strategy:
--------------------------------------------------------------------------------
1 randomized controlled trial.pt. (340611)
2 controlled clinical trial.pt. (85213)
3 randomized.ab. (243875)
4 placebo.ab. (135354)
5 drug therapy.fs. (1580528)
6 randomly.ab. (174990)
7 trial.ab. (250886)
8 groups.ab. (1141737)
9 or/1-8 (2946306)
10 exp animals/ not humans.sh. (3765892)
11 9 not 10 (2502948)
12 cisplatin/ae, tu, to (14735)
13 cisplatin.tw. (35823)
14 cis-diamminedichloroplatinum.tw. (1989)
15 platinum compounds.tw. or platinum compounds/ae, to, tu (1366)
16 exp organoplatinum compounds/ae, to, tu (6449)
17 (oxaliplatin or carboplatin).tw. (13012)
18 or/12-17 (51975)
19 exp peripheral nervous system diseases/ci, pc (6830)
20 exp central nervous system diseases/ci, pc (89001)
21 (neuropath$ or neuro$ or nerv$).tw. (1392830)
22 or/19-21 (1457786)
23 18 and 22 (5142)
24 exp neuroprotective agents/ (57571)
25 chemoprotect$.mp. (1147)
26 Protective Agents/ (3135)
27 neuroprotective agents/ (19938)
28 (protect$ or neuroprotect$).tw. (464836)
29 (ORG2766 or ORG 2766).tw. (216)
30 Adrenocorticotropic Hormone/ (43262)
31 (acth or corticotropin or corticotrophin or adrenocorticotropin or adrenocorticotrophin).tw. (42979)
32 glutathione/ or glutathione.tw. (90417)
33 amifostine.tw. or amifostine/ (1591)
34 exp nerve growth factors/ (35075)
35 (nerve adj3 growth adj3 factor$).tw. (14391)
36 neurotrophin 3.tw. (2014)
37 exp antidotes/ (47996)
38 antidote$.tw. (3477)
39 vitamin E.tw. or vitamin E/ (29477)
40 (alc or acetyl l carnitine).tw. (1658)
41 Acetylcarnitine/ (993)
42 or/24-41 (741678)
43 11 and 18 and 22 and 42 (268)
44 remove duplicates from 43 (263)
45 44 and 20100801:20130304.(ed). (34)

Appendix 3. EMBASE (OvidSP) search strategy

Database: Embase <1980 to 2013 Week 09>
Search Strategy:
--------------------------------------------------------------------------------
1 crossover-procedure.sh. (36349)
2 double-blind procedure.sh. (113402)
3 single-blind procedure.sh. (17075)
4 randomized controlled trial.sh. (338076)
5 (random$ or crossover$ or cross over$ or placebo$ or (doubl$ adj blind$) or allocat$).tw,ot. (935629)
6 trial.ti. (141499)
7 or/1-6 (1066673)
8 (animal/ or nonhuman/ or animal experiment/) and human/ (1243614)
9 animal/ or nonanimal/ or animal experiment/ (3363752)
10 9 not 8 (2783529)
11 7 not 10 (978201)
12 limit 11 to embase (763556)
13 CISPLATIN/ae, to [Adverse Drug Reaction, Drug Toxicity] (25725)
14 cisplatin.tw. (48796)
15 cis-diamminedichloroplatinum.mp. (2168)
16 Platinum Derivative/ae, to [Adverse Drug Reaction, Drug Toxicity] (1122)
17 (platinum compound or platinum derivative).mp. (6528)
18 Platinum Complex/ae, to [Adverse Drug Reaction, Drug Toxicity] (836)
19 oxaliplatin.tw. or OXALIPLATIN/ (17733)
20 carboplatin.tw. or CARBOPLATIN/ (40774)
21 or/13-20 (108555)
22 exp Peripheral Neuropathy/ (46553)
23 (neuropath$ or neuro$ or nerv$).mp. (2599138)
24 22 or 23 (2599437)
25 21 and 24 (20122)
26 Neuroprotective Agent/ (8475)
27 Neuroprotection/ (41483)
28 (chemoprotect$ or neuroprotect$ or protect$).mp. (704538)
29 (ORG 2766 or ORG2766).mp. (442)
30 CORTICOTROPIN/ (52750)
31 (acth or corticotropin or corticotrophin or adrenocorticotropin or adrenocorticotrophin).mp. (74650)
32 GLUTATHIONE/ or Glutathione.tw. (109305)
33 amifostine.tw. or AMIFOSTINE/ (3366)
34 Nerve Growth Factor/ (20503)
35 (nerve adj growth adj factor).tw. (16261)
36 neurotrophin 3.tw. or Neurotrophin 3/ (3856)
37 antidote$.tw. or Antidote/ (7719)
38 vitamin E.tw. or Alpha Tocopherol/ (57279)
39 (ALC or acetly l carnitine).tw. (1870)
40 or/26-39 (938266)
41 12 and 25 and 40 (194)
42 remove duplicates from 41 (193)

Appendix 4. CINAHL (EBSCOhost) search strategy

Tuesday, March 05, 2013 8:30:37 AM

S46 S44 AND S45 14
S45 EM 20100801-20130305 949,875
S44 S18 and S26 and S30 and S43 50
S43 S31 or S32 or S33 or S34 or S35 or S36 or S37 or S38 or S39 or S40 or S41 78,095
S42 (MH "Carnitine") or acetyl l carnitine or alc 0
S41 ("vitamin e") or (MH "Vitamin E") 4,118
S40 ("antidotes") or (MH "Antidotes") 806
S39 neurotrophin 3 46
S38 growth and factor 11,765
S37 ("amifostine") or (MH "Amifostine") 167
S36 (glutathione) or (MH "Glutathione") 2,778
S35 acth or corticotropin or corticotrophin or adrenocorticotropin or adrenocorticotrophin 799
S34 (MH "Corticotropin-Releasing Hormone") or (MH "Adrenocorticotropic Hormone") 932
S33 ORG 2766 or ORG2766 2
S32 chemoprotect* or neuroprotect* or protect* 59,269
S31 (MH "Neuroprotective Agents+") 1,741
S30 S27 or S28 or S29 181,864
S29 (MH "Peripheral Nervous System Diseases/CI/PC") 499
S28 (MH "Central Nervous System Diseases+/CI/PC") 16,400
S27 neuropath* or neuro* or nerv* 168,132
S26 S19 or S20 or S22 or S23 or S24 or S25 5,202
S25 (MH "Carboplatin") 1,158
S24 oxaliplatin or carboplatin 2,449
S23 ((platinum or organoplatunum) and compound*) 307
S22 (MH "Platinum/AE/TU") 146
S21 cis-diaminedichloroplatinum 0
S20 TI cisplatin or AB cisplatin 2,355
S19 (MH "Cisplatin/AE/PO/TU") 1,348
S18 S1 or S2 or S3 or S4 or S5 or S6 or S7 or S8 or S9 or S10 or S11 or S12 or S13 or S14 or S15 or S16 or S17 593,468
S17 ABAB design* 79
S16 TI random* or AB random* 119,989
S15 ( TI (cross?over or placebo* or control* or factorial or sham? or dummy) ) or ( AB (cross?over or placebo* or control* or factorial or sham? or dummy) ) 245,939
S14 ( TI (clin* or intervention* or compar* or experiment* or preventive or therapeutic) or AB (clin* or intervention* or compar* or experiment* or preventive or therapeutic) ) and ( TI (trial*) or AB (trial*) ) 83,802
S13 ( TI (meta?analys* or systematic review*) ) or ( AB (meta?analys* or systematic review*) ) 25,697
S12 ( TI (single* or doubl* or tripl* or trebl*) or AB (single* or doubl* or tripl* or trebl*) ) and ( TI (blind* or mask*) or AB (blind* or mask*) ) 19,319
S11 PT ("clinical trial" or "systematic review") 106,730
S10 (MH "Factorial Design") 860
S9 (MH "Concurrent Prospective Studies") or (MH "Prospective Studies") 199,928
S8 (MH "Meta Analysis") 15,806
S7 (MH "Solomon Four-Group Design") or (MH "Static Group Comparison") 32
S6 (MH "Quasi-Experimental Studies") 5,858
S5 (MH "Placebos") 8,083
S4 (MH "Double-Blind Studies") or (MH "Triple-Blind Studies") 26,197
S3 (MH "Clinical Trials+") 156,771
S2 (MH "Crossover Design") 10,227
S1 (MH "Random Assignment") or (MH "Random Sample") or (MH "Simple Random Sample") or (MH "Stratified Random Sample") or (MH "Systematic Random Sample") 60,15

Appendix 5. LILACS (IAHx) search strategy

(MH:cisplatin/ae or MH:cisplatin/tu or MH:cisplatin/to or TW:cisplatin or TW:cisplatino or TW:cis-diamminedichloroplatinum or MH:platinum compounds/ae or MH: platinum compounds/tu or MH:platinum compoounds/to or TW:platinum compounds or MH:D02.691.800$/ae or MH:D02.691.800$/tu or MH:D02.691.800$/to or TW:oxaliplatin or TW:carboplatin) and (MH:A08.800$ or MH:A08.186$ or neuropath$ or nerv$) and (neuroprotective agents or chemoprotect$ or protective or org2766 or org 2766 or Adrenocorticotropic Hormone or acth or corticotropin or corticotrophin or adrenocorticotropin or adrenocorticotrophin or amifostine or antidote$ or MH:D23.529.850$ or neurotrophin or "vitamin E" or alc or acetyl or carnitine or acetylcarnitine or "nerve growth factor") AND ((PT:"Randomized Controlled Trial" or "Randomized Controlled trial" or "Ensayo Clínico Controlado Aleatorio" or "Ensaio Clínico Controlado Aleatório" or PT:"Controlled Clinical Trial" or "Ensayo Clínico Controlado" or "Ensaio Clínico Controlado" or "Random allocation" or "Distribución Aleatoria" or "Distribuição Aleatória" or randon$ or Randomized or randomly or "double blind" or "duplo-cego" or "duplo-cego" or "single blind" or "simples-cego" or "simples cego" or placebo$ or trial or groups) AND NOT (B01.050$ AND NOT (humans or humanos or humanos)))

What's new

DateEventDescription
27 September 2013New citation required and conclusions have changedNine new included trials, one of a new intervention (retinoic acid)
30 August 2013New search has been performedNew search (4 March 2013) incorporated

History

Protocol first published: Issue 2, 2005
Review first published: Issue 1, 2007

DateEventDescription
12 October 2010New citation required but conclusions have not changedAmended author name
7 September 2010New search has been performedSearches updated to August 2010.
20 May 2008AmendedConverted to new review format.
5 October 2006New citation required and conclusions have changedSubstantive amendment

Contributions of authors

All authors reviewed the selected literature. First drafts were prepared by Dr. Albers (amifostine), Dr. Cavaletti (Org 2766), and Drs. Chaudhry and Donehower (glutathione, diethyldithiocarbamate, and vitamin E). Dr. Albers prepared the first draft of the report, which was reviewed, edited, revised, and approved by the other authors. Evaluation of the studies identified in the 2010 and 2013 reviews were performed by all of the authors, after which Dr. Albers performed the pooled analyses and prepared the draft update to include the additional materials, which was reviewed, edited, revised, and approved by the other authors.

Declarations of interest

Dr Albers has the following conflict of interest statement.

"None of the potential conflicts of interest noted below relates directly to any of the material discussed in the current review. In the interest of erring on the side of full disclosure, however, I include the following:

Within the time of this review, Dr. Albers has received personal compensation for activities with Amylin Pharmaceuticals, Dow Chemical Co., Dow AgroSciences, Eli Lilly & Company, Lilly Research Laboratories, Periphagen (formerly Diamyd), Polymedix, Veristat, Wyeth Pharmaceuticals, or by firms representing companies in litigation. These activities have been as a consultant, advisory board member, data monitoring committee member, mortality and morbidity review committee member, participating study investigator, or expert witness. He also has received funding support for clinical research from government agencies, foundations, and private industry. Two immediate family members hold stock and/or stock options in companies whose products relate to the practice of medicine. These relationships are unrelated to the chemotherapy agents or chemo-neuroprotectants discussed in the review."

Dr Cavaletti has acted in the past as a paid consultant to Sigma-Tau IFR, Serono International SA, Rinat Neuroscience Co., Guilford Pharmaceuticals, and Eisai Pharmaceuticals, which manufacture different neuroprotective agents, and to Debiopharm SA which manufactures oxaliplatin. In the 36 months prior to submission of this updated review he has no known conflicts of interest.

Dr Chaudhry has served as a medical record reviewer and provided expert witness testimony for the Department of Justice Injury Compensation Program. Dr. Chaudhry has served as a consultant for clinical trials for Novartis. He receives compensation for serving on the editoria board of Neurologist. Dr. Chaudhry also receives royalities from Johns Hopkins University for use of Total Neuropathy Score (TNS).

Dr Donehower serves on the scientific advisory board of two companies involved in the development of new anticancer drugs.

Sources of support

Internal sources

  • None, Other.

External sources

  • None, Other.

Differences between protocol and review

The protocol was published in 2005 (Albers 2005). Beginning with the 2010 update we revised the risk of bias methodology according to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008, updated Higgins 2011).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Argyriou 2006

MethodsProspective, randomised, open label with blind assessment
Participants

30 participants with variety of cancers scheduled to receive cisplatin-based regimens plus other chemotherapy drugs (including 5 who received docetaxel)

14 participants received vitamin E (vit E) supplementation and 16 participants served as controls (no vit E)

InterventionsVit E 600 mg/day during chemotherapy and for 3 months after completion of treatment
Outcomes
  1. Sural SNAP amplitude showed a significant decline in the control group relative to the vit E group

  2. Superficial peroneal SNAP amplitude showed a significant decline in the control group relative to the vit E group

  3. Ulnar SNAP amplitude showed a significant decline in control group relative to the vit E group

  4. The overall incidence of peripheral neuropathy differed significantly (5/16 vit E vs 13/19 no vit E)

NotesThe trial authors concluded that 1. vit E was well tolerated and effectively protected against cisplatin neurotoxicity, a result supported by electrophysiology, although 2. due to the lack of a placebo group, they were unable to rule out the possibility that bias contaminated participant self reported information
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but the "simple" randomisation method was not described
Allocation concealment (selection bias)Low riskOpaque, sealed envelopes containing random numbers (I or II)
Blinding (performance bias and detection bias)
Participant
High riskNot done, as participants received vit E or no vit E
Blinding (performance bias and detection bias)
Observer
Low riskBoth neurologists were blinded to group assignment until study completion
Incomplete outcome data (attrition bias)
All outcomes
Low riskEvaluated neurotoxicity on all participants completing the trial and evaluated efficacy using intention-to-treat analyses
Selective reporting (reporting bias)Low riskYes, as above
Other biasLow riskNo evidence of other bias identified

Argyriou 2006a

MethodsProspective, randomised, open label with blind assessment
ParticipantsInitially participants with colon cancer scheduled to receive FOLFOX-4, which included oxaliplatin 85 mg/m² every 2 weeks for 12 courses. 20 participants were randomised to treatment with oxcarbazepine and 20 to no treatment (16 participants in each group completed the study for n = 32 total)
InterventionsOxcarbazepine, initiated at 150 mg/day and titrated over 4 weeks to 600 mg twice daily and maintained for 20 weeks)
Outcomes
  1. Sural SNAP amplitude showed a significant decline in the control group relative to the oxcarbazepine group

  2. Superficial peroneal SNAP amplitude showed a significant decline in the control group relative to the oxcarbazepine group

  3. Ulnar SNAP amplitude showed no significant group difference

  4. The overall incidence of peripheral neuropathy differed significantly (9/20 oxcarbazepine vs 16/20 no treatment).

  5. The severity of neuropathy (total neuropathy score) significantly favoured the oxcarbazepine group

NotesThe trial authors concluded that oxcarbazepine might be able to protect against oxaliplatin-induced neuropathy. They acknowledged that the small sample size and the lack of a placebo group were limitations of the study design, but that larger placebo-controlled trials were warranted
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomisation method not specifically described, other than that there was a 1:1 ratio
Allocation concealment (selection bias)Unclear riskDescribed as "concealed", known only to the randomisation co-ordinator
Blinding (performance bias and detection bias)
Participant
High risk"Open label" trial
Blinding (performance bias and detection bias)
Observer
Low riskThe evaluators and the senior oncologist were blinded to participant group assignment
Incomplete outcome data (attrition bias)
All outcomes
Low riskInvestigators evaluated neurotoxicity in all participants completing the trial and measured efficacy using intention-to-treat analyses
Selective reporting (reporting bias)Low riskYes, as above
Other biasUnclear riskNo evidence of other bias identified

Arrieta 2011

MethodsProspective, randomised, placebo-controlled trial
ParticipantsHistologically-confirmed stage IIIB/IV NSCLC treated with cisplatin 80 mg/m² AND paclitaxil 175 mg/m²
Interventions

Retinoic acid (ATRA), 20 mg/m²/day beginning 1 week prior to chemotherapy initiation and continuing until completion of two courses

45 intervention and 47 control participants

OutcomesNCSs including sural, median, and ulnar sensory response (and peroneal motor) amplitude and latency measures, with quantitative results converted to a non-parametric "grade of damage," ranked from zero to three for latency and amplitude measures
NotesPeriod of evaluation (ie. 6 weeks to the end of second course of chemotherapy) was very likely inadequate. Also, the investigators did not separate motor and sensory electrophysiology, which is physiologically nonsensical
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low riskNone detected
Blinding (performance bias and detection bias)
Participant
Low riskBlinded
Blinding (performance bias and detection bias)
Observer
Low riskNone apparent
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone
Selective reporting (reporting bias)Low riskNone identified
Other biasHigh riskSignificant differences between study and control groups at baseline

Bogliun 1996

MethodsProspective, randomised, placebo-controlled
Participants54 participants with ovarian cancer treated with cisplatin (50 mg/m² and 75 mg/m² x 3 weeks); 27 participants received GSH and 27 participants served as controls
InterventionsGSH 2.5 g before cisplatin
Outcomes

For GSH vs control group:

  1. VPT: 2- to 3-fold increase vs 7- to 10-fold increase

  2. Sural amplitude decreases of 12% and 35% for low and high dose CDDP (GSH) and of 58% and 68% for high and low dose CDDP (control)

  3. NIS changed > 12 points in 5/19 vs 8/16

  4. NSS symptoms of neuropathy 14/19 vs 16/16

Notes1. No statistics used because of small numbers
2. Trend towards less peripheral neuropathy with GSH in all measures. The authors concluded that, despite the small numbers and lack of statistical analyses, neuroprotection was not complete but there was a trend toward less severe toxicity after cotreatment with GSH
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskUnclear
Blinding (performance bias and detection bias)
Participant
High riskRandomised but not blinded
Blinding (performance bias and detection bias)
Observer
High riskSame. The analyses of data were performed without knowledge of treatment
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskFew subjects lost to follow-up
Selective reporting (reporting bias)High riskNo formal statistical analysis presented
Other biasLow riskNone identified

Cascinu 1995

MethodsProspective, randomised, placebo-controlled
Participants50 participants with ovarian cancer treated with cisplatin (40 mg/m² every week x 9 weeks); 25 participants received GSH and 25 participants served as controls
InterventionsGSH 1.5 g/m² or placebo before cisplatin
Outcomes

1. Sural SNAP: significant change in control group only

2. Ulnar SNAP: significant change in control group only

3. Median SNAP: significant change in control group only

4. At 9 weeks, 0 participants in the GSH group developed neurotoxicity by WHO criteria vs 16/18 in the control group and at 15 weeks, the figures were 4/24 in the GSH group vs 16/18 in the control group

NotesLong-term follow-up unclear. The trial authors believed that the results established GSH as a promising and partially effective agent for the prevention of cisplatin-induced and oxaliplatin-induced neurotoxicity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom, computer-generated
Allocation concealment (selection bias)Low riskAdequate, concealed envelopes
Blinding (performance bias and detection bias)
Participant
Low riskPlacebo-controlled
Blinding (performance bias and detection bias)
Observer
Low riskThe same blinded evaluator examined all participants
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on assessable participants
Selective reporting (reporting bias)Unclear riskBased on assessable participants
Other biasUnclear riskNone identified

Cascinu 2002

MethodsProspective, randomised, placebo-controlled
Participants52 participants with colorectal cancer treated with oxaliplatin (100 mg/m² x 2 every 2 weeks); 26 participants received GSH and 26 placebo-treated participants served as controls
Interventions

GSH 1.5 g/m² or normal saline as placebo before administration of oxaliplatin

Oxaliplatin 100 mg/m² x 2 every 2 weeks

Outcomes

Neurotoxicity (NCI CTC)

Neurophysiology (sural sensory nerve conduction)

NotesGSH reduced symptoms and signs of neuropathy significantly. GSH was partially protective on measures of sural amplitude and latency. The trial authors believed that the results established GSH as a promising and partially effective agent for the prevention of cisplatin-induced and oxaliplatin-induced neurotoxicity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed cards from a computer-generated list in sealed envelopes
Allocation concealment (selection bias)Low riskUsed cards from a computer-generated list in sealed envelopes
Blinding (performance bias and detection bias)
Participant
Low riskDouble-blinded RCT
Blinding (performance bias and detection bias)
Observer
Low riskDouble-blinded RCT
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAnalyses based on evaluable participants
Selective reporting (reporting bias)Unclear riskAnalyses based on evaluable participants
Other biasLow riskNone identified

Chay 2010

MethodsProspective, randomised, placebo-controlled
Participants27 participants (19 intervention and 8 control) with histologically verified colorectal cancer receiving oxaliplatin and either XELOX (including oxaliplatin 130 mg/m² on day 1 every 21 days, received by 22 of 27 participants) or FOLFOX (including oxaliplatin um 85 mg/m² on day 1 every 2 weeks, received by 5 of 22 participants) for 12 cycles of chemotherapy; 78% of participants received > 600 mg/m² of oxaliplatin-based chemotherapy
InterventionsCalcium gluconate 1 g (10 mL of 10% calcium gluconate) + 15% magnesium sulfate 1 g diluted into 100 mL of normal saline infused over 15 minutes before and after oxaliplatin infusion (Arm A) or placebo (Arm B)
Outcomes

Neuropathy was measured by clinical assessment and NCS

NCS included secondary outcomes of sural, superficial peroneal, median, ulnar, and radial sensory nerves, plus median, ulnar, radial, posterior tibial, and peroneal motor nerves. The results were considered abnormal if each of the studies was outside the normal values of the laboratory controls.

Incidence of subjective neuropathy and grade 3 numbness in both groups were compared, as were differences in all objective neuropathy.

Notes

The planned follow-up was for a total of 3 years, with review every 3 months for the first year, then every 4 months the second year, and then every 6 months in subsequent years

Due to the trial termination, only 19 participants reached the end of the treatment for study. A total of 13 participants completed the planned 6 months of adjuvant chemotherapy. No participants in the treatment arm terminated chemotherapy prematurely while 3 participants in the placebo arm terminated treatment because of grade 3 neurotoxicity

Overall 22 out of 27 participants experienced neuropathy. The subjective neuropathy rate was 77% in Arm A and 86% in Arm B (P = 0.6). At the end of treatment, three participants in Arm A and 0 in Arm B had grade 3 numbness (P = 0.09). There was no significant difference in neuropathy between arms, whether during or at the end of treatment. The median objective neuropathy score was 6 in Arm A and 0 in Arm B (P = 0.02), indicating that the Ca/Mg treatment group had worse objective neuropathy scores than the placebo group
Conclusion: premature closure of this study

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStates that the trial is randomised but the method is not described
Allocation concealment (selection bias)Low riskNo details
Blinding (performance bias and detection bias)
Participant
Low riskNo details, but participants said to be blinded
Blinding (performance bias and detection bias)
Observer
Low riskObserver blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskTrial terminated early
Selective reporting (reporting bias)Low riskNone identified
Other biasLow riskNone identified

Colombo 1995

MethodsProspective, randomised, placebo-controlled study
ParticipantsWomen with relapsed ovarian carcinoma treated with weekly cisplatin
Interventions16 receiving glutathione (GSH) and 17 controls
OutcomesProvided results of sural sensory NCS amplitudes (mean), and used the NCI-CTC neurotoxicity scale
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot described
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described
Selective reporting (reporting bias)High riskNo details as to neurological assessment provided. No P values given for any significance (although calculable from the data provided). No objective data provided except mean sural amplitude without significance values
Other biasLow riskNone identified

DeVos 2005

MethodsRandomised phase II study
ParticipantsA randomised phase II study of paclitaxel with carboplatin with/without amifostine, as first line treatment of 90 women with advanced ovarian carcinoma
InterventionsAmifostine, 740 mg/m² preceding chemotherapy
OutcomesSymptoms of neurotoxicity and standard NCI-CTC rating
Notes

There are several problems with the study:

  1. The two groups are not the same. The ones with worse tumour type are in control group. More participants in the intervention arm had treatment delays

  2. It is not clear if the authors are making a case for a positive effect of amifostine in this study. They are assuming that it works for cisplatin and using pooled data to show that it works.

  3. Too many subgroups tested. In over all there is no difference, for grade 1, intervention group is worse, for grade 2 to 3 the control group is worse

  4. Toxicity is worse in the intervention group.

  5. Clearly no subjective change or even QOL change but no clear data provided to see if CTC of neurotoxicity was based on objective criteria.

  6. This is more about taxanes given the modest neurotoxicity of carboplatin in most patients

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot described. Unclear if participants were blinded, as control group did not receive placebo
Blinding (performance bias and detection bias)
Observer
High riskNot done
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk10 did not complete (5 each arm), 1 received low dose; information not clear on other 46
Selective reporting (reporting bias)Low riskNone detected
Other biasLow riskNone identified

Gallardo 1999

MethodsAn open, single-blinded pilot study to investigate the feasibility of 5-day scheduling of amifostine with radiotherapy and cisplatin (total dose 400 mg/m²)
Participants20 women with locally advanced, histologically diagnosed cervical cancer, treated with radiotherapy randomised to receive cisplatin at 20 mg/m² for 5 days in 2 cycles (beginning day 1 and day 22) and 100 mg/m² for 2 cycles with amifostine before cisplatin infusion (Group A) or cisplatin in the same dose without amifostine (Group B)
InterventionsAmifostine 825 mg/m² before cisplatin infusion
OutcomesNeurotoxicity grade (presumably NCI-CTC neurotoxicity)
NotesNeurotoxicity scale not specified, but from NCI
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskNot specified
Allocation concealment (selection bias)High riskPilot
Blinding (performance bias and detection bias)
Participant
Unclear riskParticipants
Blinding (performance bias and detection bias)
Observer
High riskObserver not blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskNot applicable
Selective reporting (reporting bias)Low riskNone detected
Other biasUnclear riskSame

Gandara 1995

MethodsProspective, randomised, placebo-controlled
Participants214 participants with ovarian cancer, SCLC, or NSCLC treated with cisplatin (100 mg/m² every 4 weeks x 6); 106 participants received DDTC and 108 participants received placebo. Data were available for n = 195 participants from the combined lung and ovarian cancer populations (placebo, 99 participants; DDTC, 96 participants)
InterventionsDDTC 1.6 g/m² 15 min before cisplatin
OutcomesNCI toxicity rating scale showed 13 of 96 (13%) in the DDTC group and 12 of 99 (12%) in the placebo group developed neuropathy (P = not significant)
NotesAdverse effects were reported in all study participants with severe adverse events in 27 control group and 30 of DDTC arm. The authors concluded that DDTC is not effective against protecting cisplatin-induced peripheral neuropathy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskPresumably, but not described
Blinding (performance bias and detection bias)
Participant
Low riskPlacebo-controlled
Blinding (performance bias and detection bias)
Observer
Low riskDescribed as blinded, including a blinded interim safety analysis, Independent statistical analyses
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on evaluable participants but a small percentage were lost to follow-up
Selective reporting (reporting bias)Unclear riskSame
Other biasLow riskNone detected

Grothey 2011

MethodsProspective, randomised, placebo-controlled, double-blind
Participants102 participants with colon cancer; 50 received Ca/Mg and 52 received placebo
InterventionsCa/Mg
OutcomesNCI-CTC adverse event score for neuropathy
NotesData appear to support the hypothesis that Ca/Mg infusions (marginally) decrease oxaliplatin-induced chronic sensory motor neuropathy but not acute cold-induced paraesthesias and cramps. However, the study was not completed for 6 months and had early closure (due to reports of treatment interference)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised but not described
Allocation concealment (selection bias)Unclear riskPresumably, but not described
Blinding (performance bias and detection bias)
Participant
Low riskPlacebo-controlled
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described. Independent statistical analyses
Incomplete outcome data (attrition bias)
All outcomes
Low riskBased on evaluable subjects but small percentage lost to follow-up
Selective reporting (reporting bias)Low riskNone detected
Other biasUnclear riskStudy closed early for "Treatment interference"

Hovestadt 1992

MethodsProspective, randomised, placebo-controlled
Participants18 women with epithelial ovarian cancer treated with cisplatin (75 mg/m²) and cyclophosphamide (750 mg/m²) every 3 weeks up to 9 cycles; 7 participants received Org 2766 and 11 participants served as controls
InterventionsOrg 2766 low dose (0.25 mg/m²) and high dose (1 mg/m²), immediately before cisplatin and 24 hours later
OutcomesMean VPT in placebo-treated participants was higher than in the low- and high-dose Org 2766-treated participants at 1 month, intermediate 1 to 4 months after treatment, and higher again after 4 to 12 and 12 to 24 months)
NotesDescriptive analysis only without formal statistical tests; the number of evaluable participants decreased during the study. The authors suggested that treatment with Org 2766 to prevent a cisplatin-induced neuropathy should possibly be continued up to 4 months after the last cycle of cisplatin
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskPresumably done, but not described
Blinding (performance bias and detection bias)
Participant
Low riskPlacebo-controlled
Blinding (performance bias and detection bias)
Observer
Low riskPlacebo-controlled
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on evaluable participants, but substantial dropout
Selective reporting (reporting bias)Unclear riskSame
Other biasLow riskNone identified

Ishibashi 2010

MethodsProspective, randomised, placebo-controlled
Participants33 participants with metastatic colorectal cancer treated with FOLFOX, which included oxaliplatin, 85 mg/m² every 2 weeks for 6 cycles; 17 Ca/Mg-treated and 16 control participants
InterventionsCa (850 mg) and Mg (720 mg) infusions, before and after infusion of oxaliplatin or placebo
OutcomesNCI-CTC and Debiopharm Neurotoxicity Scale (DEB-NTS)
NotesFOLFOX chemotherapy includes administration of 5-fluorouracil and l-leucovorin with each of 6, 2-week treatment cycles
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not specifically described
Allocation concealment (selection bias)Low riskCentralised allocation via random number assignment
Blinding (performance bias and detection bias)
Participant
Low riskDescribed as "double-blind" study
Blinding (performance bias and detection bias)
Observer
Low riskDescribed as "double-blind" study
Incomplete outcome data (attrition bias)
All outcomes
Low riskEarly termination of enrolment because of relatively "poorer" performance in the Ca/Mg group at interim analyses
Selective reporting (reporting bias)Unclear riskYes, based on data to time of termination
Other biasUnclear riskNo evidence of other bias identified

Kanat 2003

MethodsProspective, randomised
Participants38 participants with NSCLC treated with paclitaxel (175 mg/m²) and carboplatin (AUC = 6) were randomised; 19 participants received amifostine and 19 participants served as controls
InterventionsAmifostine 910 mg/m² every 3 weeks x 6
OutcomesThe mean SNAP amplitudes for both groups were comparable at baseline and also after 6 cycles of chemotherapy, there being no decline (clinically or statistically apparent) in the mean amplitudes for either group after treatment. Paraesthesias "grade 2" (reflecting an adverse sensory symptom outcome) developed in 8 of 19 participants in the carboplatin and paclitaxel plus amifostine group compared to 18 of 19 in the carboplatin and paclitaxel only group (P = 0.018)
NotesThe trial authors concluded that the addition of amifostine to carboplatin and paclitaxel may prevent or reduce the incidence of neurotoxicity in the treatment of NSCLC, but they cautioned in the text that the data from their trial were insufficient to support use of amifostine as a neuroprotective agent for paclitaxel and carboplatin chemotherapy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskUnclear, as not described
Blinding (performance bias and detection bias)
Participant
High riskRandomised but no placebo
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAll data included
Selective reporting (reporting bias)Unclear riskNo subjects dropped out of study
Other biasLow riskNone detected

Kemp 1996

MethodsProspective, randomised
Participants242 participants with advanced ovarian cancer treated with cisplatin (100 mg/m²) and cyclophosphamide (1000 mg/m²) every 3 weeks x 6 cycles; 122 participants received amifostine, 120 participants served as controls
InterventionsAmifostine 910 mg/m² pretreatment
OutcomesNeurotoxicity, defined as symptoms of peripheral neuropathy or a decrease in the neurological function daily activity score was related to the cumulative dose of cisplatin among participants with ovarian cancer who were treated with cisplatin and cyclophosphamide (Kemp 1996). By treatment cycle 5, there was a significant difference (P = 0.015) between the groups, favouring the amifostine group. Following the last treatment cycle, the NCI neurological toxicity rating (grades 0, 1, 2, or 3) was significantly reduced (P = 0.029) by pretreatment with amifostine (122 participants pre-treated with amifostine, 120 control participants)
NotesThe authors concluded that pretreatment with amifostine reduced the neurotoxicity associated with cisplatin chemotherapy, based on reduction of the NCI toxicity rating scale
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskPresumably, but not described
Blinding (performance bias and detection bias)
Participant
High riskRandomised but not placebo-controlled
Blinding (performance bias and detection bias)
Observer
Low riskEvaluations performed by a third party blinded to treatment or adverse events
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnclear if difference in dropouts between groups
Selective reporting (reporting bias)Low riskUsed intent to treat analyses
Other biasLow riskNone identified

Knijn 2011

MethodsRetrospective analyses without randomisation (intervention at discretion of treating physicians)
Participants755 previously untreated colorectal cancer patients who had been randomised to received capecitabine, oxaliplatin and bevacizumab or the same with the addition of cetuximab (CBC). 6 cycles over 6 months. 732 participants were evaluable
InterventionsCa/Mg, IV 2.25 mmol calcium glubionate plus MgCl 4 mMol in 100 mL glucose over 15 minutes, before and after oxaliplatin infusion retrospectively given at the discretion of the treating physician
OutcomesNCI-CTC v 3.0
NotesVery confusing retrospective dosing. Only reduced grade 1 neurotoxicity but not grade ≥ 2; and only early not late?
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskNot randomised; at discretion of treating physicians
Allocation concealment (selection bias)High riskAs above
Blinding (performance bias and detection bias)
Participant
High riskNot done
Blinding (performance bias and detection bias)
Observer
High riskNot done
Incomplete outcome data (attrition bias)
All outcomes
High riskUnknown, but inadequate handling of unavailable data
Selective reporting (reporting bias)Unclear riskUnknown
Other biasUnclear riskNot detected

Kottschade 2011

MethodsProspective, randomised, placebo-controlled
ParticipantsColorectal cancer (but also breast, lung, and other cancers) treated with taxanes (109), cisplatin (8), carboplatin (2), oxaliplatin (50) or combination (20); total 189 evaluable (of 207 enrolled)
InterventionsVitamin E 300 mg twice daily or placebo
OutcomesNCI-CTC NCI-CTC adverse event score for neuropathy 3.0
NotesDifferent types of malignancy were not of comparable distribution in intervention and control groups, although the chemotherapy treatments were similar. The inclusion of a large number of participants receiving taxanes was confounding
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number sequence
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
Participant
Low riskSubject blinded
Blinding (performance bias and detection bias)
Observer
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk18 cancellations/withdrawals out of 207 participants
Selective reporting (reporting bias)Low riskNone identified
Other biasLow riskNone identified

Lin 2006

MethodsProspective, randomised, placebo-controlled
Participants14 participants with colorectal cancer treated with oxaliplatin (85 mg/m² every 2 weeks for 12 cycles, plus weekly fluorouracil and leucovorin); 5 participants received N-acetylcysteine (NAC) and 9 served as placebo controls
InterventionsNAC 1200 mg one and one-half hours before each oxaliplatin treatment or placebo
OutcomesSensory (sural SNAP) amplitude, distal latency, and conduction velocity, and motor (median compound muscle action potential (CMAP)) amplitude, distal latency, conduction velocity, and F wave latency were measured at baseline and after 4, 8, and 12 cycles of chemotherapy. Clincal neurotoxicity was assessed every 2 weeks using the NCI-CTC rating scale. After 12 cycles of treatment, the incidence of ≥ Grade 1, 2, and 3 neurotoxicity was 80%, 20%, and 0% among the 5 participants in the NAC group, respectively, and 100%, 89%, and 33% in the control group (P = 0.01)
NotesThe nerve conduction data were reported only for the NAC group, indicating no significant deterioration over the full trial
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskDescribed only as randomised and placebo-controlled
Blinding (performance bias and detection bias)
Observer
Unclear riskPresumably, but not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described, but all data evaluated
Selective reporting (reporting bias)Unclear riskReported nerve conduction results from the NAC group but not the control group
Other biasUnclear riskNo evidence of other bias identified

Lorusso 2003

MethodsProspective, randomised
Participants187 participants with ovarian cancer treated with carboplatin and paclitaxel every 21 days for 6 cycles; 93 participants received amifostine and 94 participants served as controls
InterventionsAmifostine 910 mg/m² pretreatment
OutcomesAmifostine appeared to be protective against neurotoxicity (grade 3 to 4 neurotoxicity 3.7% vs 7.2%; P = 0.02)
NotesThe authors concluded that amifostine could exert some protection from the cumulative toxicity associated with carboplatin and paclitaxel
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list
Allocation concealment (selection bias)Low riskRandomisation performed centrally to avoid bias
Blinding (performance bias and detection bias)
Participant
High riskNot placebo controlled
Blinding (performance bias and detection bias)
Observer
Unclear riskPerformed by "dedicated" physicians but unclear if blinded
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on evaluable participants but small proportion of missing data
Selective reporting (reporting bias)Unclear riskBased on evaluable participants
Other biasLow riskNone identified

Lu 2008

MethodsProspective, randomised, placebo-controlled
ParticipantsPatients (n = 92; 46 in each group) with digestive tract tumours (colorectal or gastric carcinoma) treated with an oxaliplatin regimen (FOLFOX 4): oxaliplatin 85 mg/m² every 2 weeks; 4-week cycle repeated for 6 cycles
InterventionsAmifostine, 500 mg/m² every 4 weeks for 6 cycles, or placebo
OutcomesNCI-CTC
NotesMore haematological toxicity in PC+A arm; however mean values were similar
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomised using random number table
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot described
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low risk7 withdrawals in the AMIF group; 10 withdrawals in the placebo group; well described
Selective reporting (reporting bias)Low riskNone detected
Other biasLow riskNone detected

Milla 2009

MethodsProspective, randomised, placebo-controlled
Participants27 participants with colorectal cancer treated with FOLFOX4, which includes oxaliplatin (85 mg/m² with each 2 week cycle up to 12 cycles) plus other drugs (none known to be neurotoxic); 14 participants received GSH and 13 participants received saline placebo
InterventionsGSH; 1500 mg/m² or placebo before each oxaliplatin treatment
OutcomesAt the end of treatment, only moderate neurotoxicity reported in the GSH arm (50% grade 1 and 50% grade 2), whereas in the placebo arm the neurotoxicity was more severe (69% grade 2 and 31% grade 3). The difference was considered statistically significant (Mann-Whitney test; P = 0.0037)
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskDescribed only as randomised and placebo-controlled
Blinding (performance bias and detection bias)
Observer
Unclear riskPresumably but not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo dropouts (all data included)
Selective reporting (reporting bias)Unclear riskNot described but data from all subjects included
Other biasUnclear riskNo evidence of other bias identified

Pace 2003

MethodsProspective, randomised, placebo-controlled (control participants were untreated)
Participants27 participants with various solid tumours (lung, ovarian, rhinopharyngeal, gastric, testicular, oesophagus, ethmoid, and tongue cancer) treated with cisplatin (cumulative dose > 300 mg/m²); 13 participants treated with vitamin E (vit E) and 14 participants served as controls
InterventionsVit E 300 mg/day starting before cisplatin and continuing up to 3 months after cisplatin treatment
OutcomesThe median SNAP amplitudes were reduced by a greater degree in those without vit E than those taking vit E (without vit E group: baseline 14.5 ± 8.5 µv; 6 months later 13.6 ± 9.2 µv; vit E group: baseline 15.5 ± 6.3 µv; 6 months later 13.7 ± 5.5 µv). The differences between sural SNAPs in the 2 groups were not significant
NotesOf 47 patients enrolled, 20 dropped out mainly for disease progression. Clinical impairment on neurological examination was measured by an non-validated scale. The trial authors concluded that supplemental vit E decreases the incidence and severity of neurotoxicity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
High riskParticipants were not blinded
Blinding (performance bias and detection bias)
Observer
High riskNeurologists performing examinations were not blinded to treatment status
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on evaluable participants, although substantial drop out
Selective reporting (reporting bias)Unclear riskBased on evaluable participants, although substantial drop out
Other biasLow riskNone identified

Planting 1999

MethodsProspective, randomised, placebo-controlled
Participants74 participants with advanced head and neck cancer treated with cisplatin (70 mg/m² weekly); 37 participants received amifostine and 37 participants served as controls
InterventionsAmifostine 740 mg/m² immediately before cisplatin
OutcomesParticipants receiving amifostine showed significantly less subclinical neurotoxicity as measured by the VPT relative to controls
NotesThe trial authors explained that the borderline significant group difference for the right hand VPT reflected an imbalance at baseline for the groups and limited data. The authors concluded that amifostine reduced the risk of subclinical neurotoxicity caused by cisplatin but did not result in a higher cisplatin dose intensity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot described
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskBased on evaluable data, but there was limited drop out
Selective reporting (reporting bias)Unclear riskSame
Other biasLow riskNone identified

Roberts 1997

MethodsProspective, randomised, placebo-controlled
Participants196 participants with epithelial ovarian cancer treated with cisplatin (75 to 100 mg/m²) and cyclophosphamide (600 to 1000 mg/m²); 129 participants treated with Org 2766 and 67 participants served as controls
InterventionsOrg 2766 2 mg/m² or 4 mg/m²
OutcomesVPT increased during the study, independent of receiving Org 2766, with no difference in the rate of change or the degree of neuropathy
NotesNo evidence of efficacy in preventing or slowing development of neuropathy. The authors concluded that no benefit could be demonstrated using Org 2766 and suggested that high Org 2766 dose might eventually increase the peripheral neurotoxicity of cisplatin
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskRandomised but method not described
Blinding (performance bias and detection bias)
Participant
Low riskDecribed as blinded, placebo-controlled study
Blinding (performance bias and detection bias)
Observer
Unclear riskPresumably, but not described
Incomplete outcome data (attrition bias)
All outcomes
Low riskBased on evaluable participants, but limited drop out
Selective reporting (reporting bias)Low riskBased on evaluable participants, but limited drop out
Other biasLow riskNone identified

Schmidinger 2000

MethodsProspective, randomised, placebo-controlled
Participants20 participants with non-small cell lung cancer (NSCLC) and head and neck cancer treated with cisplatin (80 mg/m² x every 4 weeks); 11 participants treated with GSH and 9 participants served as controls
InterventionsGSH 5 g/m² before cisplatin or placebo
OutcomesNo difference in clinical or nerve conduction measurement between the 2 groups
NotesThe trial authors concluded that the combination of GSH and cisplatin was safe and the antitumour efficacy of cisplatin not impaired. They identified no difference between GSH-treated and control groups
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskRandomised but method not described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot specifically described
Blinding (performance bias and detection bias)
Observer
Unclear riskNot specifically described
Incomplete outcome data (attrition bias)
All outcomes
Low riskBased on evaluable participants but only 1 participant dropped out (in control group)
Selective reporting (reporting bias)Low riskBased on evaluable participants but only 1 participant dropped out (in control group)
Other biasLow riskNone identified

Smyth 1997

MethodsProspective, randomised, placebo-controlled
Participants151 participants with ovarian cancer treated with cisplatin (100 mg/m² x every 3 weeks x 6 courses); 74 participants received GSH and 77 participants served as controls
InterventionsGSH 3 g/m² before cisplatin
OutcomesMean increase in Hospital Anxiety and Depression score was 0.8 in the GSH group and 2.5 in the placebo group (depression score)
45 of 47 in Rotterdam had better scores in GSH
NotesParticipants reported improvement in QOL if they received GSH
They had significantly less tingling in hands and feet
GSH allowed more cycles of cisplatin because of less toxicity. The authors concluded that participants receiving GSH had a clear improvement in quality of life with significantly less tingling in their hand and feet and received more cycles of cisplatin because of less toxicity
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskCentral randomisations
Blinding (performance bias and detection bias)
Participant
Unclear riskPresumably (placebo controlled), but not described
Blinding (performance bias and detection bias)
Observer
Unclear riskPresumably (placebo controlled), but not described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on evaluable participants but substantial drop out
Selective reporting (reporting bias)Unclear riskAs above, analyses performed on relatively small subset of evaluable participants
Other biasLow riskNone identified

van der Hoop 1990

MethodsProspective, randomised, placebo-controlled
Participants55 participants with epithelial ovarian cancer treated with cisplatin (75 mg/m²) and cyclophosphamide (750 mg/m²); 33 participants received Org 2766 and 22 participants served as controls
InterventionsOrg 2766 low dose (0.25 mg/m²) and high dose (1 mg/m²), immediately before and after cisplatin
OutcomesIn the high dose Org 2766 group, the VPT increased about 2-fold, significantly less than the nearly 8-fold increase in the placebo group
NotesThe authors felt that Org 2766 prevented or attenuated cisplatin neuropathy
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Low riskDone before study, and treatment codes were not revealed to clinicians
Blinding (performance bias and detection bias)
Participant
Low riskPlacebo-controlled
Blinding (performance bias and detection bias)
Observer
Low riskTreatment codes were not revealed to clinicians
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analyses based on all enrolled participants
Selective reporting (reporting bias)Low riskIntention-to-treat analyses based on all enrolled participants
Other biasLow riskNone identified

van Gerven 1994

  1. a

    AUC: area under the curve
    DDTC: diethyldithiocarbamate
    GSH: glutathione
    NCI-CTC: National Cancer Institute Common Toxicity Criteria
    NCS: nerve conduction study
    NIS: Neuropathy Impairment Scale
    NSS: Neuropathy Symptom Scale
    NSCLC: non-small cell lung cancer
    SCLC: small cell lung cancer
    SNAP: sensory nerve action potential
    VPT: vibration perception threshold
    vs: versus

MethodsProspective, randomised, placebo-controlled
Participants42 participants with testicular and adenocarcinoma of unknown primary treated with cisplatin (100 mg/m² for at least 4 cycles) and with different combinations of etoposide, bleomicin and ifosphamide; 19 participants treated with Org 2766 and 23 participants served as controls
InterventionsOrg 2766 2 mg/d x 5 days or placebo
OutcomesBorderline significant difference in degree of VPT favouring Org 2766 vs placebo. Symptom scores were not significantly different.
NotesThe trial authors indicated that Org 2766 cannot completely prevent cisplatin neuropathy but may ameliorate nerve damage
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised but method not described
Allocation concealment (selection bias)Unclear riskRandomised but method not described
Blinding (performance bias and detection bias)
Participant
Unclear riskNot described
Blinding (performance bias and detection bias)
Observer
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskBased on participants completing 4 cycles of chemotherapy
Selective reporting (reporting bias)Low riskAs above, few eligible participants had missing data
Other biasLow riskNone identified

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Ali 2009Review of existing studies
Ao 2012Meta-analysis of existing data
Argyriou 2005Unable to separate the effects of cisplatin from those of paclitaxel
Block 2005Review article
Bogliun 1992Neither the control group nor the intervention group developed neurotoxicity, so unable to assess efficacy
Cancer Care Ontario 2012Review article
Capizzi 1995Review article
Cassidy 1998Randomised, placebo-controlled trial that was discontinued prematurely because of nausea and vomiting, limiting analyses. Nevertheless, the available data suggested that nimodipine exacerbated (not prevented) neurotoxicity
Catalano 1999Abstract
Chen 2012Not a randomised controlled trial; analyses based on retrospective data
Culy 2001Review article
De Grandis 2007Review article
De Vos 2005Unable to separate the effects of carboplatin from those of paclitaxel
Durand 2003Reports of treatment of acute sensory symptoms, not prevention of neuropathy
Gamelin 2004Retrospective, non-randomised study
Gamelin 2008Letter
Gedlicka 2003Letter
Gispen 1992No details of study provided
Glover 1987Phase I trial
Glover 1989Phase I trial
Glover 2003Treatment schedule not comparable
Gradishar 2001Phase II study, not a randomised controlled trial
Grothey 2005Review article
Haigentz 2003Phase I trial
Heidenreich 1999Limited information
Hensley 2009Description of practice guideline
Hilkens 1995Study involved dosing of cisplatin
Hilpert 2005Unable to separate the effects of carboplatin from those of paclitaxel
Hochster 2007Letter
Kesari 2005Letter
Leong 2003Only two doses of carboplatin
Lissoni 1997Details of neuropathy not provided
Lissoni 1999Groups not comparable and previous therapy unknown
Lissoni 2002Not a randomised trial
Miller 2008Unable to separate the effects of cisplatin from those of docetaxel
Mollman 1988Study of risk factors associated with cisplatin neuropathy
Moore 2003Phase II, open label study without placebo or any comparison group
Pace 2005Letter
Pace 2010Substantial dropout rate, excluding intention-to-treat analyses
Penz 2001Pilot study, not controlled trial
Rick 2001Open label, unblinded trial
Wang 2007Randomised but neither blinded nor placebo-controlled
Wen 2013Meta-analysis of calcium/magnesium infusions for the prevention of oxaliplatin-related neurotoxicity in people with colorectal cancer
Wilkes 2007Review article

Characteristics of studies awaiting assessment [ordered by study ID]

Dong 2010

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting translation

Pang 2010

Methods 
Participants 
Interventions 
Outcomes 
NotesAwaiting translation

Romano 2011

Methods 
Participants 
Interventions 
Outcomes 
NotesArticle not obtainable

Ancillary