Repetitive Transcranial Magnetic Stimulation: Is it an Effective Treatment for Cancer Pain?

Cancer pain refers to pain caused directly by a malignant tumor or pain arising from cancer-related treatments and diagnostic procedures. Its mechanisms are complex and typically involve both nociceptive pain and neuropathic pain, which may exist independently or concurrently. These two types of pain have different mechanisms and manifestations and often coexist in patients with cancer [21, 22].

Nociceptive pain is a sensory response to actual or potential tissue damage, transmitted through the activation of nociceptors. This type of pain serves as a normal protective response of the body to harmful stimuli, aiming to prevent further damage and promote healing [23]. The mechanisms of cancer-related nociceptive pain involve direct tissue damage by the cancer itself or its treatments, such as surgery, chemotherapy, and radiotherapy. When free nerve endings in the skin, muscles, joints, and visceral organs are stimulated, nociceptors are activated, generating action potentials. These signals are transmitted via Aδ fibers and C fibers to the dorsal horn of the spinal cord [24‐26]. In the dorsal horn, primary sensory neurons form synapses with secondary neurons, transmitting signals through the release of neurotransmitters such as glutamate and substance P. The secondary neurons then relay the signals via the spinothalamic tract to the thalamus and subsequently to the primary sensory cortex of the brain, where they are processed and perceived [27‐29].

Neuropathic pain is caused by damage or dysfunction of the nervous system [30]. This type of pain may originate from the cancer itself invading or compressing neural tissues or from nerve damage due to cancer treatments such as surgery, radiotherapy, and chemotherapy [31]. Unlike nociceptive pain, which is a normal response to external noxious stimuli, neuropathic pain can occur even in the absence of such stimuli [32, 33]. It is generally believed that neuroplasticity mediates the persistence of neuropathic pain [34, 35]. In neuropathic pain, neuroplasticity manifests through various changes, including central sensitization, peripheral sensitization, synaptic plasticity, neurogenesis and aberrant connectivity, and emotional and cognitive influences. These changes can lead to the persistence and amplification of pain. Central sensitization refers to the increased sensitivity of neurons in the spinal cord and brain to pain stimuli [36]. Persistent pain stimulation can lead to an increase in the number and function of synapses in the dorsal horn neurons, enhancing their efficiency and response to pain signals, and even generating pain in the absence of new stimuli. Peripheral sensitization refers to the increased sensitivity of nociceptors following peripheral nerve damage. Noxious stimuli activate glutamate NMDA receptors, leading to calcium influx and triggering calcium-dependent intracellular pathways, particularly the calcium/calmodulin-dependent protein kinase II (CaMKII) pathway, which induces long-term potentiation (LTP), resulting in persistent pain [37, 38]. Additionally, damaged nerves may attempt to regenerate, but this often leads to abnormal neural connections, resulting in incorrect signal transmission and persistent pain [39, 40]. Lastly, neuropathic pain is not solely a physiological phenomenon; it also involves emotional and cognitive changes [41, 42]. Chronic cancer patients with pain often experience psychological issues such as anxiety and depression, which, in turn, exacerbate pain through neuroplasticity mechanisms [43].

Cancer pain is typically a combination of both types of pain, known as mixed pain [44]. The proportion of neuropathic and nociceptive pain can vary at different stages and in different types of cancer. Primary tumors or metastases can lead to nerve compression or invasion, resulting in neuropathic pain [45], while inflammation and damage to the tumor and surrounding tissues can cause nociceptive pain [46]. Cancer treatments, such as surgery, may lead to incisional pain (nociceptive pain), and during the surgical process, nerves may be damaged, leading to neuropathic pain [47, 48].

In cancer pain, the interplay between the ascending pain modulation pathway and the descending pain modulation pathway plays a crucial role in the complexity and persistence of pain. The ascending pathway is responsible for transmitting and amplifying pain signals, leading to the perception of continuous pain [49]. Conversely, the descending pathway, which typically modulates and suppresses pain signals, may become dysregulated in certain conditions, resulting in an inability to effectively inhibit pain signals and potentially even enhancing pain perception.

The ascending pain modulation pathway is responsible for transmitting pain signals from the periphery to the central nervous system, allowing the brain to perceive, locate, and respond to pain stimuli. The descending pain modulation pathway, a complex network of neurons, regulates and controls pain perception through descending neural signals [50]. The primary function of this pathway is to inhibit or enhance pain signals transmitted from the periphery to the central nervous system, thereby influencing pain sensation and response [51, 52]. The descending pathway can reduce pain signal transmission through various inhibitory mechanisms, including the periaqueductal gray (PAG) to nucleus raphe magnus (NRM) pathway and the PAG to locus coeruleus (LC) pathway [53]. The PAG activates the NRM, which releases serotonin (5-HT) to inhibit the activity of spinal dorsal horn neurons via 5-HT1A receptors [54, 55]. Similarly, the PAG activates the LC, which releases norepinephrine (NA) to inhibit spinal dorsal horn neurons via α2-adrenergic receptors [56, 57]. In chronic cancer pain, levels of 5-HT and NA may decrease, or their receptor sensitivity may decline [23], leading to weakened descending inhibitory signals [58]. In addition to the reduction of neurotransmitters, damage to the PAG and NRM can result in ineffective transmission of pain inhibitory signals [59]. Cancer pain is often accompanied by neuroinflammation within the central nervous system [60]. This inflammatory response can alter neuronal function through cytokines and chemical signals, reducing the release or efficacy of inhibitory neurotransmitters [61]. Glial cells, such as astrocytes and microglia, may become activated and release pro-inflammatory mediators. These mediators can disrupt the normal function of the descending pain modulation pathway, obstructing inhibitory signal transmission. Moreover, chronic cancer pain may be associated with decreased cortical and corticospinal motor inhibition mechanisms. Chronic pain is reflected in neuroimaging as reduced volumes of the hippocampus and ventromedial prefrontal cortex (VMPFC) [62, 63]. There is a reduction in gray matter density in regions such as the cingulate gyrus, insula, prefrontal cortex, dorsolateral, somatosensory, thalamus, motor cortex, and brainstem [64]. Long-term pain in neurophysiology can manifest as a normal resting motor threshold (RMT) and motor evoked potential (MEP) amplitude, a tendency for reduced intracortical facilitation (ICF), significantly reduced intracortical inhibition (ICI), and a shortened cortical silent period (CSP). These results suggest a potential correlation between motor cortex disinhibition and chronic pain [65].

Previous studies have indicated that rTMS can effectively alleviate pain, with the stimulation of the primary motor cortex (M1) being the most extensively researched area. Transcranial magnetic stimulation of the unilateral M1 has shown diffuse analgesic effects on both experimental and clinical pain [66]. These effects are likely related to multiple mechanisms (Fig. 1).

The analgesic effects of rTMS stimulation of the M1 area may involve the direct inhibition of nociceptive signal transmission in the spinal cord. Previous studies have demonstrated that the motor cortex directly participates in the modulation of sensory information processing. rTMS stimulation of the M1 area can result in significant metabolic enhancement in the ipsilateral thalamus. Thalamic activation can induce changes in the activity of cortical-subcortical regions such as the PAG, subsequently triggering descending inhibition to the spinal cord and attenuating spinal nociceptive reflexes [67‐69]. Animal studies have shown that M1 stimulation can modulate pain signal transmission by inhibiting the activity of spinal-thalamic neurons [70], indicating that M1 stimulation can directly regulate nociceptive transmission in the spinal cord. rTMS stimulation of the M1 area can also inhibit NMDA receptors, thereby reducing the excitability of spinal dorsal horn neurons, weakening the transmission and perception of pain signals, and inhibiting central sensitization [71]. According to the Central Sensitization Inventory score, transcranial magnetic stimulation can reduce central sensitization by 70% [72]. However, contradictory evidence exists, as some studies have shown that stimulating the M1 area in healthy volunteers did not alter the nociceptive flexion reflex, a spinal reflex arc-mediated response, suggesting that rTMS might not affect neural modulation at the spinal level [73]. This contradictory conclusion warrants further investigation. rTMS can also influence hemodynamic changes in the nervous system. Neuroimaging studies have shown that rTMS induces hemodynamic changes not only in the motor areas [74] but also in cortical and subcortical regions involved in pain processing and modulation, such as the cingulate gyrus [75], insula [76], orbitofrontal cortex [77], prefrontal cortex [78], thalamus [79], and striatum [80]. The increased blood flow in these pain-related regions may affect the transmission and processing of nociceptive signals, thereby improving the subjective experience of pain [81]. Changes in blood flow in structures related to the affective component of pain may enhance the emotional state of patients with pain [82]. The analgesic effects of rTMS have also been attributed to the modulation of endogenous opioid systems. Stimulation of the M1 area with rTMS significantly increases serum β-endorphin levels [83] and enhances opioid receptor occupancy [84]. The fact that naloxone significantly reduces the analgesic effects of M1 stimulation [85] further supports the involvement of endogenous opioids in rTMS-induced pain relief. Animal studies have also demonstrated that rTMS increases extracellular dopamine concentrations in the nucleus accumbens and dorsal striatum [86]. Dopamine has been shown to play a crucial role in pain perception and modulation [87].

We identified five studies related to rTMS treatment for pain directly caused by malignant tumors, including three randomized controlled trials [88‐90] and two case reports [91].

Malignant visceral pain (MVP) is a type of visceral pain associated with cancer, typically characterized by diffuse, difficult-to-localize pain that often exhibits intermittent exacerbation or relief, causing significant discomfort to patients [103]. Current research suggests that the occurrence of malignant visceral pain not only is related to the sensitization of visceral sensory afferent nerves, the hyperexcitability of spinal ascending neurons (central sensitization), and the dysregulation of descending modulatory pathways [104] but also is associated with cross-sensitization between organs, dual branching of axons in visceral sensory afferent nerves, or the convergence of multiple visceral afferent nerves on spinal neurons [105, 106]. Conventional opioid therapy is often ineffective in treating malignant visceral pain, whereas rTMS can significantly alleviate this condition [107]. In a study by Khedr et al. [88], 34 patients with malignant visceral pain from Egypt were included. All of them had developed resistance to drug treatment for at least 2 months or had experienced severe adverse reactions to drugs. All patients followed the same regimen and were required not to change during the study: tramadol hydrochloride 100 mg twice daily, scopolamine 20 mg three times per day, and amitriptyline 25 mg twice daily. The pain was localized to the trunk (right-side referred pain, left-side referred pain, upper abdominal pain). These patients were randomly assigned in a 1:1 ratio to a control group (sham rTMS stimulation) and an experimental group (active rTMS stimulation). The treatment protocol for the experimental group consisted of 20 Hz, 10 trains, 80% RMT, with an inter-train interval of 30 s, totaling 2000 pulses, targeting the M1 area contralateral to the pain site, repeated daily for a total of ten sessions. The control group received sham transcranial magnetic stimulation with identical parameters, but the coil was elevated and angled away from the head to replicate the subjective sensation of transcranial magnetic stimulation without inducing the actual current. Changes in the visual analog scale (VAS), verbal descriptor scale (VDS), and Hamilton Depression Rating Scale (HAMD) were observed before, during, and after treatment. The results showed that at baseline, there was no significant difference in VDS scores (p = 0.810) and VAS scores (p = 0.073) between the experimental group and the control group. However, after the 5th and 10th treatments and at 15 days after the end of sessions, the VDS scores (p = 0.001, p = 0.003, p = 0.006) and VAS scores (p = 0.005, P = 0.011, and P = 0.053) of the experimental group were significantly lower than those of the control group. Repeated measures analysis of variance showed that the interaction between time and group was significant (df = 2.712, F = 4.423, p = 0.008) (df = 2.768, F = 2.729, p = 0.049), indicating that there were differences in score changes between the experimental group and the control group at different time points.

Chronic pain resulting from direct or indirect damage to the nervous system (including the central and peripheral nervous systems) by malignant tumors can be termed neuropathic pain secondary to malignancy (NPSM) [108]. The pathological mechanisms of NPSM and malignant visceral pain may both involve central and peripheral sensitization and the release of inflammatory mediators [109]. Both conditions share similar characteristics, such as deep, diffuse, or stabbing pain, poor response to conventional analgesics, and overlapping or radiating pain. rTMS has also demonstrated efficacy in the treatment of NPSM. Eman M. Khedr et al. conducted another randomized clinical trial [89] involving 34 patients with malignant unilateral NP [Douleur Neuropathique (Neuropathic Pain) 4 (DN4) score ≥ 4] who were resistant to drug treatment for at least 2 months. All patients used the same and unchangeable treatment regimen: tramadol hydrochloride 100 mg twice daily, pregabalin 75 mg twice daily, gabapentin 400 mg twice daily, and amitriptyline 25 mg twice daily. In this study, the patient's pain distribution was extensive, affecting both upper limbs, the left lower limb, and the chest. Similar to the previous experiment, the 34 patients were randomly divided into a control group (sham rTMS stimulation) and an experimental group (real rTMS stimulation) in a 1:1 ratio. The treatment protocol was the same as in the previous study. In addition to observing VDS, VAS, and HAM-D scores before, during, and after treatment, the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) was also monitored. The results showed that at baseline, there was no significant difference in VDS scores (p = 0.846), VAS scores (p = 0.518), and LANSS scores (p = 0.736) between the experimental and control group. However, after the 10th treatment and at 15 days after the end of sessions, the VDS scores (p < 0.001, p = 0.004) and VAS scores (p = 0.001, p = 0.014) of the experimental group were significantly lower than those of the control group. The LANSS score of the experimental group was only different from that of the control group after the 10th treatment (p = 0.038).

The aforementioned studies demonstrate that rTMS can reduce pain and depression scores in patients with malignant visceral pain and NPSM, significantly improving both their pain symptoms and psychological state. This suggests that rTMS may be a promising alternative therapy, not only lowering pain levels but also indirectly influencing pain by alleviating depressive symptoms. However, follow-up assessments indicate that these effects do not persist beyond 1 month after the completion of the treatment course, which we attribute to the limited number of treatment sessions. Whether repeated rTMS treatments can produce cumulative effects to prolong analgesia is a question that requires further investigation.

In another study, Ying Tang et al. conducted a double-blind, randomized controlled trial on 41 patients with advanced non-small cell lung cancer (NSCLC) who had a Numeric Rating Scale (NRS) score of ≥ 4 and were receiving opioid treatment [90]. They found that repetitive transcranial magnetic stimulation (rTMS) could alleviate pain in patients with advanced NSCLC. Patients were randomly assigned to the control group (sham rTMS) or the experimental group (real rTMS). The treatment protocol for the experimental group involved 10 Hz, 15 trains, 80% of RMT, with an interval of 3 s, totaling 1500 pulses, targeting the left DLPFC. The control group used the same treatment parameters, but only produced sound without magnetic stimulation output. Both groups received stimulation once daily, 5 days a week, for 3 consecutive weeks, totaling 15 sessions. The effects of rTMS on pain, analgesic demand, quality of life, anxiety, and depression were assessed by observing changes in NRS, oral morphine equivalents (OME), the World Health Organization Quality of Life-BREF (WHOQOL-BREF), the Hamilton Anxiety Rating Scale (HAM-A), and the HAM-D. The results showed that both the real rTMS group and the sham rTMS group experienced pain relief after treatment. The NRS scores of both groups gradually decreased from the 3rd day and reached their lowest point after the 3rd week of treatment. Notably, after the 2nd and 3rd weeks of treatment, the scores in the real rTMS group were significantly lower than those in the sham rTMS group. Additionally, after 3 weeks of treatment, the WHOQOL-BREF scores in all domains significantly improved in both groups. The HAM-A and HAM-D scores also showed significant improvement in the real rTMS group. This trial is one of the few studies targeting the DLPFC to achieve pain inhibition in patients with cancer, and it preliminarily demonstrated that rTMS targeting the DLPFC can reduce pain intensity caused by NSCLC, decrease the daily dosage of opioid medications, and improve the quality of life and anxiety/depression in patients with NSCLC. Although there is insufficient evidence to definitively demonstrate the analgesic effect of high-frequency rTMS on the DLPFC, its effect on emotional regulation has been confirmed [95‐97]. rTMS may improve pain by alleviating negative emotions of anxiety and depression, regulating cognition, and enhancing attention.

Julien Nizard et al. reported a case of rTMS treatment for pain caused by rectal cancer with multiple organ metastases [91]. The patient was a young female with rectal adenocarcinoma with metastases to the lungs, liver, and peritoneum, who had undergone chemotherapy, radiotherapy, and pelvic resection. Despite combined treatment with oral morphine, pregabalin, and amitriptyline, her NRS score remained at 8–10/10. She was administered five consecutive rTMS treatments, with a protocol of 10 Hz, 20 trains, 80% RMT, with 50-s intervals, totaling 2000 pulses, targeting the right M1 area. Results showed significant pain relief within days after the first rTMS session. Medication usage was also significantly reduced, with the medication quantification scale (MQS) decreasing from 126 to 56 points. Additionally, her level of consciousness improved, and symptoms of anxiety and depression were alleviated.

Julien Nizard et al. also found that rTMS helped alleviate pain caused by cutaneous T-cell lymphoma [91]. The patient, a middle-aged woman with cutaneous T-cell lymphoma, had undergone chemotherapy and experienced severe diffuse limb pain (NRS 7/10) with generalized pruritus. She also suffered from severe depression due to her condition [Hospital Anxiety and Depression Scale (HAD) score of 9/21]. She was treated with the same rTMS protocol as the previous case. After five treatment sessions, her pain significantly decreased, with the NRS score dropping from 7 to 2. Her mood improved, and the HAD score decreased to 1/21.

The above reports demonstrate the effectiveness of rTMS in the treatment of pain in patients with metastatic rectal adenocarcinoma and cutaneous T-cell lymphoma, while also improving psychological symptoms, thereby highlighting the therapeutic value of rTMS. These findings support rTMS as a beneficial adjunctive therapy in managing severe cancer pain that is refractory to conventional pharmacological treatments.

In summary, rTMS appears to demonstrate potential in alleviating pain directly caused by malignant tumors, including malignant visceral pain, neuropathic pain NP, and pain management in patients with NSCLC. However, these studies generally involve small sample sizes and short follow-up periods, and the long-term durability of the treatment effects has yet to be fully validated. This limitation constrains the supporting evidence for the widespread application of rTMS in clinical practice.

We included two pilot studies related to rTMS treatment for pain induced by adjuvant cancer therapy [92, 93].

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and serious side effect of cancer treatment [110]. CIPN significantly affects the quality of life of patients with cancer, often manifesting as sensory disturbances, pain, numbness, loss of sensation, and motor dysfunction. It frequently presents as dose-limiting toxicity, forcing some patients to reduce or discontinue their chemotherapy regimens [111].

Yuko Goto et al. conducted a study on 11 Japanese female patients who met the diagnostic criteria for CIPN after treatment with taxanes or oxaliplatin [92]. The treatment protocol involved stimulation at 5 Hz, 10 trains, 90% RMT, with 50-s intervals, totaling 500 pulses, targeting the M1 area contralateral to the pain site. Changes in P-VAS (pain visual analog scale), the Japanese version of the McGill Pain Questionnaire 2 (SF-MPQ2), and D-VAS (discomfort visual analog scale) were observed to determine the effect of rTMS on pain intensity and dysesthesia. Adverse events were recorded throughout the study. The results showed significant reductions in P-VAS, D-VAS, and SF-MPQ2 scores in the targeted limb and three other (non-targeted) limbs, with no severe adverse events reported. This study confirmed the efficacy of rTMS in improving CIPN.

Another study supported this finding. Zhenzhuang Yan et al. conducted a study [93] involving 30 Chinese patients with multiple myeloma who developed grade 2 or higher CIPN after chemotherapy. These patients primarily exhibited somatosensory-related symptoms and were also receiving vitamin B12, vitamin B1, gabapentin, amitriptyline, pregabalin, and opioid interventions. The treatment protocol involved stimulation at 10 Hz, 15 trains, 80% RMT, with 3-s intervals, totaling 1400 pulses, alternating between bilateral M1 areas. rTMS was administered once daily, 5 days a week, for 6 weeks, totaling 30 sessions. The study assessed the impact of rTMS on pain, CIPN symptom severity, and quality of life using VAS, nerve conduction velocity (NCV), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-CIPN 20-item scale (EORTC QLQ-CIPN20). The results showed that 80.0% of patients experienced a reduction in CIPN symptoms, with some patients reducing or even discontinuing their medication. VAS scores significantly decreased, and improvements in sensory conduction velocity (SCV) and motor conduction velocity (MCV) were observed. Additionally, all patients showed significant reductions in EORTC QLQ-CIPN20 scores. No adverse events were reported throughout the study. This study further confirmed that rTMS alleviates CIPN-induced pain, reduces peripheral nerve damage, and enhances patients' quality of life.

The two studies mentioned above investigated the efficacy of rTMS in the treatment of CIPN and yielded positive conclusions. Through different experimental designs and patient populations, these studies provide robust evidence supporting the role of rTMS in alleviating CIPN-related pain and improving patients' quality of life.

Pain induced by surgical treatment for malignant tumors is a common and complex issue among patients with cancer [112‐115]. Postoperative pain in patients with malignant tumors can be categorized into acute and chronic pain. Acute pain is typically associated with factors such as inflammatory responses, localized ischemia, and nerve compression, and its duration is relatively short [116, 117]. Chronic pain, on the other hand, may persist for weeks or even months and is often linked to nerve damage during surgery or psychological stress factors [118‐120]. Opioids are the first-line choice for managing acute postoperative pain, especially following surgery for malignant tumors. However, the potential for addiction, tolerance, and other side effects associated with prolonged opioid use should not be overlooked [121].

Monika Kataria et al. conducted a randomized controlled trial [94] involving 34 patients with post-mastectomy pain syndrome (PMPS) caused by breast cancer surgery, all of whom had VAS scores ≥ 4. The 34 patients were randomly divided into two groups in a 1:1 ratio: a control group (sham rTMS stimulation) and an experimental group (real rTMS stimulation). The real rTMS group received 10-Hz stimulation, 20 trains, 80% RMT, with 60-s intervals, totaling 1200 pulses, targeting the contralateral M1 area, administered five times per week for 3 consecutive weeks, totaling 15 sessions. In the sham rTMS group, the coil was elevated away from the head to prevent inducing brain currents. Pain changes were assessed using VAS, the Short Form McGill Pain Questionnaire (SF-MPQ), the Functional Assessment of Cancer Therapy-Breast (FACT-B), and Quantitative Sensory Testing (QST). Cold and heat pain were objectively measured using the MEDOC TSA-II (2001) device. The results showed that the VAS score (p < 0.0001) and SF-MPQ score (p < 0.0001) of the experimental group were significantly lower than the baseline, and there was also a significant difference compared with the control group (p < 0.0001), suggesting the effectiveness of rTMS in intervening in pain. Although the scores of the control group also decreased to a certain extent, we believe that this may be related to other factors such as the psychological suggestion effect of the study and the volatility of pain. Additionally, FACT-B scores significantly increased after real rTMS intervention. Real rTMS also significantly reduced the detection thresholds for cold and warmth as well as the cold pain threshold and heat pain tolerance threshold at the affected site. This study demonstrated that rTMS not only can alleviate PMPS pain but also can improve temperature pain thresholds, further validating the potential of rTMS in relieving PMPS pain and enhancing patients' quality of life.

The significance of rTMS in the management of cancer-related symptoms lies in its multifaceted therapeutic potential, extending beyond pain relief. By precisely targeting different brain regions and neural networks, rTMS can enhance the psychological well-being [95‐97], motor function [98‐100], and neurological function [101] of patients with cancer, thus indirectly alleviating pain symptoms. Additionally, it can help patients better cope with discomfort and side effects during tumor treatment, enhancing their adherence to treatment and encouraging a more positive engagement with various cancer therapy regimens.

rTMS can improve physical strength and endurance in patients with cancer. Ellen Carl et al. [98] conducted a study where 30 right-handed adult female breast cancer survivors who had completed primary treatment were randomly assigned in a 1:1 ratio to either the real rTMS group or the sham rTMS group. The real rTMS group received stimulation at 20 Hz, 20 trains, 110% of the motor threshold (MT), with 20-s intervals, totaling 900 pulses, targeting the left DLPFC area, four times a week for 2 consecutive weeks, totaling eight sessions. After the treatment, patients in the real rTMS group increased their average daily step count by 400 steps, while the sham rTMS group decreased their average daily step count by nearly 600 steps. This demonstrates that rTMS intervention in the DLPFC area can help increase physical activity in breast patients with cancer.

rTMS also aids in improving motor function in patients with malignant tumors. Melina Engelhardt et al. [99] conducted a study with 30 German patients who experienced motor function deterioration after surgical tumor resection. These patients were randomly assigned in a 1:1 ratio to either the real rTMS group or the sham rTMS group. The real rTMS group received stimulation at 1 Hz, 110% RMT, totaling 900 pulses, targeting the contralateral M1 area. For the sham rTMS group, a plastic adapter was placed between the coil and the head to prevent the induction of current. Both groups underwent continuous intervention for 7 days within 1 week, receiving one session per day, totaling seven sessions. After the intervention, the Fugl-Meyer scores of the real rTMS group were slightly higher than those of the control group. Additionally, the real rTMS group outperformed the control group in the British Medical Research Council (BMRC) scores for the upper limbs. These findings suggest that rTMS can promote early upper limb motor recovery. Nicoleta Jemna et al. [100] also reported a case where rTMS improved ataxia in a cancer patient. They applied two rTMS treatments to a patient with ovarian cancer and paraneoplastic cerebellar ataxia (PCA): 1 Hz at 100% MT targeting three cerebellar regions (4 cm to the right of the inion, on the inion, and 4 cm to the left of the inion), and 10 Hz at 120% MT, totaling 3000 pulses, targeting the left DLPFC area. After 20 consecutive treatment sessions, the patient was able to walk unassisted. Additionally, the Beck Depression Inventory-II score decreased from 28 to 20. Posture imaging parameters indicated improved cerebellar function, with the global anterio-posterior body sway score increasing from 56 to 64 and the statokinesigram (SKG) area decreasing from 451.68 to 127.28 mm [2]. Eye-tracking (ET) results showed reduced intrusions of micro-saccadic movements, improved saccadic gain, and normalized average and peak velocities for horizontal and vertical saccades. The patient's clinical assessment, psychological scales, ET, and posture imaging parameters all showed significant improvement, preliminarily demonstrating the effectiveness of rTMS in treating PCA.

rTMS can also alleviate chemotherapy-related cognitive impairment (CRCI) in patients with malignant tumors. Kuo et al. [101] conducted a study on a right-handed Caucasian female with left breast cancer who had undergone four cycles of adjuvant chemotherapy with docetaxel and cyclophosphamide. Unfortunately, the patient experienced progressive memory difficulties and decreased attention post-chemotherapy, significantly impacting her daily life. The researchers administered ten sessions of intermittent theta burst stimulation (iTBS) rTMS treatment with parameters set at 60–70% RMT, a 50-Hz triplet burst, a 2-s "on" window (30 pulses), and an 8-s "off" window (no pulses), totaling 600 pulses, targeting the left DLPFC area. Post-treatment results indicated that although the patient reported no subjective changes, the Rey Auditory Verbal Learning Test (RAVLT) revealed significant improvements in immediate recall, delayed recall, learning, and response inhibition. Additionally, resting-state functional connectivity increased between the stimulation site and several brain regions, including the right superior temporal gyrus, right anterior cingulate cortex, right gyrus rectus, right thalamus, left posterior cingulate cortex, and left middle temporal gyrus. These findings suggest that rTMS can improve CRCI by restoring disrupted connectivity in the DLPFC.

The three studies mentioned above provide preliminary evidence that rTMS can improve physical strength, endurance, motor function, and cognitive ability in patients with malignant tumors. Existing research demonstrates a bidirectional relationship between cancer pain and physical capacity, where the presence of pain often exacerbates patient fatigue, while reduced physical strength and fatigue may increase pain sensitivity [122]. Decreased physical strength further impacts pain perception, leading to heightened sensitivity to pain. A study on gastrointestinal patients with cancer revealed a close association between postoperative fatigue and increased pain perception, where fatigue reduces patients’ tolerance to pain, thus aggravating their pain symptoms [123]. The improvement in physical strength due to rTMS plays a crucial role in alleviating pain. Additionally, regular physical activity and endurance training have been shown to increase pain tolerance and reduce pain sensitivity, a phenomenon known as exercise-induced hypoalgesia (EIH) [124, 125]. Through rTMS, patients with malignant tumors can enhance their physical strength, endurance, motor function, and cognitive capacity. The recovery of basic physical and cognitive abilities enables them to engage in more physical activity and endurance training, leading to hypoalgesia, reduced pain sensitivity, and improved pain tolerance. Ultimately, patients experience reduced pain levels, and their quality of life is significantly improved.