Abstract
Background
Oxaliplatin, a key drug in the treatment of colorectal cancer (CRC), can cause oxaliplatin-induced peripheral neuropathy (OIPN) in a dose-dependent manner. These symptoms can severely affect daily life, and chronic OIPN often limits treatment continuation because of its correlation with the cumulative dose of oxaliplatin. Currently, effective preventive measures are unavailable. However, surgical glove compression therapy may reduce paclitaxel-induced neuropathy, suggesting its potential in preventing OIPN.
Methods
This multicentre, randomised, open-label, phase II/III trial evaluates surgical glove compression therapy to investigate the possible preventive effects of OIPN in patients with CRC receiving adjuvant capecitabine plus oxaliplatin chemotherapy. Patients with stage III CRC undergoing curative surgery will be enrolled and randomised into two groups. The intervention group will wear two layers of tight-fitting surgical gloves from 30 min before to 30 min after oxaliplatin infusion, whereas the control group will receive standard care. The primary endpoint is the incidence of grade ≥2 chemotherapy-induced peripheral neuropathy (CIPN) based on the Common Terminology Criteria for Adverse Events criteria. Secondary endpoints include quality of life assessments (Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item), duration and extent of OIPN as assessed using the Debiopharm Neurologic and Sensory Toxicity Criteria, chemotherapy completion rates, and adverse events. To detect a significant reduction in the incidence of CIPN, 170 patients will be enrolled (36% in the control group vs 15% in the intervention group). The planned case enrolment period is from 1 November 2024 to 31 October 2026.
Ethics and dissemination
This trial was approved by the Institutional Review Board of Hiroshima University, Japan (approval no. CRB2024-0008), and has been registered with the Japan Registry of Clinical Trials (jRCTs062240066). The results of this study will be submitted for publication in a peer-reviewed journal and shared with the scientific community at international conferences.
Trial registration number
jRCTs062240066
Keywords: CHEMOTHERAPY, Gastrointestinal tumours, Colorectal surgery
STRENGTHS AND LIMITATIONS OF THIS STUDY.
Large-scale, multicentre, randomised controlled trial designed to evaluate the efficacy of a promising preventive method for oxaliplatin-induced peripheral neuropathy.
This study monitors patients throughout adjuvant capecitabine plus oxaliplatin therapy and beyond, enabling assessment of cumulative neuropathy and the coasting phenomenon, which were not adequately evaluated in prior studies.
The trial combines clinician-based Common Terminology Criteria for Adverse Events grading with patient-reported outcomes (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item), allowing a holistic evaluation of neuropathy and its impact on quality of life.
Because the intervention requires patients to wear tight-fitting gloves, true blinding is impossible, which may introduce reporting bias in subjective outcome measures.
This study did not evaluate neurophysiological tests, quantitative sensory tests or physiological parameters such as reduced blood flow and local drug distribution; thus, the underlying biological mechanisms of compression therapy remain unexplained.
Background
Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related deaths worldwide. The treatment options for CRC include endoscopic therapy, surgery, chemotherapy and radiation therapy, depending on the stage and progression of the disease. Postoperative adjuvant chemotherapy is a systemic chemotherapy administered for a limited period after surgery to control recurrence and improve prognosis.1,4 It is recommended in patients with stage III node-positive CRC who have undergone curative resection. Oxaliplatin, a key drug used in the treatment of CRC, is typically combined with 5-fluorouracil/leucovorin or capecitabine. However, oxaliplatin causes oxaliplatin-induced peripheral neuropathy (OIPN) in a dose-dependent manner.5 Acute OIPN symptoms, such as cold dysesthesia and muscle cramps, are transient and usually resolve within a few days; however, chronic OIPN is a significant condition characterised by sensory and motor neuropathy, including symptoms such as numbness, dysesthesia and dysalgesia. These symptoms can severely affect daily life, and chronic OIPN often limits treatment continuation because of its correlation with the cumulative dose of oxaliplatin.6 Overcoming OIPN remains a critical issue for patients undergoing oxaliplatin-based chemotherapy.7
Currently, there are no effective drugs or medical devices with solid evidence for preventing OIPN.8 9 Although vitamin B12, calcium-magnesium preparations, carbamazepine, gabapentin, pregabalin and certain Chinese herbal medicines (eg, goshajinkigan) are empirically used for OIPN prevention, evidence supporting their efficacy is insufficient. Chronic OIPN, once developed, can be irreversible, making preventive strategies crucial along with postonset symptomatic treatment and neuropathy management.
Paclitaxel, another anticancer drug, induces peripheral neuropathy similar to that caused by oxaliplatin. Recent studies have reported that peripheral circulation suppression therapy using surgical gloves effectively prevents paclitaxel-induced peripheral neuropathy. In cases where nab-paclitaxel (albumin-bound paclitaxel) is administered, the frequency of grade 2 or higher peripheral neuropathy, according to the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0, is significantly reduced when surgical gloves are worn.10 11 Kotani et al conducted a double-blind trial using differently sized gloves in paclitaxel-treated patients, reporting no preventive effect.12 However, because participants could readily distinguish between normal and tight-fitting gloves, the integrity of blinding was questionable, and subjective reporting bias could not be excluded. More recently, Zhang et al recently reported positive results in oxaliplatin-treated patients using compression sleeves and stockings.13 Their randomised trial showed reduced neuropathy incidence after four cycles, but limitations included a single-centre design, small sample size (n=60), and absence of long-term follow-up without assessment of incidence of chronic OIPN. Surgical gloves are inexpensive, technically simple to use, and if proven to be effective in preventing OIPN, offer excellent cost-effectiveness, making them a highly promising preventive strategy.
Based on this background, we designed a multicentre randomised controlled trial to evaluate the possible preventive effect of surgical glove compression therapy on the onset of OIPN in CRC patients receiving adjuvant chemotherapy.
Methods
Design
This study is a multicentre, randomised, open-label, phase II/III controlled trial comparing surgical glove compression therapy with standard therapy for the prevention of OIPN. This study will be conducted at 16 institutions affiliated with the Hiroshima Surgical Study Group of Clinical Oncology (Hiroshima, Japan). The planned case enrolment period is from 1 November 2024 to 31 October 2026.
The patient selection criteria are as follows: (1) histologically diagnosed stage III colorectal adenocarcinoma undergoing curative surgery with lymph node dissection; (2) scheduled to receive eight cycles of capecitabine plus oxaliplatin (CAPOX) therapy as adjuvant chemotherapy within 8 weeks after surgery; (3) age 18 years or older with Eastern Cooperative Oncology Group performance status 0 or 1 and (4) provided written informed consent. The exclusion criteria are as follows: (1) severe peripheral or central neuropathy with functional impairment; (2) medications that may affect peripheral neuropathy; (3) history of hypersensitivity to oxaliplatin or similar agents; (4) presence of severe psychiatric disorders; (5) history of systemic chemotherapy or radiation therapy for antitumour effects; (6) history of active synchronous or metachronous malignancies; (7) unrecovered postoperative complications; (8) presence of severe gastrointestinal or systemic symptoms; (9) hepatitis B with a positive hepatitis B surface antigen; (10) positive for HIV antigen or antibodies; (11) patients who are pregnant or may be pregnant, patients who do not intend to use contraception during the trial period and patients who are breastfeeding; (12) blood tests within 14 days prior to enrolment that demonstrate leucocyte counts of <3–12×10⁹/L, neutrophil counts of <1.0×10⁹/L), platelet counts of <1000×10⁹/L, haemoglobin levels of <9.0 g/dL, serum aspartate aminotransferase concentration of >100 U/L or serum creatinine concentrations of >1.5 mg/dL; (13) patients with a hand size requiring a surgical glove size ≥5 (smallest available glove size in the study) and (14) other conditions deemed inappropriate by the investigators.
Randomisation
Patients who provide consent for the study will be enrolled using the electronic data capture system, randomised and assigned to either the control or experimental group. The stratification factors for randomisation include institution (expected enrolment of more than eight cases vs less than eight cases), gender and age (≥65 or <60). Enrolled patients will receive the scheduled chemotherapy within 2 weeks of study enrolment.
Intervention
The intervention group will wear two layers of tight-fitting surgical gloves (one size smaller than the standard fit) from 30 min before until 30 min after the chemotherapy infusion. The gloves will be provided by an approved manufacturer (Emblem latex-free surgical gloves; Sanko Chemical Industry Co.). The control group will receive the standard treatment without compression gloves. Glove selection was standardised using a predefined size chart based on palm circumference. Research staff at each participating site received standardised training on glove fitting and application to minimise interindividual and interfacility variability in compression.
Chemotherapy
The patients will receive 6 months of CAPOX therapy as adjuvant chemotherapy. Treatment with CAPOX includes a 2-hour intravenous infusion of 130 mg/m2 oxaliplatin on day 1 and oral capecitabine (2000 or 1500 mg/m2/day) from the evening of day 1 to the morning of day 15. The starting dose of capecitabine is dependent on the creatinine clearance value (CCr) at the time of enrolment and age, as follows: 2000 mg/m2/day (1000 mg/m2/time) for 50 mL/min≥CCr; 1500 mg/m2/day (750 mg/m2/time) for 30 mL/min≤CCr <50 mL/min or ≥70 years old. One course is for 3 weeks (21 days), and up to eight courses will be administered unless the criteria for discontinuation of the protocol treatment are met. The dosing, withdrawal, dose reduction and discontinuation criteria are the same as those used in previous clinical trials in Japan.14
From consent acquisition until the end of adjuvant chemotherapy, calcium gluconate, magnesium sulphate, glutathione, l-glutamine, vitamin preparations, Goshajinkigan, Shakuyakukanzoto, opioid receptor agonists, pregabalin, gabapentin, mirtazapine, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and other medications that could potentially affect peripheral neuropathy.
Outcomes
The primary outcome is the incidence of chemotherapy-induced peripheral neuropathy (CIPN) (CTCAE grade≥2) of the hand. Secondary outcomes are as follows: (1) quality of life, as assessed using the Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12 (FACT/GOG-Ntx-12) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item (EORTC QLQ-CIPN20); (2) duration and extent of OIPN as assessed using the Debiopharm Neurologic and Sensory Toxicity Criteria (DEB-NTC); (3) completion rate and relative dose intensity of CAPOX therapy; (4) number of courses with oxaliplatin; (5) adverse events (AEs) other than peripheral neuropathy; (6) surgical glove safety and (7) number of treatment courses to the development of peripheral sensory neuropathy, incidence rate, oxaliplatin dose intensity at the time of development and anatomical site of initial symptoms. Safety assessments collected information on AEs such as blood flow impairment, pain and allergic skin reactions occurring during or after glove application, based on CTCAE V.5.0. These surveys will collect data before each course of treatment, after the final course of treatment, and at 6 months and 1 year post-treatment.
Sample size calculation
In a large Japanese trial of postoperative adjuvant chemotherapy (CAPOX therapy), the incidence of chronic OIPN with CTCAE grade 2 or higher was approximately 36%.14 On the basis of previous studies, the incidence of CIPN is estimated to be 36% and 15% in the control and intervention groups, respectively. To achieve 80% detection power at the 5% significance level, 170 participants (85 per group) are required to account for a 10% dropout rate. The main study scheme is shown in figure 1.
Figure 1. Study scheme. CAPOX, capecitabine plus oxaliplatin; CIPN, chemotherapy-induced peripheral neuropathy; CTCAE, Common Terminology Criteria for Adverse Events; DEB-NTC, Debiopharm Neurologic and Sensory Toxicity Criteria; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-CIPN20, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy 20-item; FACT/GOG-Ntx-12, Functional Assessment of Cancer Therapy/Gynecological Oncology Group-Neurotoxicity-12; QOL, quality of life.
Data monitoring and safety assessments
The principal investigator will prepare a case report form promptly after collecting the evaluation data and AEs. The implementation status will be regularly reported to the Ethical Committee for Clinical Research of Hiroshima University every year from the day the implementation plan is published in the Japan Registry of Clinical Trials (jRCT). No interim analysis will be conducted. The principal investigator will discontinue or suspend clinical research on the participant in the following cases: (1) when the research participant withdraws consent to participate in the research; (2) when it turns out that the eligibility (inclusion criteria/exclusion criteria) is not met after registration; (3) if the continuation of the study is judged unfavourable due to deterioration of the primary disease; (4) when it is difficult to continue the study due to exacerbation of complications; (5) when it is difficult to continue the study due to AEs or (6) when the principal investigator determines that it is appropriate to discontinue the research. This clinical trial will be terminated when the following occur: (1) when critical information regarding the quality, safety or efficacy of research equipment is obtained; (2) when it is judged difficult to achieve the planned number of cases within the study period; (3) when information that undermines the ethical validity or scientific rationality of the research is obtained and (4) based on the aforementioned events, if the review committee recommends or instructs to discontinue.
Statistical analysis plan
The primary analysis population for evaluating efficacy will be the Full Analysis Set, while the Per Protocol Set will be used as a secondary analysis population when necessary to confirm the stability of the analysis results.
For the primary outcome, the incidence rate of CIPN of CTCAE grade 2 or higher will be calculated for each group. This calculation will be based on the number of cases in which CTCAE grade 2 or higher CIPN was observed during the period from the first oxaliplatin administration to the scheduled end date of the observation period for the last enrolled study subject. The point estimate and the 95% CI of the incidence rate will be calculated using the number of analysed cases as the denominator. The onset of CIPN will be counted per subject (minimum 0, maximum 1 per subject). Additionally, differences in incidence rates will be examined using Fisher’s exact test.
For the FACT/GOG-NTX-12 score, an analysis will be performed using a mixed-effects model for repeated measures (MMRM), with treatment group, time point, baseline and the interaction between treatment group and time point as fixed effects. The difference between groups in the score will be examined using a t-test.
For the EORTC QLQ-CIPN20 score, an analysis will also be conducted using MMRM, with treatment group, time point, baseline and the interaction between treatment group and time point as fixed effects. The difference between groups in the score will be examined using a t-test.
For the DEB-NTC analysis, the number of cases for each grade will be summarised for each evaluation time point and for each experimental/control group. The differences in grades between groups will be examined using a t-test.
For other outcomes, comparisons between the control group and the experimental treatment group will be conducted using either Fisher’s exact test or a t-test. In all analyses, statistical significance was set at a p value <0.05. All statistical analyses were performed using JMP Pro 18 software package (SAS Institute Inc., Cary, NC, USA).
Patient and public involvement
The patients and/or the public were not involved in the design, conduct, reporting or dissemination of this research.
Ethics and dissemination
This clinical trial will be performed in accordance with the principles of the Declaration of Helsinki. Written informed consent will be obtained from all patients before their inclusion in the study (online supplemental file 1). The protocol was approved by the Ethical Committee for Clinical Research of Hiroshima University, Japan (CRB: 2024–0008), and has been prospectively registered in the jRCT (jRCTs062240066). A primary endpoint report will be provided to the competent authorities and the Ethical Committee for Clinical Research of Hiroshima University within 1 year after the completion of the study. Trial results will be presented at an academic conference or published in a peer-reviewed journal. The datasets used in this study will be available from the corresponding author on reasonable request.
Discussion
This study aims to evaluate the efficacy of finger compression therapy for preventing CIPN, an issue unresolved by previous research, through a large-scale, multicentre randomised control trial (RCT). Its novelty lies in evaluating the preventive effect against chronic OPIN, a major challenge in OIPN and assessing long-term efficacy. If successful, this trial will provide a simple and cost-effective supportive care strategy to improve patients’ quality of life and ensure optimal chemotherapy dosing. However, being an open-label study means the influence of bias cannot be excluded, and it cannot verify the physiological mechanism of its preventive effect. Nevertheless, since compression therapy is a treatment intervention recognisable to the subject, achieving complete blinding is impossible, making it unfeasible to plan a double-blind RCT.
CIPN arises through mechanisms that vary, depending on the type of chemotherapeutic agent.8 Chemotherapeutic agents can damage various components of nerve cells following their metabolism in the body. Paclitaxel, for which compression therapy using surgical gloves has shown a preventative effect, can cause mitochondrial dysfunction in nerve cells, perineuronal inflammation, increased sodium channel expression leading to nerve hyperexcitability, direct neuronal apoptosis and reduced blood flow to the peripheral nerves.15 16
In contrast, the pathogenesis of OIPN involves a complex interplay of mechanisms.5 Acute OIPN is primarily linked to increased sensory nerve excitability due to rapid calcium chelation and alterations in the voltage-gated sodium channels.17 The severity of acute OIPN is associated with the subsequent development of chronic OIPN,18 which results from nuclear DNA damage in dorsal root ganglion cells, mitochondrial dysfunction,5 oxidative stress19 and neuroinflammation caused by glial cell activation.20 At the peripheral nerve level, damage to sensory nerve fibres due to axonal transport defects, progressive axonal degeneration, ion channel hyperactivity and neurovascular barrier disruption has also been implicated in chronic OIPN.21 22 Surgical glove compression therapy during oxaliplatin administration may reduce neuronal exposure to oxaliplatin at the peripheral nerve level, potentially preventing or mitigating acute and chronic OIPN by decreasing ion channel hyperactivity and minimising damage to sensory nerve fibres. However, this method is unlikely to prevent neuropathy at the dorsal root ganglion cell level, highlighting a limitation in its ability to fully counteract OIPN.
The surgical gloves used in this study are class II medical devices (Medical Device Certificate No. 221ADBZX00109000) that are widely used in clinical settings for infection prevention. These gloves are available in various sizes to accommodate different hand dimensions. In this study, surgical gloves are worn in a double-layer configuration to provide compression therapy. This approach represents an off-label use of these medical devices, as no prior studies or clinical experiences have evaluated their use for the prevention of chronic OIPN. OIPN also affects the feet, and surgical glove compression therapy is not expected to address peripheral neuropathy in this area. If the results of this study confirm the efficacy of compression therapy of the hands, similar approaches using compression stockings for the feet should be explored in future studies.
The primary endpoint of this study is assessed using the National Cancer Institute CTCAE (NCI-CTCAE).23 This tool enables clinicians to evaluate the severity of neuropathy by determining the extent to which patients experience limitations in daily activities, with the severity classified into grades. Peripheral neuropathy of moderate or higher severity (grade 2 or above in the NCI-CTCAE V.5.0) necessitates consideration of treatment modifications, such as extending the drug withdrawal period or discontinuing oxaliplatin. In this study, the onset of peripheral neuropathy is defined as the occurrence of grade 2 or higher neuropathy in the fingers, regardless of whether one or both hands are affected.
Secondary endpoints include the FACT/GOG-Ntx-1224 and EORTC QLQ-CIPN20 quality of life assessment scales,25 which evaluate CIPN-related patient-reported outcomes. Patients complete these scales and reflect their subjective experiences, complementing the clinician-assessed NCI-CTCAE. These scales were selected as key evaluation metrics because the prevention of OIPN aims to preserve both quality of life and uninterrupted chemotherapy. The DEB-NTC will be used to evaluate the persistence of OIPN symptoms. The DEB-NTC categorises the symptoms severity based on symptom durations of either less than or more than 7 days.26
Previous studies investigating surgical glove compression therapy for paclitaxel-induced neuropathy in patients with breast cancer have demonstrated its safety,10 11 suggesting a minimal risk associated with hand compression. However, given the different chemotherapeutic agents used in this study, a safety evaluation is included as an endpoint.
Preventing chronic OIPN has the potential to enhance patients’ quality of life and enable the continuation and completion of chemotherapy while maintaining the dose intensity. If this study verifies the preventive effect of compression therapy on OIPN, it could be applied to future research on the molecular mechanisms underlying compression therapy’s protective effects, including physiological and quantitative testing, potentially leading to expanded indications for other chemotherapeutic agents.
Supplementary material
Acknowledgements
We acknowledge the Clinical Research Center in Hiroshima (Hiroshima, Japan) for their assistance in developing the study protocol. We would also like to thank Editage (www.editage.com) for English language editing.
Footnotes
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-110878).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
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.
Collaborators: Members of the Hiroshima Surgical Group of Clinical Oncology (HiSCO): Yosuke Shimizu, Hironori Kobayashi, Masahiko Fujimori, Masahiro Nakahara, Masakazu Tokunaga, Masatoshi Kochi, Manabu Kurayoshi, Yuji Takakura, Yuzo Hirata, Tomohiro Adachi, Masanori Yoshimitsu, Tetsuhiro Hara, Shoichiro Mukai, Hisaaki Yoshinaka, Mohei Koyama, Haruki Sada, Masashi Miguchi, Masami Yamauchi, Daisuke Sumitani, Kosuke Ono, Keiso Matsubara, Shinnosuke Uegami, Kensuke Shinbara, Yasufumi Saitoh, Naoki Murao, Satoshi Ikeda, Ikki Nakashima, Kazuhiro Toyota, Wataru Shimizu, Hiroyuki Sawada, Hiroshi Okuda, Kazuhiro Taguchi, Toshiyuki Moriuchi, Shohei Shiozaki, Manabu Shimomura, Koki Imaoka, Saki Satoh, Mizuki Yamaguchi, Kazuki Matsubara, Takuya Yano, Atsuhiro Watanabe, Tomoaki Bekki, Masahiro Ohira, Tsuyoshi Kobayashi and Hideki Ohdan.
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