Article Text

Protocol
Efficacy and safety of drug therapy for the prevention and treatment of chemotherapy-induced peripheral neuropathy: a protocol for a systematic review and network meta-analysis
  1. Miki Takenaka Sato1,
  2. Takeshi Hasegawa2,3,
  3. Hisashi Noma4,
  4. Hideki Sugita5,6,
  5. Erika Ota7,8
  1. 1Department of Clinical Pharmacy, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan
  2. 2Showa University Research Administration Center (SURAC), Showa University, Shinagawa-ku, Tokyo, Japan
  3. 3Division of Nephrology, Department of Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan
  4. 4Department of Data Science, The Institute of Statistical Mathematics, Tachikawa, Tokyo, Japan
  5. 5Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Shinagawa-ku, Tokyo, Japan
  6. 6Department of Pharmacy, Showa University Fujigaoka Hospital, Yokohama, Kanagawa, Japan
  7. 7Global Health Nursing, Graduate School of Nursing Science, St Luke's International University, Chuo-ku, Tokyo, Japan
  8. 8Tokyo Foundation for Policy Research, Minato-ku, Tokyo, Japan
  1. Correspondence to Dr Miki Takenaka Sato; m-takenaka{at}pharm.showa-u.ac.jp

Abstract

Introduction Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common dose-limiting side effects of chemotherapeutic drugs. Numerous clinical trials of various targeted drugs for the prevention or treatment of CIPN have been conducted; however, previous systematic reviews with direct comparisons have failed to demonstrate the efficacy of these drugs in the prevention or treatment of CIPN. In addition, no systematic reviews have indirectly compared CIPN prevention and treatment. This article describes a protocol for evaluating the efficacy and safety of drug therapy for the prevention and treatment of CIPN. The results of the proposed systematic review with network meta-analysis (NMA) will provide new insights into the prevention and treatment of CIPN.

Methods and analysis We will conduct a literature search in MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov to find relevant articles published through January 2023. We will include studies that investigated the efficacy and safety of vitamin B12, goshajinkigan, non-steroidal anti-inflammatory analgesics, opioids, calcium and magnesium, antidepressants and anticonvulsants on CIPN. Two authors will individually screen the retrieved reports and review the full text based on the selection criteria. The primary outcome is the incidence and severity of CIPN. The risk of bias will be assessed using V.2.0 of the Cochrane risk-of-bias tool. We will apply a frequentist random-effects NMA model to pool effect sizes across trials using risk ratios and mean differences with their 95% CIs. Competing interventions will be ranked using the surface under cumulative ranking probabilities. Heterogeneity will be assessed using the heterogeneity variance τ2, Cochran’s Q test and I² statistic.

Ethics and dissemination This review does not require ethical approval. The research will be published in a peer-reviewed journal.

PROSPERO registration number CRD42022371829.

  • ONCOLOGY
  • Neuropathology
  • CHEMOTHERAPY
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Strengths and limitations of this study

  • A network meta-analysis focusing on individual randomised controlled trials (RCTs) will evaluate the efficacy and safety of drug therapies in the prevention and treatment of chemotherapy-induced peripheral neuropathy.

  • We will use the Grading of Recommendations Assessment, Development and Evaluation approach to assess the quality of evidence.

  • Bias in RCTs will be assessed using the Cochrane risk-of-bias tool, V.2.0.

Introduction

Description of the condition

Peripheral neuropathy is more commonly seen in patients with diabetes, HIV infection and in those receiving chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is primarily a sensory neuropathy and may be accompanied by motor and autonomic changes.1 CIPN is often a dose-limiting side effect of platinum-based compounds, vinca alkaloids, taxanes and the proteasome inhibitor bortezomib.2 Symptoms can be acute or chronic with nearly 90% of patients developing at least one acute neuropathy symptom during the first cycle of treatment.3 Chronic neuropathy symptom tends to have a wide range of incidence, from 13% to 70%, depending on the type and dose of chemotherapy.4–6

In many patients, dose reduction or treatment discontinuation is implemented once signs of CIPN appear, but this strategy may ultimately have a negative impact on the overall survival.7 Symptoms persist in more than half of patients after treatment discontinuation.1 8 Additionally, CIPN symptoms have a negative impact on the quality of life (QoL) of a growing population of cancer survivors.9 The pathological mechanisms by which chemotherapeutic agents damage the nervous system structures causing CIPN are multifactorial and involve microtubule destruction, oxidative stress and mitochondrial damage, altered ion channel activity, myelin damage, DNA damage, problems in the immune systems and neuroinflammation.10

The first-line treatments for peripheral neuropathy include anticonvulsants, tricyclic antidepressants and selective serotonin-norepinephrine reuptake inhibitors.11 The pharmacological management of CIPN is multifaceted and includes serotonin-norepinephrine reuptake inhibitors, drugs used to treat bipolar disorder, anticonvulsants and analgesics. The non-pharmacological approaches primarily include natural products (eg, vitamin and herbal supplements), exercise, dietary modifications and ice.

Description of the intervention

In real-world clinical practice, vitamin B12, goshajinkigan, gabapentin, pregabalin, duloxetine, non-steroidal anti-inflammatory analgesics (NSAIDs), opioids and calcium/magnesium are frequently administered to prevent and treat CIPN. However, the specific methods for the prevention and treatment of CIPN have not yet been established.

In the prevention of CIPN, the different agents examined in clinical trials are often selected based on their putative effects on the underlying mechanism, including acetyl-L-carnitine, amifostine, N-acetylcysteine, amitriptyline, nimodipine, glutathione, carbamazepine, vitamin E, omega-3 fatty acids, and oxycarbazepine.4 12–16

Duloxetine is one of the few agents with proven efficacy in the treatment of CIPN based on the results of randomised controlled trials (RCTs).17 This finding is reflected in the American Society of Clinical Oncology clinical practice guidelines and is the only treatment with sufficient evidence to recommend its use. Tricyclic antidepressants, gabapentin and topical gels (composed of baclofen, amitriptyline, and ketamine) are also used based on their efficacy in other neuropathic pain syndromes.4

This study will focus on the effects of CIPN preventive and therapeutic drugs that are frequently used in real-world clinical practice, namely, vitamin B12, goshajinkigan, carbamazepine, oxcarbazepine, pregabalin, mirogabalin, gabapentin, amitriptyline, duloxetine, venlafaxine, NSAIDs, ketamine, oxycodone and calcium and magnesium.

How these drugs work

Mecobalamin is an endogenous vitamin B12 that has a high affinity for nervous tissues and can regulate the metabolism of various substances by stimulating the synthesis of lecithin and acetylcholine. Mecobalamin is commonly used to treat neurological disorders.18

Goshajinkigan is a Japanese herbal medicine (Kampo) that contains 10 crude drug extracts (achyranthes root, rehmannia root, dioscorea, rhizome, cornus fruit, alisma rhizome plant seed, moutan bark, pariah sclerotium, aconite root and cinnamon bark). It is widely used in the treatment of taxane neuropathy and diabetic neuropathy because it affects the sensory nerves.19 20 Additionally, it ameliorates allodynia in a mouse model of injury by suppressing the expression of activated microglia-derived tumour necrosis factor-α.21

Gabapentin, pregabalin and mirogabalin are anticonvulsants that exhibit antinociceptive effects by blocking the voltage-dependent calcium channels at the presynaptic terminals and downregulating excitatory neurotransmitters.22–26 Milogabalin is effective in patients with diabetic peripheral neuropathy and CIPN.27 28 Carbamazepine is a sodium channel blocker and may have neuroprotective effects in patients receiving oxaliplatin.29 Oxcarbazepine acts on the sodium and calcium channels and may be more effective against oxaliplatin-induced nerve damage.

Amitriptyline is a tricyclic antidepressant that inhibits the reuptake of serotonin and norepinephrine.30 Additionally, repeated administration of amitriptyline reduced the incidence of mechanical allodynia in rats treated with oxaliplatin.31 Venlafaxine and duloxetine are serotonin-norepinephrine reuptake inhibitors that act on serotonergic and noradrenergic neurons, but have little or no effect on cholinergic or histaminergic receptors.32 Venlafaxine, a more potent inhibitor of serotonin at low doses and norepinephrine at higher doses, has been used as a preventive therapy treatment against CIPN.23 Unlike venlafaxine, duloxetine is a balanced inhibitor of serotonin and norepinephrine reuptake, and has been applied clinically to treat rather than prevent CIPN.33

Infusion of calcium and magnesium is one of the most promising strategies for CIPN prevention. The increase in extracellular calcium concentration through the intravenous delivery of calcium and magnesium promotes the blockage of sodium channels.34 35

NSAIDs are not effective in the treatment of neuropathic pain. They may be used as adjunctive agents for the treatment of nociceptive pain that may develop alongside neuropathic pain.

Opioids are effective in treating somatic pain but are not recommended for long-term treatment of neuropathic pain and are used as a second-line treatment.

Why is this review important?

CIPN is one of the most frequent dose-limiting side effects of chemotherapy.2 4 Although numerous clinical trials have been conducted to prevent or treat CIPN using various targeted drugs, previous systematic reviews with direct comparisons have failed to demonstrate the efficacy of drug therapy in the prevention or treatment of CIPN.36–38 No systematic reviews of CIPN have indirectly compared the available pharmacological options for its prevention and treatment. In addition, the comparative efficacy and safety of drug therapy for the prevention and treatment of CIPN remain uncertain. Hence, our network meta-analysis (NMA) will provide new relevant insights regarding the prevention and treatment of CIPN. In addition, the appropriate management of CIPN involves the maintenance of patient’s QoL and leads to adequate cancer treatment. Therefore, it is important to systematically assess the comparative efficacy and safety of drugs for the prevention or treatment of CIPN.

Objectives

This systematic review and NMA will examine the efficacy and safety of drug therapy for the prevention and treatment of CIPN.

Methods and analysis

Methods

This protocol is compliant with the standards of the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement39 and is registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (first version: 11 November 2022). The completed systematic review will be presented according to the PRISMA extension for NMA extension statement to structure the contents of the final report.40 This study will commence in August 2023 and will end in April 2024.

Criteria for considering the studies for this review

Types of studies

RCTs (placebo-controlled or head-to-head trials) will be included. Non-randomised studies, cluster RCTs, quasi-RCTs, in vitro studies, animal studies, extended abstracts and observational studies will be excluded. RCTs based on individual randomisations are usually performed to assess the comparative effectiveness of these pharmacological treatments, and cluster-based randomisations are not adopted in general.

Types of participants

We will include adults (aged≥18 years) diagnosed with cancer, who are currently undergoing or have previously undergone chemotherapy, and are at risk of CIPN. CIPN will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) V.5.0.41

Types of interventions

We will include studies investigating the efficacy and safety of the following comparator medications: vitamin B12, goshajinkigan, NSAIDs, opioids (ie, ketamine and oxycodone), calcium and magnesium, antidepressants (ie, amitriptyline, duloxetine and venlafaxine) and anticonvulsants (ie, carbamazepine, oxcarbazepine, pregabalin, mirogabalin and gabapentin) for CIPN.

We will include a control group comprising of patients receiving placebo and an intervention group comprising of patients receiving the drugs listed as comparator medications.

Types of outcome measures

We will create a table containing the summary of findings on the primary and secondary outcomes.

Primary outcome

We will examine the incidence rates and severity of CIPN. These will be evaluated using the CTCAE V.5.0 neuropathy sensory subscale and neurotoxicity criteria of Debiopharm (DEB-NTC).42 The severity of CIPN according to the CTCAE V.5.0 neuropathic sensory subscale is as follows: grade 0 (no symptoms), grade 1 (mild sensory symptoms, not interfering with daily function), grade 2 (moderate sensory symptoms, limiting daily function), grade 3 (severe sensory symptoms, limiting daily function and self-care) and grade 4 (life threatening).41 The severity of CIPN according to the DEB-NTC is as follows: grade 0 (no symptoms), grade 1 (transient dysesthesia and/or paresthesia lasting less than 7 days), grade 2 (transient dysesthesia and/or paresthesia lasting for 7 days or longer) and grade 3 (proprioceptor impairment inducing functional discomfort in everyday life).43 The incidence of CIPN is calculated using the diagnostic criteria for CIPN as defined in the individual RCTs.

Secondary outcome

We will also examine the following outcomes at the same measurement time as the primary outcomes:

Efficacy outcomes

  • The time until onset (days) of CIPN.

  • Percentage of patients who experienced reduction in the severity of pain.

  • Subjective degree of CIPN.

  • Rate of chemotherapy treatment discontinuation.

  • Changes in the severity of CIPN

  • QoL. QoL are assessed using the European Organization for Research and Treatment of Cancer QoL Questionnaire (EORTC QLQ)-C3044 and EORTC QLQ-CIPN20.45

  • Rate of response to chemotherapy. Treatment efficacy is evaluated according to the Response Evaluation Criteria in Solid Tumours V.1.1.46

Safety outcome

  • Risk of adverse events (ie, nausea, vomiting, somnolence, constipation, dizziness, dry mouth and headache) from the intervention. The adverse events are evaluated using the CTCAE V.5.0.41

For the outcome measures, we will use risk ratios (RRs) for incidence rates and severity of CIPN, percentage of patients who experienced reduction in the severity of pain, rate of chemotherapy treatment discontinuation, rate of response to chemotherapy, changes in the severity of CIPN and risk of adverse events. Also, we will use a mean difference (MD) for time until onset (days) of CIPN, and will use standardised mean differences (SMDs) for the subjective degree of CIPN and QoL.

Search methods for identification of studies

To identify the studies for inclusion in this review, the MEDLINE, PubMed, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov databases will be searched to find relevant articles published from inception through July 2023. A search strategy was developed based on the advice of a librarian with experience in systematic reviews. The key search terms (Medical Subject Headings and keywords) used included CIPN, vitamin B12, goshajinkigan, NSAIDs, opioids (ie, ketamine and oxycodone), calcium and magnesium, antidepressants (ie, amitriptyline, duloxetine and venlafaxine) and anticonvulsants (ie, carbamazepine, oxcarbazepine, pregabalin, mirogabalin and gabapentin). This search will be conducted electronically (online supplemental additional file 1).

Data collection

Selection of studies

EndNote software (EndNoteX9; Thomson Reuters) will be used to collect citations and remove duplicate articles. Two authors (MTS and HS) will individually screen all reports retrieved through electronic and manual searches stored in the software programme. The titles and abstracts (if available) of all reports retrieved by electronic and manual searches stored in the software programme will be individually screened. Studies that do not meet the selection criteria will be discarded and the reasons for exclusion will be noted in a table. After the initial phase, the authors (MTS and HS) will individually review the full text of the remaining studies to determine whether they should be included or excluded in the final analysis. Any disagreements will be resolved through discussion and referral to a third-party author (TH). The PRISMA flowchart illustrates the study selection process.

Data extraction and management

Two authors (MTS and HS) will independently extract the studies that meet the following criteria: study design, author name, follow-up period, number of comparison groups, number of sites, total number of patients, country of recruitment and treatment, year of publication, sample characteristics (population, size, ethnicity, sex, age, type of chemotherapy, diagnostic criteria of both cancer and CIPN and inclusion and exclusion criteria), interventions and control details (type of drug used in the interventions, type of drug used in the control, dose and duration of treatment), clinical data before and after the intervention and patient-centred outcomes before and after the intervention. Any disagreement will be discussed and referred to the third author (TH), if necessary.

Assessment of risk of bias in included studies

The risk of bias evaluation of all included studies will be performed by two authors (MTS and HS) individually using the Cochrane risk-of-bias tool V.2.047 as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions V.6.3.48 The third author will resolve the disparity between the primary reviewers. The difference in the assessment of the risk of bias will be resolved by a fourth reviewer. We will assess the following domains of the risk of bias: (1) randomisation process, (2) deviations from the intended interventions, (3) missing outcome data, (4) measurement of the outcome, (5) selection of the reported result, and (6) overall bias.

Strategy for data synthesis

We will conduct a pairwise meta-analyses of all direct comparisons using the DerSimonian-Laird-type random-effects model. To assess the statistical heterogeneity of the treatment effects, we will use the heterogeneity variance τ2, Cochran’s Q test and I²-statistic. The 95% CIs of the I²-statistic will be calculated using the non-central χ²-based approach. We will assess the presence of statistical heterogeneity by visually inspecting forest plots for pairwise meta-analyses and calculating the I² statistic. We will regard heterogeneity as substantial if an I² was greater than 50%. Also, we will quantitatively interpret the size of τ2 estimate and its significance by the Cochran’s Q test. To assess publication bias, we will present the results of comparison-adjusted funnel plots when a meta-analysis is performed on enough studies (10 or more). We will assess for publication biases in funnel plots using Egger’s test. The comparative effectiveness will be evaluated using a frequentist NMA by combining direct and indirect evidence on the network of evidence. First, we will summarise the geometry of the evidence network using a network plot. Second, synthesis analyses will be conducted using the contrast-based, random-effects NMA model to assess the comparative efficacy and safety. Finally, a surface under the cumulative ranking curve will be generated to assess the treatment ranking. Validities of the consistency assumptions on the networks will be evaluated by the local and global inconsistency tests. All statistical analyses will be conducted using the Stata software (V.17.0; Stata Corporation, College Station, Texas, USA).

Measurement of treatment effect

We will calculate the RR and corresponding 95% CIs for dichotomous outcomes using a random-effects model. Moreover, we will estimate the MD and its corresponding 95% CI for continuous outcomes measured using the same units, and the SMD and its corresponding 95% CI for continuous outcomes, where different scales will be used to evaluate the same outcome.

Dealing with missing data

We will not request for missing participant outcome data from trial researchers to reduce the workload and to ensure the completion of the review within a reasonable time frame.

Analyses of the efficacy outcomes will be carried out on an intention-to-treat basis.

Subgroup analysis

We will conduct a subgroup analysis of the different chemotherapy regimens, intervention drugs, type of drug therapy (treatment or prevention), and type of cancer.

Sensitivity analysis

We will perform a sensitivity analysis to evaluate the risk of primary outcomes, excluding studies with a high risk of bias (allocation concealment and incomplete outcome data).

Summary of findings and assessment of the certainty of evidence

A table containing the summary of findings for the primary and secondary outcomes will be created following the procedures described in the Cochrane Handbook for Systematic Reviews of Interventions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to assess the quality of evidence for the following outcomes: incidence rates and severity of CIPN, percentage of patients who experienced reduction in the severity of pain, changes in the severity of CIPN, risk of adverse events, time until onset (days) of CIPN and QoL. GRADE assesses the risk of bias, directness of evidence, consistency and precision of the results and publication bias. The level of evidence can be lowered by one level from ‘high quality’ in the presence of serious limitations (or by two levels for very serious limitations). These assessments take into account factors like risk of bias, indirectness of evidence, serious inconsistency, imprecision of effect estimates, or potential publication bias.

Patient and public involvement

The protocol for this systematic review as well as the design, implementation, reporting or dissemination of the study will not involve patients or the general public.

Ethics and dissemination

The protocol for this systematic review will be published in peer-reviewed journals and presented at relevant national and international meetings. Formal ethical approval is not required, as the researcher will not identify individuals in the article. The efficacy and safety of pharmacotherapy for the prevention and treatment of CIPN analysed in this review provide evidence that can be used as a reference for the prevention and treatment of patients with CIPN. The results of the final analysis will be published and subsequently disseminated at the university and on various social media platforms. The results will also be presented at a conference, and the research findings will be submitted to a peer-reviewed journal.

Ethics statements

Patient consent for publication

References

Supplementary materials

  • Supplementary Data

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Footnotes

  • Contributors Conception: MTS. Design of the study: MTS, TH, HN, HS and EO. Statistical analysis: HN. Construction of the search strategy: MTS. Drafting of the manuscript: MTS and TH. Interpretation of data: MTS, TH, HN, HS and EO. Selection of studies, extraction of data from the included studies, assessment of risk of bias and summary of evidence: MTS, TH and HS. All authors have approved the publication of this protocol.

  • Funding This work was supported by JSPS KAKENHI (Grant Number 19K03092) from the Japan Society for the Promotion of Science.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.