Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most frequent side effects caused by antineoplastic agents, with a prevalence from 19% to over 85%. Clinically, CIPN is a mostly sensory neuropathy that may be accompanied by motor and autonomic changes of varying intensity and duration. Due to its high prevalence among cancer patients, CIPN constitutes a major problem for both cancer patients and survivors as well as for their health care providers, especially because, at the moment, there is no single effective method of preventing CIPN; moreover, the possibilities of treating this syndrome are very limited. There are six main substance groups that cause damage to peripheral sensory, motor and autonomic neurons, which result in the development of CIPN: platinum-based antineoplastic agents, vinca alkaloids, epothilones (ixabepilone), taxanes, proteasome inhibitors (bortezomib) and immunomodulatory drugs (thalidomide). Among them, the most neurotoxic are platinum-based agents, taxanes, ixabepilone and thalidomide; other less neurotoxic but also commonly used drugs are bortezomib and vinca alkaloids. This paper reviews the clinical picture of CIPN and the neurotoxicity mechanisms of the most common antineoplastic agents. A better understanding of the risk factors and underlying mechanisms of CIPN is needed to develop effective preventive and therapeutic strategies.

Mechanisms of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel and paclitaxel which interfere with the cancer cell cycle – leading to cell death and tumor degradation – and cause severe acute and chronic peripheral neuropathies We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches

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Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia, and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer, peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund’s adjuvant injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel therapeutic strategies for pathological pain.

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Interleukin-6: an emerging regulator of pathological pain

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with chemotherapy, but researchers rarely study its risk factors, fall risk, and prevalence in long-term breast cancer survivors. We aimed to determine CIPN prevalence, risk factors, and association with psychological distress and falls among long-term breast cancer survivors. We conducted Cross-sectional analyses among postmenopausal women with a history of stage I–III breast cancer who received taxane-based chemotherapy. Participants reported neuropathic symptoms of tingling/numbness in hands and/or feet on a 0–10 numerical rating scale. We conducted multivariate logistic regression analyses to evaluate risk factors associated with the presence of CIPN and the relationship between CIPN and anxiety, depression, insomnia, and patient-reported falls. Among 296 participants, 173 (58.4 %) reported CIPN symptoms, 91 (30.7 %) rated their symptoms as mild, and 82 (27.7 %) rated them moderate to severe. Compared with women of normal weight, being obese was associated with increased risk of CIPN (adjusted OR 1.94, 95 % CI: 1.03–3.65). Patients with CIPN reported greater insomnia severity, anxiety, and depression than those without (all p < 0.05). Severity of CIPN was associated with higher rates of falls, with 23.8, 31.9, and 41.5 % in the “no CIPN,” “mild,” and “moderate-to-severe” groups, respectively, experiencing falls (p = 0.028). The majority of long-term breast cancer survivors who received taxane-based chemotherapy reported CIPN symptoms; obesity was a significant risk factor. Those with CIPN also reported increased psychological distress and falls. Interventions need to target CIPN and comorbid psychological symptoms, and incorporate fall prevention strategies for aging breast cancer survivors.

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Long-term chemotherapy-induced peripheral neuropathy among breast cancer survivors: prevalence, risk factors, and fall risk

PurposeChemotherapy-induced peripheral neuropathy (CIPN) may persist after treatment ends and may lead to functional decline and falls This study compared objective and self-report measures of physical function, gait patterns, and falls between women cancer survivors with and without symptoms of CIPN to identify targets for functional rehabilitationMethodsA secondary data analysis of 512 women cancer survivors (age, 62 ± 6 years; time since diagnosis, 58 ± 41 years) categorized and compared women self-reporting symptoms of CIPN (CIPN+) with asymptomatic women (CIPN−) on the following: maximal leg strength, timed chair stand, physical function battery, gait characteristics (speed; step number, rate, and length; base of support), self-report physical function and disability, and falls in the past yearResultsAfter an average of 6 years after treatment, 47% of women still reported symptoms of CIPN CIPN+ had significantly worse self-report and objectively measured function than did CIPN−, with the except

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Falls, Functioning, and Disability Among Women With Persistent Symptoms of Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition resulting from chemotherapy for cancer. Severe acute CIPN may require chemotherapy dose reduction or cessation. There is no effective CIPN prevention strategy; treatment of established chronic CIPN is limited, and the prevalence of CIPN is not known. Here we used a systematic review to identify studies reporting the prevalence of CIPN. We searched Embase, Medline, CAB Abstracts, CINAHL, PubMed central, Cochrane Library, and Web of Knowledge for relevant references and used random-effects meta-regression to estimate overall prevalence. We assessed study quality using the CONSORT and STROBE guidelines, and we report findings according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. We provide a qualitative summary of factors reported to alter the risk of CIPN. We included 31 studies with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7-78.4) when measured in the first month after chemotherapy, 60.0% (36.4-81.6) at 3months and 30.0% (6.4-53.5) at 6months or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there was some evidence of publication bias. Genetic risk factors were reported in 4 studies. Clinical risk factors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clearance, and specific sensory changes during chemotherapy. Although CIPN prevalence decreases with time, at 6months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post-chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that require further study.

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Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

31 Chemotherapy-induced Q4 peripheral neuropathy (CIPN) is a disabling pain condition resulting from chemo32 therapy for cancer. Severe acute CIPN may require chemotherapy dose reduction or cessation. There is no 33 effective CIPN prevention strategy; treatment of established chronic CIPN is limited, and the prevalence 34 of CIPN is not known. Here we used a systematic review to identify studies reporting the prevalence of 35 CIPN. We searched Embase, Medline, CAB Abstracts, CINAHL, PubMed central, Cochrane Library, and 36 Web of Knowledge for relevant references and used random-effects meta-regression to estimate overall 37 prevalence. We assessed study quality using the CONSORT and STROBE guidelines, and we report findings 38 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. 39 We provide a qualitative summary of factors reported to alter the risk of CIPN. We included 31 studies 40 with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7–78.4) when measured 41 in the first month after chemotherapy, 60.0% (36.4–81.6) at 3 months and 30.0% (6.4–53.5) at 6 months 42 or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there 43 was some evidence of publication bias. Genetic risk factors were reported in 4 studies. Clinical risk fac44 tors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clear45 ance, and specific sensory changes during chemotherapy. Although CIPN prevalence decreases with 46 time, at 6 months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post47 chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that 48 require further study. 49 2014 The Authors. Published by Elsevier B.V. on behalf of International Association for the Study of 50 Pain. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ 51 by-nc-nd/3.0/).

Incidence, Prevalence and Predictors of Chemotherapy Induced Peripheral Neuropathy

208 Background: Cancer-treatment related peripheral neuropathic pain is a challenging clinical problem as current interventions have limited efficacy and significant toxicities. This study aims to examine the analgesic effect of high-concentration 8% capsaicin patch in this cohort of patients. Methods: A single arm study was conducted. Patients with long-term peripheral neuropathic pain received a single application of 8% transdermal capsaicin patch to the affected area (chest wall, hands or feet). Assessments at baseline, 4 weeks and 12 weeks post-treatment included: Brief Pain Inventory (BPI) short form (pain severity and interference with function); Hospital Anxiety and Depression Scale (HADS). The primary efficacy measure was a clinically significant improvement in pain (≥ 30% reduction in total BPI score (responders) from baseline to 4 weeks and 12 weeks). Secondary efficacy measures assessed worst pain, function and associated changes in mood. Results: 19 patients, median age 61.5 all had peripheral...

Investigating high-concentration 8% capsaicin patch in chronic cancer-treatment related peripheral neuropathic pain.

BACKGROUND: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a disabling side effect of chemotherapy. Severe CIPN may require chemotherapy dose reduction or cessation. There is no effective CIPN prevention strategy; treatment of established CIPN is limited, and the prevalence of CIPN is not known. Here we aim to calculate overall CIPN prevalence from published studies, and to identify risk factors for CIPN. METHODS: We used systematic review to identify studies reporting the prevalence of CIPN, and used random effects meta-regression to estimate the overall prevalence. We assessed study quality using the CONSORT and STROBE guidelines. We provide a qualitative summary of factors reported to alter the risk of CIPN. RESULTS: We included 31 studies with data from 4179 patients in our analysis. CIPN prevalence was 68.1% (57.7 to 78.4) when measured in the first month after chemotherapy, 60.0% (36.4 to 81.6) at three months and 30.0% (6.4 to 53.5) at six months or more. Different chemotherapy drugs were associated with differences in CIPN prevalence, and there was some evidence of publication bias. Genetic risk factors were reported in four studies. Clinical risk factors, identified in 4 of 31 studies, included neuropathy at baseline, smoking, abnormal creatinine clearance and specific sensory changes during chemotherapy. CONCLUSIONS: Although CIPN prevalence decreases with time, at six months 30% of patients continue to suffer from CIPN. Routine CIPN surveillance during post chemotherapy follow-up is needed. A number of genetic and clinical risk factors were identified that require further study.

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Cn-16incidence, prevalence and predictors of chemotherapy induced peripheral neuropathy: a systematic review and meta-analysis

Abstract Background There is a lack of standardized objective and reliable assessment tools for chemotherapy-induced peripheral neuropathy (CIPN). In vivo reflectance confocal microscopy (RCM) imaging offers a non-invasive method to identify peripheral neuropathy markers, namely Meissner’s corpuscles (MC). This study investigated the feasibility and value of RCM in CIPN. Patients and Methods Reflectance confocal microscopy was performed on the fingertip to evaluate MC density in 45 healthy controls and 9 patients with cancer (prior, during, and post-chemotherapy). Quantification was completed by 2 reviewers (one blinded), with maximum MC count/3 × 3 mm image reported. Quantitative Sensory Testing (QST; thermal and mechanical detection thresholds), Grooved pegboard test, and patient-reported outcomes measures (PROMS) were conducted for comparison. Results In controls (25 females, 20 males; 24-81 years), females exhibited greater mean MC density compared with males (49.9 ± 7.1 vs 30.9 ± 4.2 MC/3 × 3 mm; P = .03). Differences existed across age by decade (P < .0001). Meissner’s corpuscle density was correlated with mechanical detection (ρ = −0.51), warm detection (ρ = −0.47), cold pain (ρ = 0.49) thresholds (P < .01); and completion time on the Grooved pegboard test in both hands (P ≤ .02). At baseline, patients had reduced MC density vs age and gender-matched controls (P = .03). Longitudinal assessment of MC density revealed significant relationships with QST and PROMS. Inter-rater reliability of MC count showed an intraclass correlation of 0.96 (P < .0001). Conclusions The findings support the clinical utility of RCM in CIPN as it provides meaningful markers of sensory nerve dysfunction. Novel, prospective assessment demonstrated the ability to detect subclinical deficits in patients at risk of CIPN and potential to monitor neuropathy progression.

Sabrina Ramnarine

Papers

Incidence, prevalence, and predictors of chemotherapy-induced peripheral neuropathy: A systematic review and meta-analysis.

Incidence, Prevalence and Predictors of Chemotherapy Induced Peripheral Neuropathy

Investigating high-concentration 8% capsaicin patch in chronic cancer-treatment related peripheral neuropathic pain.

Cn-16incidence, prevalence and predictors of chemotherapy induced peripheral neuropathy: a systematic review and meta-analysis

The Value of In Vivo Reflectance Confocal Microscopy as an Assessment Tool in Chemotherapy-Induced Peripheral Neuropathy: A Pilot Study