Introduction
Background
Over 60% of people with bowel cancer suffer from chronic chemotherapy-induced peripheral neuropathy (CIPN), even 2 years after completion or discontinuation of cancer treatment [ 1 ]. The high prevalence of debilitating CIPN-associated symptoms, including pain and dysaesthesia, arises from heavy reliance on the platinum-containing anticancer agent oxaliplatin. Oxaliplatin is placed in the World Health Organisation’s List of Essential Medicines as the first-line and adjuvant therapy for management of colorectal cancer [ 2 ]. Its mechanism of action is through DNA binding to form toxic DNA-platinum adducts, which inhibit cancer cell proliferation and induce apoptosis [ 3 ]. However, effectiveness of oxaliplatin for cancer comes at a cost, with severe neurotoxicity in the peripheral nervous system commonly induced. Oxaliplatin can be readily taken up intracellularly through transporters of sensory neurons within the dorsal root ganglia, and transformed into its metabolite oxalate which is a potent calcium ion chelator [ 4 ]. Oxalate-mediated loss of calcium homeostasis alters cation conductance (e.g., sodium), contributing to neuronal depolarisation, nociceptive hypersensitivity, and excitotoxicity [ 4 – 6 ]. Notably, CIPN is regarded as the most common dose-limiting factor for oxaliplatin [ 7 ], often resulting in dose reduction or premature discontinuation, which may increase the risk of cancer recurrence and metastasis [ 8 , 9 ]. Cumulative sensory nerve damage may be irreversible [ 1 ], with painful oxaliplatin-induced symptoms persisting even after cessation of oxaliplatin administration, potentially progressing to chronic CIPN [ 1 , 4 ].
Chronic oxaliplatin-induced CIPN poses substantial negative impacts on bowel cancer patients’ functionality and quality of life [ 10 ]. Symptoms such as pain and numbness in distal extremities alter proprioception, leading to reduced mobility and increased risk of falls, which is particularly burdensome for daily living [ 6 , 10 , 11 ]. Cancer survivors with CIPN are also more likely to experience depression and anxiety [ 6 , 12 , 13 ]. Decreased physical activity, combined with chronic psychological distress, exacerbates pain perception and further worsens individuals’ quality of life [ 14 ]. CIPN is often refractory to conventional pharmacological interventions, with no established treatment protocol to effectively manage painful CIPN [ 6 ]. Currently, the only medication suggested for use is duloxetine [ 15 , 16 ], but evidence from a systematic review and meta-analysis published in 2023 showed limited efficacy of duloxetine for alleviating CIPN-associated neuropathic pain, whilst also contributing to a potential increase in the likelihood of adverse events (AEs), such as fatigue and nausea [ 17 , 18 ]. Given the detrimental impacts of chemotherapy-induced pain and the inadequacies in current treatment options, further research into effective management strategies is warranted.
Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that can modulate neuronal discharge and induce neuroplasticity to alter pain perception at a cortical level. TMS involves positioning encapsulated coil windings which generate electromagnetic fields on relevant regions of the cerebral cortex [ 19 ]. Repetitive electrical pulses activate the descending nociceptive modulation pathway originating from the thalamus, thus increasing neurotransmitter release downstream at opioidergic synapses to inhibit pain transmission [ 19 – 21 ]. Extensive research supports rTMS efficacy for neuropathic pain [ 19 , 21 ], with emerging evidence demonstrating its analgesic potential to mitigate chemotherapy-induced pain in cancers, such as multiple myeloma and breast/gynaecological cancers [ 22 , 23 ]. However, long-term benefits of rTMS remain poorly understood [ 21 ], and no study yet has been conducted to examine its effects specifically on bowel cancer survivors. Therefore, this study will investigate both the short-term and the long-term effects (i.e., at 8 weeks and 6 months after completion of all treatment sessions) of rTMS for CIPN-associated neuropathic pain in bowel cancer patients. Further, current understanding of the true analgesic effects of rTMS is limited, as most trials target the primary motor cortex (M1), while other pain-associated sites remain underexplored [ 21 , 24 ]. Therefore, more research is needed to form robust conclusions on the effects of rTMS application on somatosensory cortices [ 25 ]. In the current study, we will apply rTMS on regions within the primary somatosensory cortex (S1), where the majority of the nociceptive fibres ascending from the thalamus terminate for pain awareness and localisation.
Objectives
Our primary aim was to evaluate the effectiveness of rTMS for mitigating chemotherapy-induced neuropathic pain in bowel cancer survivors, as assessed by changes in pain scores from baseline to post-treatment. Our secondary objectives were to: (i) investigate the immediate analgesic effects of rTMS pre- and post-intervention within an individual session, (ii) to quantify long-term effectiveness of rTMS for pain alleviation, and (iii) to qualitatively evaluate patients’ acceptance of receiving routine rTMS treatment. Based on existing evidence of rTMS for mitigating CIPN-associated neuropathic pain in a small number of patients in limited cancers [ 22 , 26 ], we expect to see a reduction in pain intensity after at least one session of rTMS. Further, as rTMS is well-demonstrated to produce long-lasting long-term-potentiation-like neuroplastic changes [ 27 ], we also expect to see prolonged symptom alleviation at follow-ups upon completion of all treatment sessions.
Methods
Study Design
The TMaC study is a randomised and patient-blinded study examining the effectiveness of rTMS, in comparison with sham stimulation, for chemotherapy-induced pain amongst bowel cancer survivors. Ethics approval was obtained through Central Adelaide Local Health Network (CALHN) Ethics Committee in South Australia on October 31, 2024 (identifier: 2024HRE00199 ). Protocol of this study was developed following Recommendations for Interventional Trials (SPIRIT checklist). The study is registered with the Australian New Zealand Clinical Trials Registry (ANCTR registration number: ACTRN12625000008426 ) in the WHO registry network. Participant recruitment is scheduled between February 2025 and June 2026, with all experimental sessions conducted in the Integrative Human Neurophysiology Laboratory at the University of Adelaide.
Eligibility Criteria
Adults (≥18 and ≤85 years) who are experiencing CIPN-associated pain at least 6 months following completion of oxaliplatin-containing chemotherapy for bowel cancer are eligible. CIPN-associated pain (i.e., oxaliplatin-induced pain) is defined as: (i) patient-reported symptoms as moderate or above, according to the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (NCI PRO-CTCAE) scale item 39 [ 28 ], and (ii) ≥30 mm score on a visual analogue scale (VAS) measuring pain or dysaesthesia intensity [ 29 ]. To facilitate timely recruitment, the study will be advertised online on social media platforms (e.g., Facebook), and promoted offline through established local networks with cancer communities (e.g., cancer voices SA), as well as in clinical settings via oncology and neurology referrals.
To ensure suitability for rTMS procedures, a compulsory TMS screening questionnaire will be administered to exclude individuals with a history of epilepsy, implanted cardiac pacemakers, implanted neurostimulators, and metallic implants [ 30 , 31 ]. Individuals with pre-existing neuropathological conditions (other than CIPN) either before or after receiving chemotherapy are also excluded. Individuals with known causes of neuropathic pain other than nerve damage from prior chemotherapy (e.g., diabetic neuropathy) or are continuing neurotoxic medications (e.g., taxanes) are excluded. The number of exclusions along with corresponding reasons for exclusion will be provided in the participant flowchart as shown in Figure 1 following CONSORT guidelines [ 32 ]. Given CIPN is highly pharmaco-resistant [ 6 ], participants taking concurrent medications, such as duloxetine, will not be excluded from the study. However, information on the medications taken (e.g., drug name, commencement date, administration frequency, and dosage) will be recorded and reported in the results to inform interpretations of treatment effectiveness.
Experimental Protocol
Experimental protocol of the TMaC study is illustrated in Figure 2 . The study consists of one initial screening session (i.e., Session 1), four treatment sessions (i.e., session 2 through to 5), and two follow-up sessions (i.e., session 6 and 7) to assess long-term effectiveness of rTMS for oxaliplatin-induced pain. Informed consent will be acquired in writing prior to enrolment. Participants will be reimbursed with a total of USD 200 in gift vouchers upon completion of all treatment sessions, as compensation for their time and travel commitments associated with study participation. They will be educated that participation is voluntary and they may withdraw at any point of the TMaC study without any consequences.
Experimental Set-Up
Sensory Nerve Conduction
Supramaximal electrical stimulation (i.e., 120% of the intensity to elicit maximal action potential) of the sural nerve will be performed in session 1, and the average peak-to-peak amplitude of sensory action potential across five trials for each leg will be used for stratification. Electrical stimulation of the sural nerve will be applied antidromically using a constant current stimulator (DS7A: Digitimer, UK) and a bipolar surface electrode which is positioned in a distal-cathodal fashion. Frequency filters are set from 20 Hz to 2 kHz, with a sweep speed of 1 msec/division. Optimal stimulation and recording sites (see Fig. 3 b) are acquired using standard sural nerve stimulation techniques [ 33 , 34 ].
rTMS Stimulation
During motor hotspot assessment and TMS treatment, a figure-8 coil connected to two magnetic stimulators (Magstim, Dyfed, UK) is positioned to the scalp over S1, with the handle oriented posteriorly and laterally at 45° to the sagittal plane to induce a posterior-to-anterior current in the cortex. To determine the target region for stimulation, participants are first asked to identify the extremity (e.g., right hand; see Fig. 3 a) most affected by CIPN. Single-pulse TMS is then applied to the first dorsal interosseous (FDI) muscle region within M1, contralateral to the side of the most-affected extremity identified by each patient. The hotspot in M1 which consistently produces the largest response in the corresponding FDI muscle is marked on the scalp using a blue permanent marker. The location 2-cm posterior to the M1 hotspot is determined as the target region within S1 for intervention [ 35 ], which is marked using a red permanent marker and registered on the Neuro-navigation system (Brainsight, UK) as reference, providing real-time guidance for accurate coil positioning throughout the experimental sessions. Each rTMS intervention session (see Fig. 4 ) consists of 180 paired pulses with the interstimulus interval set at 1.5 milliseconds, applied every 5 s for a total of 15 min [ 36 , 37 ]. rTMS intensity is identical for both pulses in the pair and is set at the lowest required intensity for generating a 0.5–1.5 mV peak-to-peak amplitude (when applied at M1) for at least five out of ten trials [ 36 , 37 ].
Sham Stimulation
The coil is positioned at approximately 90° relative to the scalp and maintained in direct contact to minimise intracortical current induction while preserving tactile sensation of coil contact, as also experienced in the active group [ 38 ]. To ensure adequate masking of group allocation, participants in the sham stimulation group undergo the same experimental procedures as those in the active condition, including identification of the target extremity for electrode placement and execution of the same verbal instructions for hotspot localisation, target region identification, and stimulation intensity determination. They are also exposed to the same “clicking” sounds produced by the coil, with the only difference being the coil orientation, which prevents neuroplasticity induction during the 15-min treatment period.
Randomisation and Blinding
Once screening is complete after session 1, each eligible consenter is registered in the study and will receive a unique code for de-identification (e.g., tmac_001). An academic staff member blinded to study data will randomly allocate eligible patients using their unique codes in Excel, and communicate each participant’s group assignment to the experimenter before session 2 commences. Participants are randomised in blocks of four, with an allocation ratio of 1:1. Past research noted varied response to rTMS across patients with differential CIPN severity grades [ 26 ], which may be attributed to differences in chemotherapy regimens [ 39 ]. Informed by this, we will stratify participants by previous chemotherapy regimen (e.g., FOLFOX and FOLFIRINOX) and by CIPN severity to ensure balanced CIPN-associated baseline characteristics. Current recommendation to optimally assess CIPN severity requires employment of both objective neurophysiology recordings and subjective patient-reported outcomes [ 40 ]. Therefore, our second stratification factor is age-adjusted sural nerve amplitude of sensory action potential (cutoff value of 7 μV for patients under 60 and 3 μV for those aged 60 and over) as an objective indicator of CIPN severity [ 23 , 41 ], with the third factor being patient-reported baseline VAS scores (i.e., 30–40 mm inclusive, 40–60 mm, and 60–100 mm inclusive).
Participants will not be revealed to their group allocation before findings of the TMaC study are finalised, unless ethically or legally obliged to do so (e.g., in the case of medical complications where accurate reporting of treatment received in the study is required). To evaluate the integrity of blinding, participants will be interviewed at the 8-week follow-up after treatment completion regarding their perceived group allocation and rationale, which will be presented in results to inform interpretation. It should be noted that the experimenter cannot be blinded to treatment assignment in order to administer active or sham stimulation correspondingly, but an independent blinded investigator will undertake data analysis to account for potential performance and assessment bias.
Outcomes
The primary outcome is pain intensity measured using the Visual Analogue Scale for pain (P-VAS). The questionnaires are administered to all patients before randomisation in session 1, immediately before and after each of the four treatment sessions from session 2 through to 5, and at the 8-week follow-up in session 6. Patients who are identified in session 6 as still maintaining benefits from rTMS treatment will receive an additional pain assessment at the 6-month follow-up in session 7 (see Fig. 2 ).
Secondary outcomes include: (i) patient-reported dysaesthesia intensity (i.e., continuous variable) using D-VAS, which is administered at the same time as P-VAS; (ii) CIPN-associated pain (i.e., continuous variable) in the week before commencing each treatment session, which is measured at the beginning of session 2 through to 7 (see Fig. 2 ), by using the eight-item (sensory) European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for CIPN (EORTIC QLQ CIPN8) [ 42 ]; and (iii) qualitative data gathered from the semi-structured interview in session 6 to analyse patients’ perspectives and acceptance of rTMS for management of chronic CIPN-associated pain.
Analysis
Sample Size Calculation
An a priori analysis was performed for sample size calculation using StataMP (Version 18.5) in collaboration with a statistician. An analysis of covariance (ANCOVA) approach was chosen to control for baseline P-VAS scores (i.e., primary outcome), which were predicted to be strongly correlated with post-treatment P-VAS scores ( r = 0.7; Karabis et al. [ 43 ]). The minimally clinically meaningful change in P-VAS scores has been reported to range between 5 mm and 20 mm (Delgado et al. [ 44 ]. In the current study, a 12 mm between-group difference in post-treatment P-VAS scores was considered sufficient to reflect a clinically significant improvement in chronic CIPN-associated pain and to inform clinical practice. The standard deviation was estimated to be 20 mm based on the variability in P-VAS scores observed in pilot rTMS trials for CIPN (Goto et al. [ 22 ], Yan et al. [ 26 ]). To achieve 80% power at the 0.05 significance level, a total of 36 participants were needed (18 per arm). The sample size was adjusted to 40 (20 per arm) to account for an anticipated 10% dropout rate, considering each participant will receive four treatment sessions and at least one follow-up 8 weeks after treatment completion.
Statistical Analysis
The primary analysis principle will be intention-to-treat, which analyses all participants based on their originally assigned treatment. Missing data will not be imputed. Additionally, a per-protocol sensitivity analysis will be performed, which only includes participants who complete at least three out of the four treatment sessions as per their initial group allocation. The statistical analysis plan was developed upon consultation with an independent statistician. The primary analysis of the primary outcome (i.e., difference in P-VAS scores between baseline and the 8-week follow-up) will be conducted using ANCOVA in StataMP (Version 18.5). For the secondary analysis, mixed-effects linear regression models will be employed to assess main and interaction effects of time and treatment group (sham vs. rTMS) on each of the pain and dysaesthesia outcomes, including P-VAS, D-VAS, and EORTIC QLQ CIPN8 scores. To account for repeated measures within patients, an unstructured covariance matrix will be specified. If the model fails to converge, other covariance structures (e.g., exchangeable, autoregressive order 1) will be tested until model-convergence is achieved. Both primary and secondary analyses will be adjusted for the corresponding baseline values of each outcome variable to enhance veracity and reliability, due to anticipated strong correlations between the baseline and post-treatment values. Stratification factors (i.e., sural a-SNAP and chemotherapy regimen) will be included as covariates in ANCOVA, and as fixed effects in the mixed-effects models. A one-way ANOVA will be run to compare experimental conditions that may influence plasticity induction, including session time, room temperature, and humidity. Unless otherwise specified, data are expressed as mean ± standard deviation in tables, and as standard error of the mean in error-bars of line graphs for visual clarity. Significance is set at p < 0.05.
Thematic Analysis
Interviews will be recorded upon written informed consent and transcribed verbatim. Qualitative data will be analysed using NVivo (Version 15) based on the six-phase approach [ 45 ]. In phase one, an investigator notes down initial ideas relevant to patients’ experience after thorough review of the full data, which informs generation of the codes (e.g., initial session, routine appointments, acceptance) in phase two. The investigator will then re-read the full transcript to identify content that matches patterns related to each code in phase three. In phase four and five, interrelated codes will be collated under broader themes, and a thematic map will be produced to visually represent the relationships between the themes and associated codes. Last, two co-investigators will review the codes, themes, and the narrative which interprets implications of the coded quotes, to ensure consistency and validity in the thematic analyses of patients’ experience in the study and their acceptance of rTMS for pain management.
Ethics and Dissemination
Ethics Approval
The study is approved by the Central Adelaide Local Health Network (CALHN) Human Ethics Committee in South Australia. The full study protocol is registered on the Research Governance and Ethics Management System (GEMS) of South Australia (identifier: 2024/HRE00199) prior to study commencement. Any amendment to the protocol will be submitted for approval by CALHN Ethics and updated on the ANCTR. Following approval of any amendments, all study personnel will receive both a clean and a track-changed version of the updated protocol by email.
Safety
rTMS techniques are considered safe and well-tolerated by human participants in both research and clinical settings [ 31 ]. Although there is a slightly elevated risk of seizures in individuals with a known history of epilepsy [ 31 ], this risk is minimised through a compulsory TMS screening questionnaire administered in the first session prior to enrolment, which excludes individuals with a history of epilepsy or seizures. All AEs will be monitored during treatment sessions and reported within 72 h to the principal investigator, who will then determine whether the AEs are treatment-emergent or non-treatment emergent. The severity of AEs will be classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 5.0) [ 46 ]. Starting from session 2, participants will report AEs occurring within the week following treatment. In the unlikely event that mild symptoms persist or serious AEs occur, participants will be advised to consult a healthcare practitioner and withdraw from the study. To comply with best practice and to maximally protect participants from exposure to undue risk, a Data Safety Monitoring Committee (DSMC) has been established to monitor incidents, oversee safety, and ensure ethical conduct throughout the study. All AEs will be reported to the DSMC, followed up, and reported in the results of the study.
Data Management and Privacy
Acknowledging that an individual’s rights to privacy and confidentiality are of paramount importance to all study personnel, we will adhere to data privacy and confidentiality guidelines throughout the TMaC study [ 47 ]. Data will be anonymised and de-identified to ensure that participants cannot be individually identified. Experimental data will remain locked in a filing cabinet, with electronic copies securely stored in password-encrypted hard drives and archived fortnightly. Data will not be made publicly available or shared for re-use upon study completion.
Dissemination Policy
Findings will be published in peer-reviewed journal articles, presented at scientific conferences, and promoted through online media platforms as appropriate. Study investigators may also engage offline dissemination activities (e.g., workshops) in collaboration with funding body, The Hospital Research Foundation. Participants will receive their individual results, group allocation, and a lay summary of the key findings after the study concludes.
Patient and Public Involvement Statement
The research proposal was developed in collaboration with the broad patient network at Cancer Voices South Australia through multiple consultation sessions, ensuring clinical relevance of the research question and acceptability of the methodology among patients. The TMaC study employs a patient-reported measure of pain as the primary outcome, a decision jointly made by study investigators and bowel cancer survivors to reflect the subjective nature of pain. Study documents, including the flyers, consent form and participant information sheet, were reviewed by bowel cancer patients to ensure clarity and comprehensibility. Patients were also involved in the design of interview items to best capture their needs and perspectives. Our chief investigator team also includes a bowel cancer survivor with lived experience of CIPN who will provide ongoing input and advice regarding the study, and its relevance to the consumer population.
Discussion
Chemotherapies play a crucial role in preventing and treating metastatic cancer; however, the long-term impact of peripheral neuropathy, which may persist even after treatment cessation, significantly degrades cancer patients’ quality of life. The value of supportive care research resides in its focus on alleviating these chronic neuropathic symptoms to restore patients’ quality of life. To the best of our knowledge, the TMaC study is the first to explore the analgesic effects of rTMS for CIPN-associated pain in bowel cancer survivors. Whilst past research has demonstrated rTMS effectiveness for neuropathic pain, its long-term impacts remain largely underexplored [ 21 , 22 , 26 ]. Our prospective study will address this gap in knowledge to further the understanding of the sustained therapeutic potential of rTMS, which spans over 6 months after treatment completion. Another strength of this work is grounded in its robust research methodology built upon previous studies [ 22 , 40 ]. We will incorporate both subjective patient-reported outcomes (i.e., pain) and objective sural nerve recordings for stratification to control for baseline differences in CIPN severity. This approach enhances the reliability of findings in rTMS effectiveness, as reduced sural a-SNAP is more frequent in patients with severe CIPN [ 40 , 48 ], which is associated with a decrease in individuals’ responsiveness to rTMS [ 26 ].
Additionally, the stimulation site (i.e., FDI of the hand region within S1) in our study considers evidence from prior research. S1 is not only an independent processing centre for the awareness and localisation of pain, but also a major relay station connecting higher order cortices, such as the prefrontal cortex for pain perception, and subcortical structures, for instance the thalamus for pain modulation [ 49 – 51 ] and the limbic system for affective processing [ 52 , 53 ]. Despite these fundamental roles, most neuromodulation research has predominantly focused on M1 [ 21 , 24 ]. It is plausible that targeting S1 may elicit profound analgesic effects, warranting further investigation to address this critical gap in knowledge. Further, current literature does not support strict somatotopic targeting of affected extremities, as applying rTMS on the hand has been shown to produce equivalent analgesic effects as stimulation of lower extremities for leg pain [ 54 , 55 ]. In fact, the hand region is the recommended stimulation target, as it is consistently identified to be a reliable stimulation site and easy-to-locate on the homunculus, due to its large cortical representation relative to the lower extremities [ 21 , 54 ]. Our research also incorporates a novel qualitative focus on patients’ perspectives and acceptance of routine rTMS treatment, reinforcing the patient-centred nature of this work. Limitations should also be acknowledged. Risk of performance bias may occur as the experimenter cannot be blinded to group assignment in order to administer corresponding treatments. However, we will employ a blinded statistician independent of the research for data analysis and interpretation to enhance veracity. Also, potential assessment bias arising from the subjective nature of pain measurements is mitigated by allocation concealment and participant-masking. Findings of this study will contribute to the fundamental understanding of long-term analgesic effects of rTMS and may provide a permanent solution to this chemotherapy-induced, pharmaco-resistant chronic neuropathic pain condition.
Acknowledgments
The authors sincerely thank our patient adviser Karen van Gorp for assisting with recruitment and reviewing study documents.
Statement of Ethics
This study is performed in accordance with the Declaration of Helsinki. Ethics approval was obtained through Central Adelaide Local Health Network (CALHN) Ethics Committee in South Australia on October 31, 2024 (identifier: 2024HRE00199). The study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12625000008426) in the WHO registry network. Written informed consent is obtained for participation in this study.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This work was supported by The Hospital Research Foundation Group in South Australia (Grant No. 2023-CP-LWABC-209). H.R.W. is the recipient of a Hospital Research Foundation Group Senior Research Fellowship and an NHMRC Investigator Grant (EL2).
Author Contributions
J.M.B. and S.K.S. conceptualised the study framework and designed the experimental approach in collaboration with all other investigators. M.S., T.J.P., and H.R.W. provided critical input to refine the study methodology. C.G., B.G., and T.J.P. assisted with participant recruitment. E.K.M. reviewed literature, produced the manuscript, and incorporated supervisory feedback from S.K.S. and J.M.B. All authors critically reviewed and approved the final version of the manuscript for publication.
Data Availability Statement
Data will not be publicly available due to privacy and ethical considerations. Further enquiries can be directed to the corresponding author E.K.M.
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