Chronic chemotherapy-induced peripheral neuropathy: living with neuropathy during and after cancer treatments

Introduction

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling complication resulting from the use of several commonly administered chemotherapy agents. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system (1). The pain caused by CIPN greatly impacts patients and limits the doses of treatment. CIPN can continue beyond the duration of therapy, exerting a considerable negative impact on the health and overall quality of life of cancer survivors. Patients with breast cancer are especially affected by this side effect because several commonly used agents for treating this condition can induce neuropathy.

Clinical manifestations of CIPN impact the peripheral nervous system, predominantly causing sensory axonal peripheral neuropathy with a distribution reminiscent of a “stocking and glove” pattern (2). Chemotherapy combinations with increased incidences often include platinum drugs, vinca alkaloids, bortezomib, and taxanes (3). While the pathogenesis and toxicity profiles vary among these agents, there exist several distinctive characteristics of CIPN that aid in distinguishing it from other forms of neuropathies (3). CIPN primarily arises due to the neurotoxic effects exerted on neurons (4). Sensory symptoms tend to outweigh those of motor or autonomic origin (3,4). Neuropathy can arise from either anatomical alteration, such as distal axonal degeneration, or physiological changes (4). Analogous to other neuropathic pain conditions, pain experienced in CIPN can be influenced by stimuli or occur independently (4).

CIPN is a well-recognized side effect associated with several conventional chemotherapy agents like platinum-based drugs, vinca alkaloids, and taxanes. Despite their more targeted cellular mechanisms, even the newer classes of medications such as antibody drug conjugates can still cause such neurotoxicity. Clinicians must evaluate the risks and advantages of using medications known to induce CIPN in patients with advanced age, impaired physical funding, or existing neuropathy or conditions predisposing them to neuropathy, such as diabetes or a family or personal history of hereditary neuropathy.

Several studies have reported on chronic CIPN and its effects on quality of life in breast cancer survivors. Chronic CIPN has been shown to lead to decreased physical activity due to pain as well as significant psychological distress (5). Cancer survivors who have CIPN frequently encounter feelings of frustration, depression, or anxiety due to their limitations in engaging in different activities or carrying out tasks autonomously (6). Exploring the enduring impacts on the quality of life in individuals with CIPN remains a critically significant research avenue. Such investigations offer valuable insights into refining prevention and treatment approaches, as well as enhancing the development of supportive care interventions that focus on improving function and well-being.

The severity and frequency of CIPN tends to increase with higher doses, potentially requiring a reduction or discontinuation of treatment to alleviate symptoms. A decrease in dosage intensity is recognized to have adverse effects on disease-free survival in the curative setting (7). Moreover, breast cancer survivors experiencing CIPN exhibit notably elevated 5-year survival rates compared to those not affected by CIPN (8). These findings suggest that it is important to identify strategies for prevention and treatment of CIPN in order to uphold dosing schedules, as a decrease in dose intensity due to CIPN could result in inferior treatment results. However, it is important to emphasize that the severity of symptoms and impact on function should be considered fully with each chemotherapy treatment particularly in patients with advanced metastatic breast cancer where treatments are ongoing, and the intent is not curative.

Presently, there lacks a standardized criterion for CIPN assessment, and the existing methods have their shortcomings (9,10). The most reliable reports of CIPN are patient reported since clinicians tend to under assess toxicity of burden. With increased integration of patient reported outcome monitoring into routine practice, our hope is the earlier responses to CIPN burden can be achieved as part of routine care. While research on functional and blood-based biomarkers for CIPN has seen growth in the last ten years, their integration into standard clinical practice remains limited due to need for validation.

Patient experience

CIPN can have a profound impact on quality of life. It is essential to have the capacity to evaluate the individual impact of CIPN reliably and effectively, whether in the setting of clinical trials testing new chemotherapeutic agents or in clinical practice where treatments are anticipated to trigger CIPN (11). The term assessment of neuropathic pain refers to assessing pain intensity, quality and treatment induced changes as well as the diagnosis of neuropathic pain (12). In recent years, several screening tools have been validated to differentiate between neuropathic pain and nociceptive pain (13). Some of these tools, such as the Neuropathic Pain Questionnaire (NPQ), ID Pain, and PainDETECT, rely solely on interview questions (14-16). The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale and the Douleur Neuropathique en 4 Questions (DN4) questionnaire combine interview questions with physical tests such as pinprick and tactile hypoesthesia and pain to light touch (17,18).

The Standardized Evaluation of Pain (StEP) incorporates six interview questions and ten physical tests (19-23). This tool evaluates pain related symptoms and signs, distinguishing between different pain phenotypes that reflect varying underlying mechanisms. In addition to its diagnostic value, the standardized approach to categorizing pain phenotypes, regardless of disease etiology, aligns with a mechanism-based framework for classifying and treating pain (12). These assessment tools are commonly used in neuropathic pain however it is important to note that they are not routinely used in the oncological setting and typically not included in cancer clinical trials.

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy (FACT-G) are the two most utilized questionnaires designed for assessing quality of life in cancer patients (24,25). These questionnaires have been created to evaluate a fundamental set of quality-of-life issues and are intended to complement additional modules/subscales specific to certain conditions or treatments. A module addressing paclitaxel-induced peripheral neurotoxicity has been integrated into the FACT measurement system, consisting of eleven items related to neurotoxicity and five items specifically related to paclitaxel which is known as the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG/NTX) (26,27).

The EORTC QLQ-C30 consists of five functional scales including physical, role, emotional, social, and cognitive, three symptom scales including fatigue, nausea, vomiting, pain and global health status and quality of life scale as well as six items including dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties (23). Higher scores indicate high symptom severity. The EORTC Quality of Life Questionnaire-Chemotherapy-Induced Peripheral Neuropathy (EORTC QLQ-CIPN20) is a 20-item scale that is divided into three domains for sensory (nine items), motor (eight items) and autonomic (three items) (8). This questionnaire offers subjective patient reported data that cannot be captured through objective physical exam findings, sensory or nerve conduction studies (8). This tool was applied at baseline and after therapy with weekly paclitaxel, paclitaxel/carboplatin, oxaliplatin, and cisplatin (28). This questionnaire was also used to evaluate patients receiving non-neurotoxic chemotherapy regimens such as doxorubicin/cyclophosphamide (28). The study revealed that there was no significant difference in CIPN20 scores in patients receiving non-neurotoxic chemotherapy regimens which showed that the tool was evaluating neuropathy rather than chemotherapy induced toxicity (28). The QLQ-CIPN20 allows for patient reported outcome measures to be used as a decision-making tool and offers physicians insight that aid in assessing the necessity for adjusting chemotherapy regimens and dosing before each treatment session (29).

The FACT-G scale assesses physical, social, family, emotional and functional well-being (30). The FACT-G can be used in conjunction with FACT/GOG-NTX for patients with neurotoxicity from chemotherapy (30). A prospective study assessing quality of life and CIPN amongst patients with advanced non-small cell lung cancer showed that the FACT/GOG-NTX scores were positively correlated with total FACT-G scores and thus suggesting increased CIPN symptoms were correlated with lower quality of life (27). Another study that evaluated quality of life and CIPN before and at each chemotherapy cycle revealed that patients with CIPN had significantly lower FACT-G scores than those without (31). FACT-G and quality of life scores were inversely related to current perception threshold [b=−1.8, 95% confidence interval (CI): −3.5 to −0.5 and b=−2.2, 95% CI: −4.2 to −0.2, respectively] (31).

In a study from the Netherlands, patients were studied for occurrence of taxane and oxaliplatin induced CIPN and impact on quality of life 6 months after chemotherapy (32). Housekeeping challenges were noted in 13% of patients, while 21% experienced increased dependence on others due to neurotoxicity (32). In total, the quality of life was adversely influenced by CIPN in approximately half (49%) of patients (32). Another nested qualitative study examined patient experience living with CIPN (32). It revealed patients experienced loss of confidence in walking, difficulties in daily activities including self-care, ability to perform functional roles and socializing (33). They also reported worsening nighttime symptoms which resulted in sleep disturbances (33). Poor sleep quality due to CIPN was also noted in another study by Bulls et al. (34).

CIPN symptoms have a significant impact on daily activities of living and ability to return to work for many breast cancer survivors. A small qualitative study by Chan et al. reported CIPN disrupting daily activities as well as psychological well being and ability to return to work (35). Similar studies have shown in breast cancer survivors who received chemotherapy and reported hand numbness, reduced ability to feel small objects, difficulty buttoning buttons, foot numbness and pain, trouble walking and trouble hearing; this led to patients being unable to work (36). The impact of CIPN on physical function leads to decreased mobility, loss of balance and in turn falls. In a study of breast cancer survivors, patients experiencing symptoms of CIPN were 1.8 times more prone to encountering a recent fall compared to women without symptoms (37). Approximately 33% of individuals aged 65 years and above encounter one or more falls annually (37). Despite being younger, the frequency of falls among symptomatic women in this research surpassed that of the general older adult population by 24% (37). In a small study, 19% patients receiving taxane- or platinum-based chemotherapy had at least 1 fall during chemotherapy and these falls were found to be associated with increased cycles of therapy, neuropathic symptoms, and loss of balance (38). Another study demonstrated that approximately 6 years after treatment, 47% of women reported persistent symptoms of CIPN (37). The pace of walking appeared to be reduced in individuals with CIPN compared to those without, with the former group taking noticeably more, albeit slower and shorter, steps (P<0.05) (37). Those with CIPN also reported experiencing significantly more disability and were at a 1.8 times higher risk of falling compared to those without CIPN (P<0.0001) (37). Moreover, as symptom severity increased, there was a clear linear correlation with declining function, increased disability, and a heightened risk of falls (all P<0.05) (37). Customizing rehabilitation approaches to effectively mitigate the disability and falls linked with CIPN could enhance patient safety and optimize survivorship care plans for individuals undergoing neurotoxic chemotherapy treatments (37).

The psychological impact in patients with CIPN remains vastly under-studied. It remains challenging to articulate the experience of CIPN due to the widespread nature of its symptoms. While there remains no unanimous agreement on the definition of psychological distress, most researchers concur that it can encompass various symptoms, spanning from feelings of sadness and fear to more severe manifestations like depression and anxiety (39). These symptoms can hinder daily functioning and have a substantial impact on quality of life.

A qualitative study showed that numbness, tingling, stiffness, pain, or sensation of coldness in hands and feet resulted in decreased sensory perception and hindered fine motor skills, impacting everyday activities and self-fulfillment (40). Numerous individuals expressed fatigue or an uneasy feeling in their legs, along with challenges sensing the ground beneath and determining where to place their feet, thus impacting their balance (40). The discomfort from sensitivity to cold made handing steel cutlery and retrieving items from the refrigerator unpleasant (40). Everyday tasks involving precise hand movements became challenging (40). Multiple individuals in the study emphasized the impact of neuropathy related issues on their capacity to enjoys walks in nature (40). Several individuals emphasized the significance of having overcome cancer, as it facilitated their acceptance of the adverse effects of treatment, feeling as they had limited alternatives (40). Enduring side effects during treatment proved more manageable than reintegrating into their daily routines afterward (40). Furthermore, some participants encountered a lack of empathy and pressure from others to exhibit happiness simply because they were now considered to be in good health following cancer treatment (40).

A study with patient perceptions associated with CIPN showed that patients had feelings of frustration, depression, and loss of purpose due to necessity of relinquishing pleasurable activities (41). Enhancing our comprehension of the patient journey through CIPN can lead to enhanced communication, evaluation, and treatment of symptoms.

A review conducted by Schwab and Visovsky showed that in comparison to the general population, psychological distress was more prominent in breast cancer survivors with some reports indicating the occurrence of depression and anxiety symptoms as high as 66% and 33% respectively (42). Patients who received taxane treatment and developed CIPN subsequently experienced heightened depressive symptoms (6). Bennedsgaard et al. discovered that breast cancer patients undergoing treatment with taxanes exhibited more pronounced psychological distress, including symptoms of depression, in comparison to those receiving alternative treatments (43). Heightened levels of anxiety also notably correlated with the severity of symptoms related to CIPN (44). Mental health challenges amongst breast cancer survivors pose a significant concern, warranting attention equal to that given to physical side effects of cancer treatments (42). This attention is crucial as these challenges can profoundly affect quality of life. Additionally, breast cancer survivors are found to have enduring psychological distress over the long term, underscoring the importance of screening and early recognition of symptoms (42).

Many survivors report that they did not understand the long-term side effects of chemotherapy and at times were hesitant to ask further questions due to overwhelming diagnosis and treatment plans (45). It remains crucial for clinicians to undergo discussions with patients about side effects, albeit short or long term, and to assess for impact on quality of life and psychological well being. The strong impact on quality of life and psychological factors indicates a necessity for interventions to help cancer survivors identify and promptly report CIPN symptoms, as well as mitigate its impact on daily life. Further research is required to advance the development of efficacious prevention and or treatment strategies, aiming to enhance quality of life.

Clinical presentation & pathogenesis

Patients with CIPN have symptoms including sensory loss, abnormal sensations, discomfort, numbness, and tingling, often worsened by neuropathic pain (2). The symptoms may fluctuate in both duration and severity, ranging from temporary alterations in sensation to enduring nerve damage resulting in persistent chronic pain (46). The theorized progression of CIPN is linked to the emergence of axonopathy, involving retrograde axonal damage, and neuronopathy affecting the cell bodies within the Dorsal Root Ganglia (DRG) (2). However, the exact pathophysiology remains unclear, with diverse underlying mechanisms proposed for different classes of anti-cancer drugs.

Prevalence of CIPN

The likelihood of CIPN occurrence is contingent upon the specific agent utilized. Studies have suggested rates from 19% to greater than 85% (47). The highest prevalence is seen with the use of platinum-based drugs which have prevalence rates of 70–100%; taxanes have reported rates 11–87% for grade 3 or greater CIPN (48). A meta-analysis involving 13,683 individuals diagnosed with CIPN indicated that the prevalence of neuropathic pain could reach up to 40% (49). A systematic review conducted by Seretny et al. included 31 studies with 4,179 patients. The study revealed CIPN prevalence to be 68% in the first month after chemotherapy, 60% 3 months later, and 30% at 6 months and greater (50). CIPN incidence is known not only to differ between different agents but also with dose schedules. A retrospective cohort study by Speck et al. showed that incidence of CIPN was higher in patients who received weekly paclitaxel for 12 cycles (16.1%; n=45 of 279; P<0.001) vs. docetaxel every 3 weeks for 6 cycles (2.4%; n=5 of 209; P<0.001) (51). Dose limiting CIPN was seen in 25% of patients receiving paclitaxel weekly for 12 cycles and in 14% of patients receiving paclitaxel biweekly for four cycles [odds ratio (OR) =2.11; 95% CI: 0.97–4.60] (51).

The SWOG S12714 study enrolled 1,336 patients with primary breast cancer starting taxane based treatment (52). Neuropathy was evaluated using patient reported EORTC QLQ-CIPN20 (CIPN-20) (52). The presence of significant sensory neuropathy was characterized by a rise of 8 points or higher (on a scale of 0–100, where a higher score signifies more severe symptoms) in the sensory neuropathy subscale of the CIPN-20 between the initial assessment and subsequent follow-up (52). The patients were evaluated at baseline and subsequently at 4, 8, 12 weeks and at 24, 52, 104, and 156 weeks after registration (52). Treatment with paclitaxel with a regimen consisting of weekly for 12 weeks or biweekly for 8 weeks was given to 56% of patients and docetaxel every 3 weeks for 12 weeks was given to 44% (52). The study revealed a mean baseline of patient reported CIPN-20 sensory neuropathy subscale of 6.2 with standard deviation of 12 (52). Over the course of a year of monitoring, 1,084 patients (91%) were evaluated, and clinically meaningful sensory neuropathy was found to be 19% at week 4, 33% at week 8, 46% at week 12, 45% at week 24, and 47% at week 52 (52). This large prospective cohort study with breast cancer patients receiving taxane based therapy revealed that during the initial year of treatment, clinically significant sensory neuropathy symptoms were encountered by two-thirds of patients, with nearly half persisting at the conclusion of the year (52).

Clinical risk factors for CIPN

Presently, there exists divergent viewpoints regarding the diverse risk factors linked to the occurrence of CIPN. This makes it difficult to accurately predict which subset of patients will experience CIPN. Previous studies have recognized nonmodifiable factors contributing to CIPN risk, including age, race, and genetics, as well as potentially modifiable factors, such as diabetes, sedentary lifestyle, and high systemic exposure to paclitaxel (46,53,54).

A retrospective cohort study by Hiramoto et al. analyzed potential factors associated with CIPN including age, body surface area (BSA), body mass index (BMI), metastasis at initial diagnosis, treatment history, ongoing diseases, and medical history (53). They found that older age especially >58 years was associated with increase in CIPN diagnosis (OR =2.03; 95% CI: 1.03–4.00; P=0.040) (53). BMI greater than or equal to 21.8 and BSA greater than or equal to 1.526 m² was also associated with increased incidence of CIPN (53). Another retrospective study evaluated risk factors for CIPN with paclitaxel-based therapy in breast cancer patients revealed age 57 years and older had increased risk of CIPN (OR =9.94; 95% CI: 2.06–47.9; P=0.004) (54). They also found that breast cancer survivors aged 57 years or older had a rapid development of CIPN in comparison to patients younger than 57 years [hazard ratio (HR) =3.85; 95% CI: 1.53–9.71; P=0.002] (54).

In a cohort study of 333 patients studied pre-treatment blood-based biomarkers in patients treated with paclitaxel and oxaliplatin chemotherapy (55). They found lower hemoglobin (β=−0.47; 95% CI: −0.73 to −0.21; P<0.001), higher BMI (β=0.08; 95% CI: 0.02 to 0.12; P=0.007), and older age (β=0.08; 95% CI: 0.06 to 0.11; P<0.001) had worse CIPN (55). Moreover, a prospective observational study with 268 patients evaluating clinical risk factors for CIPN induced by docetaxel and paclitaxel revealed BMI (OR =2.926, 95% CI: 1.621–5.281, P<0.001), BSA (OR =1.724, 95% CI: 1.011–2.941, P=0.045), and hypocalcemia (OR =4.899, 95% CI: 1.518–15.811, P=0.008) were risk factors for development of CIPN (56). However, only cumulative dose and BSA were found to be independent risk factors (56).

Race/ethnicity is an important clinical risk factor for the development of CIPN. SWOG S1714 prospective observational study revealed black women have two times the risk factor for development CIPN (52). Black women especially with germline mutations in SBF2 and FCAMR have increased risk for CIPN (57). Another study revealed 35% of black patients had grade 2 or higher CIPN (58).

Chemotherapy schedules also play a key factor into the risk for development of CIPN. In terms of paclitaxel and docetaxel scheduling, weekly administration of paclitaxel has demonstrated higher rates of CIPN in comparison to q3 weekly docetaxel (59).

Inflammatory and other biomarkers of risk for CIPN

Interestingly, multiple retrospective studies have indicated that individuals with lower levels of vitamin D before treatment are at increased risk of developing CIPN (60). A prospective-retrospective analysis utilizing data from the SWOG S0221 clinical trial evaluated pretreatment vitamin D insufficiency as a potential risk factor for CIPN in patients with early-stage breast cancer treated with paclitaxel (61). They found that older patients (OR =1.02; 95% CI: 1.01–1.04; P=0.005), patients self-reported as Black (OR =2.48; 95% CI: 1.57–3.86; P<0.001) or other race (OR =1.84; 95% CI: 1.06–3.07; P=0.025), or patients who were randomized to paclitaxel biweekly schedule (OR =2.37; 95% CI: 1.73–3.29; P<0.001) displayed a higher incidence of CIPN (61). Patients who were vitamin D insufficient at pretreatment showed a higher rate of grade 3 or higher CIPN than patients who were vitamin D sufficient (20.7% vs. 14.2%; OR =1.57; 95% CI: 1.14–2.15; P=0.005) (61).

Other potential risk factors include behavioral, psychosocial, and inflammatory (62). A study by Kleckner et al. studied pretreatment risk factors including inflammation, chemotherapy type, cancer stage, BMI, fatigue, anxiety, depression, use of diabetic medications, physical activity, age, and race (62). The analysis revealed fatigue, anxiety, depression, older age, baseline neuropathy and black race as predictors for development of CIPN (62). It also showed lower interleukin 6 (IL-6), lower anti-inflammatory interleukin 1 (IL-1) and higher pro-inflammatory interferon gamma (IFN-γ) as predictors for development of CIPN (62). This study showed that higher levels of pro-inflammatory markers such as IFN-γ and lower levels of anti-inflammatory markers such as interleukin 10 (IL-10) were associated with increased incidence of severe CIPN (62). Studies have also shown that there may be altered gene expression in neuroinflammatory pathways among breast cancer survivors experiencing CIPN compared to those without CIPN (63). Moreover, if fatigue, anxiety, and depression are implicated in the development of CIPN symptoms, implementing interventions to mitigate these factors could potentially prevent or alleviate the symptoms of CIPN (62).

A detailed description of genomic and other biomarkers of CIPN risk is beyond the scope of this article and have been reviewed elsewhere. Several studies have reviewed genome wide association extensively and have revealed specific single nucleotide polymorphisms (SNPs) that are correlated with an elevated likelihood of CIPN (46,64,65). Different agents have been found to be associated with unique SNPs that have predisposition to neuropathy (65). Taxanes such as paclitaxel have reported genetic polymorphisms that are known to interfere with tumor cell proliferation such as ERCC1, ERCC2, XRCC1, CCNH, CRX7, and ABCC4 (65). A genome wide association study of a large phase III clinical trial revealed early onset paclitaxel neuropathy in carriers of FGD4 polymorphisms (64). The FGD4 encodes for protein FGD1-related-F-actin binding protein (Frabin) is found in a gene that is well studied to have a role in hereditary peripheral neuropathy Charcot-Marie-Tooth disease (66). A study by Hertz et al. showed individuals with CYP2C8*3 variant had increased risk of paclitaxel related neuropathy (67). In breast cancer patients treated with taxanes, SNPs in CYP2C8 and CYP3A4 were found to be associated with grade 2 or higher CIPN in two studies (67,68). In another study with 79 breast cancer patients undergoing treatment with taxanes, SNPs in NR1IR and UGT2B7 which are involved in drug metabolism were found to be associated with CIPN (69). Vinca alkaloids such as vincristine interfere with microtubule function and thus may play a role in CIPN pathogenesis (70,71). SNP in CEP72 has been shown to be associated with CIPN in adults and children (70-76). In 48 acute lymphoblastic leukemia patients undergoing treatment with vincristine, 75% with the genotype TT developed CIPN vs. 44% with genotypes CC or CT (73). Further studies are needed to identify the role of genomic biomarkers associated with increased risk of CIPN. However, data to date have been limited due to lack of reproducibility and there is growing recognition that genomic biomarkers by themselves will be insufficient predictors (77). Studies have shown that Black women experience increased rates of taxane induced CIPN compared to White women while receiving adjuvant once weekly paclitaxel treatment for early-stage breast cancer which often leads to dose reductions and increased risk of recurrence (57,77). A prospective validation trial of germline predictors of taxane induced CIPN in black women with early-stage breast cancer revealed that germline variations failed to predict risk of CIPN in Black women receiving neoadjuvant weekly paclitaxel or every 3 weeks treatment with docetaxel (57).

Emerging biomarkers include neurofilament light chains and are under study by various groups. Enhanced comprehension of risk factors for CIPN, including genetic elements, could aid in pinpointing the most vulnerable patients for development of chronic CIPN and potentially inform novel treatment approaches in the future.

Drug classes

Neuropathy can develop due to several classes of chemotherapeutic agents (78-80). Sensory neuropathy is a common occurrence with platinum compounds. Research into the mechanisms of CIPN with platinum-based drugs has centered on the neurotoxic impact on sensory neurons within the dorsal root ganglion (4). Peripheral neurotoxicity appears to be most commonly associated with cisplatin among platinum compounds. Carboplatin is generally regarded as less neurotoxic compared to cisplatin (4). Oxaliplatin commonly causes temporary immediate effects. A significant feature of platinum-based CIPN is the phenomenon known as “coasting” (4). This term describes the observation that CIPN induced by platinum-based agents, particularly cisplatin and oxaliplatin, may deteriorate over several months after treatment cessation.

Taxanes (paclitaxel, docetaxel, cabazitaxel) are commonly employed in cancer treatment and often lead to a sensory neuropathy characterized by pain that is dose-dependent and correlated with the length of exposure, attributed to axonopathy resulting from axonal degeneration (4). Microtubules act as the pathway for axonal transport, and taxanes disrupt this process in laboratory settings, potentially causing neuropathy. Additional evidence suggests that mitochondrial damage may contribute to metabolic axonal dysfunction in CIPN (81). Cabazitaxel seems to exhibit lower overall toxicity compared to paclitaxel (76). More than half of patients undergoing treatment with paclitaxel experience an acute, temporary pain syndrome (82).

A trial involving patients who demonstrated significant peripheral neuropathy and had received taxanes (49%), oxaliplatin (44%), carboplatin/cisplatin (20%), vinca alkaloids (8%), thalidomide (3%) or a combination of these drugs revealed all patients with pain had significant numbness and tingling most severe in the lower extremities (83).

Eribulin and ixabepilone, both utilized in breast cancer treatment, are known to induce peripheral neuropathy characterized by axonal sensorimotor symptoms (84). One innovative pharmaceutical strategy involves combining a chemotherapy agent with antibodies specifically targeted to tumors. Ado-trastuzumab emtansine merges an antibody targeting HER2 (related to breast cancer) with emtansine, a compound that impedes the formation of microtubule polymers and is linked to a notable occurrence of peripheral neuropathy (85).

Neurotoxicity is not directly implicated with checkpoint inhibitors, but immune-mediated neuropathies can arise in connection with the usage of immune checkpoint inhibitors. Cases of neuropathy that are reported frequently exhibit similarities to acute or chronic inflammatory demyelinating neuropathies or vasculitic neuropathies (86).

Certain drugs, foods and nutritional agents can increase the risk of chemotherapy induced toxicity due to their inhibition of CYP3A enzymes (87,88). CYP3A enzymes play an essential role in metabolizing several chemotherapeutic agents (87). Antimycotic drugs such as azole antifungals can increase the risk of chemotherapy induced toxicity (88-92). Azole antifungals are inhibitors of cytochrome P450 enzymes and can lead to higher concentrations of chemotherapeutic agents, potentially increasing neurotoxicity (88). Antifungals also inhibit P-glycoprotein pumps which are responsible for eliminating several chemotherapeutic agents, leading to prolonged exposure and increase toxicities (88). Particularly, antifungal agents and vinca alkaloids have been shown to lead to increased risk of neurotoxicity (89-91). Moreover, grapefruit juice contains phytochemicals involved in CYP3A mediated metabolism and thus can interact with several chemotherapeutic agents (93). Several agents such as kinase inhibitors, etoposide, sirolimus have been identified to interact with grapefruit juice (94-97). Bergamottin which is found in grapefruit and lime juice has inhibitor effects on CYP3A4 and may lead to increased risk of neurotoxicity in combination with chemotherapy agents (98). Additionally, ginger is commonly used for reducing nausea and vomiting due to chemotherapeutic agents; there is currently no strong evidence to suggest increased risk of chemotherapeutic toxicities with moderate consumption (99). Other medications such as macrolide antibiotics, selective serotonin reuptake inhibitors (SSRIs), human immunodeficiency virus (HIV) protease inhibitors, and calcium channel blockers can also inhibit CYP3A and may lead to increased toxicities of chemotherapy agents (100-103). However, given insufficient data these medications or combination treatments are not contraindications to use.

Acute neuropathy

Certain chemotherapy drugs that induce neuropathy, like taxanes and oxaliplatin, can trigger an acute neuropathy syndrome alongside CIPN. Peripheral neuropathy induced by taxanes is prevalent among individuals who have survived breast cancer. During chemotherapy with taxanes, 71% (95% CI: 43.5–98.1%) of patients reported neuropathy (50). The prevalence of taxane induced peripheral neuropathy after completion of chemotherapy can range from 23% to 80% (104). The occurrence of taxane-induced peripheral neuropathy has been demonstrated to diminish over time. Initially, 68% of patients reported experiencing peripheral neuropathy within one month after completing chemotherapy; this decreased to 60% at 3 months, and further decreased to 30% at 6 months or more post-chemotherapy completion (50).

Paclitaxel can induce acute neuropathy that manifests as a sudden onset of pain syndrome, often appearing within 1 to 3 days following paclitaxel administration, and typically resolves within a week (104-106). This manifests as arthralgia/myalgias and is thought to be a form of acute neuropathy (107). This syndrome manifests in most patients and is particularly noticeable in patients who receive higher doses of paclitaxel individually (107). Symptoms indicative of paclitaxel-induced peripheral neuropathy can manifest as soon as 24 to 72 hours following the administration of high single doses of paclitaxel (108). The intensity of paclitaxel-induced neuropathy correlates with both the individual dose administered and the total cumulative dose. The symptoms evident upon presentation include numbness, paresthesia’s, and a burning sensation, typically in a glove and stockings pattern (109). Symptoms commonly exhibit symmetry and typically originate distally in the lower extremities. Patients frequently describe the simultaneous onset of symptoms in both toes and fingers, although there are instances of uneven presentations (108). While facial involvement is less prevalent, it has been reported (110).

Chronic CIPN

Chronic CIPN refers to dose related, persistent symptoms for at least two subsequent cycles without symptom free period of symmetrical distal paresthesia and dysesthesia (6). This is commonly referred to as CIPN. Symptoms may start early after initiation of neurotoxic chemotherapy regimens however most times they are truly evident after multiple cycles of neurotoxic chemotherapy (45). It is usually persistent and worsens with subsequent chemotherapy cycles (45). Even though mild symptoms may improve or completely resolve within a few months after treatment cessation, many patients experiencing severe neuropathy have reported that symptoms and deficits persist for a longer duration (109).

Symptoms of chronic CIPN include paresthesia’s, dysesthesias in the hands and feet in a stocking and glove distribution (45). A cross sectional study examining the prevalence of CIPN over an average follow-up period of 5.6 years revealed that 58.4% of individuals who survived breast cancer reported experiencing persistent peripheral neuropathy (6). This finding mirrored another investigation involving 462 female cancer survivors who participated in an exercise trial. Among them, 208 individuals (45%) experienced symptoms of CIPN approximately six years post-treatment (58).

Prevention and treatment strategies

Multiple compounds have been studied in clinical trials for their effectiveness in preventing CIPN, including antidepressants, anticonvulsants, vitamins, and minerals. However, these treatments have not shown conclusive clinical benefit (78,111-116). As a result, there is insufficient high-quality evidence to recommend any specific agent for medical prophylaxis of CIPN. Durand et al. conducted a phase II randomized, placebo-controlled clinical trial evaluating venlafaxine in the prevention of CIPN (111). They evaluated fifty patients receiving their first or second cycle of oxaliplatin in addition to venlafaxine or placebo; the results did not support its use as a preventive strategy (111). Similarly, another pilot randomized, placebo-controlled, study evaluated the use of venlafaxine in prevention of oxaliplatin neurotoxicity and did not support its use (112).

A phase II placebo-controlled clinical trial evaluating 46 patients scheduled to receive weekly paclitaxel were randomized 1:1 to receive pregabalin 75 mg or a placebo, twice daily during the 12 weeks of chemotherapy (113). There results showed that pregabalin decreased numbness yet failed to decrease tingling, pain or EORTC QLQ-CIPN20 subscales (113). Another double-blind, placebo-controlled trial investigated 143 colorectal cancer patients who were chemotherapy-naïve and received at least 1 cycle of modified fluorouracil, leucovorin, and oxaliplatin. They were assigned to receive either pregabalin or placebo for 3 days before and 3 days after each oxaliplatin treatment (114). At 6 months, results did not support the use of pregabalin for CIPN prevention (114).

Vitamins have also been studied in the prevention of CIPN but have failed to show promising results. Vitamin B was studied in a small placebo-controlled two-arm trial in patients receiving taxanes, oxaliplatin or vincristine. There was no evidence these products were useful in prevention in this context (115). Vitamin E has also been studied, and a meta-analysis including six studies including 353 patients failed to show a decreased incidence of CIPN (116).

Cryocompression

Enhancing quality of life and treatment outcomes could be achieved by averting CIPN during perioperative breast cancer treatment. At present, there are no recommended non-pharmacological or pharmacological treatments for preventing CIPN (104). Prevention of CIPN remains a challenge. Numerous clinical trials aiming to prevent CIPN have been conducted with limited sample sizes, yet none have yielded conclusive evidence for either prevention or treatment (117). Several studies have investigated the benefit of cryocompression (117-120). Cryocompression is a promising preventative strategy for CIPN, and additional confirmatory data are needed. Cryotherapy involves cooling the extremities through application of cold therapy methods such as ice packs or wearable garments, typically administered during chemotherapy (119). Compression therapy entails the utilization of stockings or gloves to diminish microvascular flow during chemotherapy (119). The vasoconstrictive impact of these techniques is believed to restrict the localized impact of chemotherapy, thereby averting toxicity to the nerves in extremities (119).

An investigative post hoc examination of the Danish Breast Cancer Cooperative Group trial, encompassing patients receiving epirubicin and cyclophosphamide followed by docetaxel or docetaxel and cyclophosphamide showed wearing frozen gloves and socks resulted in significantly reduced neuropathy both following initial as well as further cycles of docetaxel (121). Hanai et al. studied cryotherapy using frozen gloves and socks in a non-randomized control study with breast cancer patients receiving weekly paclitaxel (122). The patient’s non-dominant hand was the control group in the study. Compared to the control group, cryotherapy showed significantly less deterioration in tactile sensation (hand 27.8% vs. 80.6%; OR =20.00; P<0.01, foot 25% vs. 63.9%; OR = infinite; P<0.01) (122). A randomized controlled trial (RCT) with breast cancer patients receiving weekly paclitaxel studied cryotherapy in prevention of CIPN (123). There was no statistically significant variance observed in sensory nerve action potential amplitude between the groups (123). However, at the 6-month mark a notable correlation was observed between the extent of skin cooling and preservation of motor amplitude (123). A non-randomized control study with cancer patients receiving weekly paclitaxel or every 3 weeks docetaxel was conducted to evaluate cryocompression for treatment of CIPN (124). Patients in the cryocompression group exhibited notably more substantial decrease in skin temperature (124). Furthermore, nerve conduction studies revealed cryocompression maintained motor amplitudes at 3 months (124).

SWOG S2205 Ice-Compress is an ongoing phase III trial examining the impact of three different study methods on the prevention of CIPN which include cryocompression, continuous compression and low cyclic compression (125). The three study methods employ a device known as the Paxman Limb Cryocompression System, consisting of wraps designed to cool and or compress the arms and legs (125). This study will give further insight into cryocompression techniques in mitigating CIPN. Further data are needed to delineate the role of cooling therapy for prevention of CIPN. The phase III trial SWOG study is currently ongoing to evaluate role of cryotherapy for prevention of CIPN and will likely lead to definitive recommendation regarding utility of this approach. The guidelines from American Society of Clinical Oncology (ASCO) suggest that limb cooling therapy and compression therapy could potentially help in preventing symptoms of CIPN. However, they do not provide a recommendation for using these interventions outside of the clinical trial settings (126). The European Society for Medical Oncology (ESMO) 2020 guidelines state cryotherapy and compression therapy can be considered, however high-quality supporting evidence is limited (127).

Neuropathic pain agents

Our understanding of the pathophysiology of CIPN remains incomplete and thus treatments aimed at alleviating CIPN pain have not been shown to be successful. Trials involving agents administered to cancer patients for preventing CIPN have failed to demonstrate consistent or conclusive clinically significant advantages when compared to placebo controls (104,128). Identifying and treating CIPN encounter notable challenges. There are no established agents recommended for treating CIPN in cancer patients receiving neurotoxic treatments due to limited high-quality evidence and consideration of benefits and risks (126).

Several studies suggest that serotonin-norepinephrine reuptake inhibitors (SNRIs) may increase concentration of neurotransmitters, blocking input to dorsal horn neurons and thus reduce pain transmission (129). Duloxetine is the only SNRI that is established in treating CIPN (104). A meta-analysis examining the impact of SNRI treatment on CIPN has verified notable effectiveness and safety of duloxetine use (129). Duloxetine is thought to function by suppressing the activation of p38 phosphorylation and thereby hindering activation and nuclear migration of NF-kB transcription factor (130). This action reduces the inflammatory reaction and mitigates nerve injury by modulating nerve growth factor levels (130). Duloxetine has demonstrated a greater efficacy compared to venlafaxine in reducing CIPN symptoms (131).

Numerous neurological pain agents have undergone assessment for the treatment of CIPN including gabapentin and pregabalin. These agents have a history of known effectiveness against other neuropathic pain disorders such as diabetic peripheral neuropathy and postherpetic neuralgia. This selection occurred even though CIPN differs from other types of neuropathic pain in terms of its pathophysiology and symptom presentation (83). The way these agents work involves selective binding to the a2s subunit of voltage dependent calcium channels which are believed to be significant in neuropathic pain (132). Studies conducted on use of gabapentin or pregabalin for prevention or treatment of CIPN related pain did not yield positive results and thus they are not routinely used or recommended, although these agents are often most commonly used intervention in routine practice for CIPN. A phase III study with gabapentin vs. placebo failed to show benefit in the use of gabapentin to treat CIPN symptoms (133).

Duloxetine can be used in clinical settings for individuals with painful CIPN, based on data from RCTs (104,134). Tricyclic antidepressants, anticonvulsants or compounded topical gel treatments did not show any benefit for treatment of CIPN. The current guidelines from ASCO 2020 state that healthcare providers should evaluate and discuss delaying, reducing doses, discontinuing, or substituting alternative chemotherapy in patients who experience severe neuropathy (moderate strength recommendation) (126). A moderate strength recommendation is made for offering duloxetine to patients with pain inducing CIPN (126). The ESMO 2020 guidelines for treatment of CIPN recommend the use of duloxetine based on data supporting moderate clinical benefit (127). They also state that venlafaxine can be considered and anticonvulsants, tricyclic anti-depressants (TCA) and opioids may be used if treatment with duloxetine fails or is contraindicated (127).

Opioids

Opioids are commonly used to treat cancer related pain. However, they are not currently recommended for the treatment of CIPN. In 2015, the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain conducted a systematic review and meta-analysis of randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain. Their recommendations were applied to neuropathic pain in general and not to specific etiologies of neuropathic pain (135). Thirteen trials evaluating strong opioid use (especially oxycodone at 10–120 mg/day and morphine 90–240 mg/day) in treatment of peripheral neuropathy were evaluated with findings of moderate quality of evidence (135). They found 10 positive trials with a combined number needed to treat of 4.3 (95% CI: 3.4–5.8; P<0.01) and number needed to harm of 11.7 (95% CI: 8.4–19.3; P<0.01) (135). The studies revealed that maximum effectiveness was seen at morphine dose of 180 mg or equivalent with no benefit seen at higher doses (135). Tramadol was evaluated in 7 positive studies with tramadol extended-release (ER) up to 400 mg daily (135). Based on this data, strong opioids have weak grade recommendation in modern clinical practice guidelines for use and are only recommended as third-line agents for neuropathic pain per NeuPSIG 2015 guidelines (135). The European Federation of Neurological Societies Task Force (EFNS) provides level B evidence for use of tramadol in cancer related neuropathy based on single class II studies (136). Moreover, opioids are not recommended for prevention or treatment of CIPN per ESMO or ASCO guidelines due to weak evidence (126,127).

Topical therapy

Capsaicin is a selective agonist of the transient receptor potential vanilloid 1 ion channel (TRPV1) and activates TRPV1-expressing cutaneous nociceptors (78). Once activated, ion influx with release of vasoactive neuropeptides, depolarization, and propagation of action potentials into the brain and spinal cord occurs (78). This can be exhibited clinically as sensations of burning, warming, stinging, or itching at the application site (137). Continued exposure of capsaicin results in reversible nociceptor defunctionalisation in the applied area allowing for localized neuropathic pain relief (137,138).

Capsaicin is licensed for use only in postherpetic neuralgia and painful diabetic peripheral polyneuropathy. A randomized controlled open-label study of the long-term effects of a high concentration capsaicin patch on epidermal nerve fiber density and sensory function was conducted in healthy volunteers (139). It revealed that the capsaicin patch reduced the density of epidermal nerve fibers and showed modest reduction in tactile thresholds and sharp mechanical pain detection (139). Additionally, the QUCIP prospective, multicenter observational study evaluated the high concentration 179 mg (8% w/w) capsaicin patch in alleviating neuropathic pain and symptoms in breast cancer patients (140). Their study revealed that the painDETECT score decreased significantly from baseline 19.71±4.69 to 15.80±6.20 after initial treatment (P<0.0001) (140). Clinically significant pain relief of ≥30% increased from 25% at week 4 to 36.2%, 43.5%, and 40% at weeks 12, 24, and 36 respectively (140). Patients also reported improvement in quality of life throughout the study (140). The NeuPSIG 2015 guidelines revealed 5 out of 7 studies showed sustained efficacy of a single application of high concentration capsaicin patch 8% (179 mg) compared with low concentration 0.04% control patch (135). The final quality of evidence was high with a combined number needed to treat of 10.6 (95% CI: 7.4–19; P<0.01) (135). High concentration capsaicin patches have weak grade recommendations for use and are recommended for second line treatment for neuropathic pain per NeuPSIG 2015 guidelines (135). Maihöfner et al. recommend high dose capsaicin treatment as first line therapy in cases of localised neuropathic pain but denotes that this is an off-label use in conditions other than postherpetic neuralgia or painful diabetic peripheral neuropathy (78). The National Institute for Health and Care Excellence (NICE) guidelines for pharmacological management of neuropathic pain in adults recommends considering capsaicin cream for people with localised neuropathic pain who are unable to tolerate or prefer to avoid oral treatments. However, the guidelines state that use outside of post-herpetic neuralgia and painful diabetic peripheral polyneuropathy is off label (141). Much of the evidence for capsaicin patch for neuropathic pain is attained from studies without CIPN patients. ESMO guidelines state capsaicin 8% containing patches can be considered in patients with CIPN with level III and grade C evidence and is not mentioned in the ASCO guidelines (126,127). Capsaicin use does not have high evidence for CIPN however can be used on case-by-case basis as an off-label treatment option.

Similarly, lidocaine patches have been approved for treatment of postherpetic neuralgia and may play a role in treatment of neuropathic pain but clinical trials evaluating efficacy in CIPN are lacking (78,142). Maihöfner et al. recommend using lidocaine patches as second line treatment options for peripheral neuropathic pain in patients unable to tolerate oral medications (78). Importantly, use outside of postherpetic neuralgia would be off-label (78). NeuPSIG 2015 guidelines report weak grade recommendations for use of lidocaine patches and recommend them for second line treatment for neuropathic pain (135). CIPN is commonly associated with symptoms in multiple areas of the body and thus topical application of one patch may not provide substantial relief in such patients. Due to the lack of studies on the use of lidocaine patches for CIPN, they are not recommended in the ESMO or ASCO guidelines (126,127).

In summary, neuropathic pain is a heterogenous group of conditions resulting from various etiologies, mechanisms and displaying varying symptoms (142). Due to this heterogeneity, neuropathic pain resulting from chemotherapy may not be treated in the same manner as other forms of neuropathic pain. Topical therapies may provide benefit to some but the evidence remains weak and it is not currently a standard treatment approach for CIPN.

Acupuncture

There is great interest in non-pharmacological interventions for management of CIPN. Evidence suggesting benefit of such strategies has yet to be determined as trials are ongoing. Acupuncture is an emerging modality that has been used in Chinese medicine for several years for pain control.

A RCT by Lu et al. studied impact of acupuncture on CIPN in breast cancer patients (143). They studied women with stage I–III breast cancer with grade 1 or greater CIPN after receiving taxane containing chemotherapy (143). The patients were randomized 1:1 to immediate acupuncture group or waitlist control group (143). Patients in the immediate acupuncture group received a total of 18 acupuncture sessions over 8 weeks whereas patients in the control group received usual care over the 8 weeks (143). The measurements used in the study were patient neurotoxicity questionnaire (PNQ), FACT-NTX and brief pain inventory-short form (BPI-SF) (143). The PNQ uses questions to allow for patients to elicit and grade the subjective symptoms of CIPN impairment in daily life activities (144). In the initial 8-week intervention, response rates where measured and defined as one unit change in sensory or motor scores on the PNQ and were found to be 65% in the acupuncture arm (95% CI: 41–85%) vs. 35% (95% CI: 15–59%) in the control group (143). Approximately 60% of the patients in the acupuncture group reported at least one point improvement in PNQ sensory scores and 35% reported at least one point improvement in motor scores (143). This trial showed improvement in neuropathic pain symptoms with the use of acupuncture (143).

An ongoing phase III trial of acupuncture for CIPN treatment (ACT) is studying the efficacy of an 8-week course of electroacupuncture vs. sham acupuncture for the treatment of CIPN and these results will yield important information on the use of acupuncture in CIPN patients (145).

Physical therapy/exercise

Individuals experiencing CIPN typically encounter a range of symptoms, such as pain, muscle weakness, difficulty with balance, unsteady gait and decreased or absent reflexes (146). Due to these factors, motor impairments such as compromised balance, reduced walking speeds, and weakened limb strength are frequently observed, leading to increase falls (147).

The effects of exercise on patients including patients with chemotherapy related side effects such as neuropathy demonstrated that engaging in physical activity can diminish motor impairments caused by CIPN and enhance coordination (146). Physical activity is frequently employed for neural rehabilitation after injury, yet its effectiveness for prevention and or treatment of CIPN has not been fully assessed (148). An exploratory study compared standard of care to a physical therapy home program throughout adjuvant taxane chemotherapy for stage I–III patients with breast cancer (148). The study showed notable trends suggesting reduction in pain although this was not found to be statistically significant. However, a reduction in pain over time was found to be statistically significant (OR =0.85; 95% CI: 0.76–0.94) (148). Patients were also noted to have improvement in pain pressure thresholds and grip dynamometry (148).

A non-randomized trial completed in Australia studied supervised and home-based exercise in 29 patients with CIPN for at least 3 months post treatment (149). The exercise regimen comprised of resistance training, balance, and cardiovascular training (149). The primary outcome was measured using total neuropathy score-clinical version (TNSc) (149). The TNSc encompasses clinician rated items related to vibration, pinprick, muscle strength and reflex and patient reported symptoms (150). Exercise decreased CIPN severity from pre- to post-intervention (P=0.001) (149).

A randomized study using home-based exercise compared to usual care in patients initiating neurotoxic chemotherapy was conducted to study CIPN (151). The patients were evaluated pre intervention and post intervention using two patient reported outcomes of CIPN severity (151). The study revealed that exercise reduced CIPN symptoms of numbness/tingling (−0.42 units, P=0.061) and hot/coldness in hands/feet (−0.46 units, P=0.045) (151). A randomized control blinded trial compared sensorimotor training and whole-body vibration training to oncology control group and healthy age and gender matched control group (152). The primary endpoint of the study was to evaluate potential use of neuromuscular stimulating exercise to reduce CIPN symptoms (152). The patients in the exercise intervention groups showed improved motor and sensory symptoms (152).

The multi center STOP trial assessed supervised movement-based interventions for preventing CIPN (153). The trial randomized 158 patients to 1 of 3 arms which consisted of sensorimotor training, vibration training or usual care (153). Sensorimotor training involved postural control on an unstable surface and vibration training involved patients standing on a vibration platform (153). The patients in the intervention arms underwent twice weekly 15-to-30-minute sessions with trained sports therapists. The primary endpoint for the study was incidence of CIPN during chemotherapy which was evaluated by physical exam and the coprimary end point was time to diagnosis of CIPN (153). The study concluded that the incidence of CIPN was lower in the intervention arms with 30% in sensorimotor training, 41% in vibration training and 71% in usual care and time to CIPN was also found to be longer in the intervention arms (153). An ongoing trial (NCT04888988) is evaluating walking and resistance training in home-based settings for CIPN (154). Home-based physical therapy programs could potentially alleviate pain associated with CIPN (118). However, additional studies are needed to validate the effectiveness of a physical therapy home program in addressing CIPN symptoms (148). The ESMO guidelines recommend starting training aimed at coordination, sensorimotor skills, and fine motor skills with the emergence of CIPN symptoms (127).

Dance & rhythmic movement

Music based medicine incorporated with physical activity shows promise in addressing sensorimotor symptoms associated with CIPN (155). A single center, prospective, two-arm RCT trial evaluated the effects of neurologic dance training (NDT) through adapted tango vs. home exercise in improving dynamics of posture and gait that are predictive for fall risks and postural control deficits amongst breast cancer survivors with CIPN (155). The main outcome measure was high gamma activity during oddball paradigm relative to activity at baseline task of quiet bilateral standing with eyes open (155). Prior studies have shown that high gamma activity is related to age performance deficits occurring during challenging balance tasks (156). At 8 weeks of NDT completion, high gamma activity was found to be lower during visual and auditory tasks in comparison to quiet bilateral standing with eyes open before NDT (155). These results are promising for the use of NDT for CIPN treatment.

Yoga

Yoga is a form of meditative movement therapy that incorporates stretching, flexibility and balance training (157). An ongoing three arm randomized education and usual care-controlled trial in cancer survivors with chronic CIPN is currently underway (157). The pilot study showed that yoga decreased symptoms associated with CIPN, enhanced quality of life, and boosted functional reach scores (157). In an RCT, breast and gynecological cancer survivors with moderate to severe CIPN with a score of 4 or more based on a numeric rating scale (NRS) for at least 3 months after chemotherapy were assigned to 8 weeks of usual care or yoga (158). The NRS is scored 0–10 based on severity of pain with 0 being none and 10 being the most severe. At 8 weeks, NRS pain was shown to decrease by 1.95 points in yoga vs. 0.65 in usual care (158). Functional reach, a quantifiable functional assessment indicating fall risk, exhibited a 7.14 cm improvement in the yoga group while it decreased by 1.65 in the usual care group (158). Yoga demonstrated safety and exhibited promising effectiveness in alleviating CIPN symptoms (158).

Scrambler therapy and transcutaneous electrical nerve stimulation (TENS) unit

Scrambler therapy represents an innovative method for pain management, aiming to alleviate pain by delivering non pain signals through cutaneous nerves to counteract impact of pain signals (159). TENS involves applying a gentle electrical current via electrodes to activate nerves (153). A randomized control trial studied scrambler therapy vs. TENS for 2 weeks in treating CIPN (159). It revealed that patients treated with scrambler therapy had a minimum 50% improvement in CIPN symptoms in comparison to those treated with TENS (159). A systematic review revealed that TENS may have some effectiveness in CIPN treatment; however, this data is limited by its observational nature (160). TENS and scrambler therapy have been compared to each other in studies however not against placebo. This creates a prospect for future research to delineate scrambler and TENS therapy efficacy in CIPN management/treatment.

A cross sectional survey of patients who were currently or previously receiving neurotoxic chemotherapy regimens was conducted to study patients use of modalities for CIPN (161). The survey revealed 29% of patients used a non-pharmacological approach for prevention of CIPN with cryotherapy used mostly up to 10% (161). In terms of treatment, 40% used a prescription medication such as gabapentin being used the most at 24% whereas duloxetine used only 8% (161); 49% of patients used non-prescription medications for treatment of CIPN with vitamin b complex being used 29% and magnesium 22% (161). Other modalities such as non-pharmacological were used in 61% of patients with exercise therapy being the most frequently used at 47% followed by massage therapy at 36% (161). Another survey evaluating patients use of various modalities for CIPN management was conducted in Japan (162). It revealed that used medications for treatment of numbness associated with CIPN were pregabalin 98.7%, vitamin B12 74.7%, and duloxetine at 46.8% (162). Pain associated with CIPN was mostly treated using nonsteroidal anti-inflammatory drugs (NSAIDs) followed by opiates and neuropathic drugs such as pregabalin (162).

Conclusions

CIPN may lead to debilitating symptoms and can substantially impact the quality of life of patients during and after treatment. Given the prevalence of chronic CIPN in patients and the apparent gaps in current literature, it is essential to undertake further investigations. These efforts would shed light on the long-term quality of life impacts on patients and may provide insights into potential interventions to alleviate this incapacitating condition.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Palliative Medicine for the series “Supportive Care After Breast Cancer: Challenges and Opportunities”. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-154/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-154/coif). The series “Supportive Care After Breast Cancer: Challenges and Opportunities” was commissioned by the editorial office without any funding or sponsorship. M.B.L. served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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