Painful Chemotherapy-induced Peripheral Neuropathy Research Articles

A review of the neurological complications of breast cancer.

Conducting broad assessments of the main burden of breast cancer is the core factor for improving overdiagnosis and overtreatment of breast cancer patients as well as their survival rates. Breast cancer patients may experience neurological complications that cause devastating effects on them. Chemotherapy-induced peripheral neuropathy (CIPN) and neuropathic pain are two of the most reported complications. Objective: This study aims to review the neurological complications of breast cancer and the ways to control and treat them. Comprehensive searches were carried out about the keywords of Breast Cancer, Neurological Complications, and Breast Cancer Consequences. These keywords were searched through the most well-known databases of MEDLINE, PUBMED, Cochrane Library, Best Evidence, CancerLit, HealthSTAR, and LegalTrac. In this regard, 83 articles were chosen to be included in this study from 2010 to 2021. The identification and treatment process of neurologic syndromes are not easy. The main neurologic syndromes which the breast cancer patients face are opsoclonus myoclonus syndrome (OMS), encephalitis, sensorimotor neuropathy, retinopathy, cerebellar degeneration, and stiff-person's syndrome. CIPN and neuropathic pain are among the most prevalent side effects which are categorized as neurological complications and mainly seen 1 year after the management of breast cancer. Aiming to minimize the burden following the treatment of breast cancer, these complications should be diagnosed and treated accurately.

Updates in the Treatment of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity associated with treatment with platinum-based agents, taxanes, vinca alkaloids, and other specific agents. The long-term consequences of this condition can result in decreased patient quality of life and can lead to reduced dose intensity, which can negatively impact disease outcomes. There are currently no evidence-based preventative strategies for CIPN and only limited options for treatment. However, there are several strategies that can be utilized to improve patient experience and outcomes as more data are gathered in the prevention and treatment setting. Before treatment, patient education on the potential side effects of chemotherapy is key, and although trials have been limited, recommending exercise and a healthy lifestyle before and while undergoing chemotherapy may provide some overall benefit. In patients who develop painful CIPN, our approach is to offer duloxetine and titrate up to 60 mg daily. Chemotherapy doses may also need to be reduced if intolerable symptoms develop during treatment. Some patients may also try acupuncture and physical therapy to help address their symptoms, although this can be limited by cost, time commitment, and patient motivation. Additionally, data on these modalities are currently limited, as studies are ongoing. Overall, approaching each patient on an individual level and tailoring treatment options for them based on overall physical condition, their disease burden, goals of care and co-morbid health conditions, and willingness to trial different approaches is necessary when addressing CIPN.

Risk factors and pharmacotherapy for chemotherapy-induced peripheral neuropathy in paclitaxel-treated female cancer survivors: A retrospective study in Japan.

Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse reaction in cancer patients treated with several cytotoxic anticancer agents including paclitaxel. Duloxetine, an antidepressant known as a serotonin-noradrenalin reuptake inhibitor, is the only agent that has moderate evidence for the use to treat painful CIPN. The present retrospective cohort study aimed to analyze risk factors for paclitaxel-induced peripheral neuropathy (PIPN), and investigate ongoing prescription drug use for PIPN in Japan. Female breast and gynecologic cancer patients who underwent paclitaxel-based chemotherapy at a single center in Japan between January 2016 and December 2019 were enrolled in this study. Patients' information obtained from electronic medical records were statistically analyzed to test possible risk factors on PIPN diagnosis. Patients' age, total paclitaxel dose, the history of female hormone-related diseases, hypertension and body mass index (BMI), but not additional platinum agents, were significantly associated with increased PIPN diagnosis. Drugs prescribed for PIPN included duloxetine, pregabalin, mecobalamin and Goshajinkigan, a polyherbal medicine, regardless of poor evidence for their effectiveness against CIPN, and were greatly different between breast and gynecologic cancer patients diagnosed with PIPN at the departments of Surgery and Gynecology, respectively. Thus, older age, greater total paclitaxel dose, the history of estrogen-related diseases, hypertension and BMI are considered risk factors for PIPN in paclitaxel-based chemotherapy of female cancer patients. It appears an urgent need to establish a guideline of evidence-based pharmacotherapy for PIPN.

Self-Reported Severity, Characteristics, and Functional Limitations of Chemotherapy-Induced Peripheral Neuropathy

BackgroundThe early identification of chemotherapy-induced peripheral neuropathy (CIPN) (e.g., numbness or tingling in the fingers or toes) is important due to its frequency and the few effective treatment options available. The identification of common patient-reported CIPN characteristics and associated functional limitations may help to facilitate patient-clinician discussions of CIPN in practice. AimsTo quantify the severity, duration, location, characteristics, and associated functional limitations of chemotherapy-induced peripheral neuropathy (CIPN) in patients receiving neurotoxic chemotherapy. DesignExploratory secondary analysis of a prospective, two-phase study SettingBreast, gastrointestinal, and multiple myeloma clinics at Dana-Farber Cancer Institute. Participants142 individuals who planned to receive at least three more cycles of neurotoxic chemotherapy after consent. MethodsParticipants self-reported CIPN using standardized measures (i.e., PRO-CTCAE™ Numbness and Tingling Items or 0-10 numerical rating scale of worst CIPN pain intensity) and/or study team generated follow up questions about CIPN location, duration, characteristics, and functional limitations prior to three consecutive clinic visits (T1, T2, T3). Participants’ responses to the CIPN self-report questionnaires were described by chemotherapy type and age. ResultsOver approximately 36.5 days (T1-T3), the percentage of participants reporting at least mild CIPN increased from 59.3% to 71%. At T3, patients with non-painful (n = 98) or painful neuropathy (n = 34) frequently reported symptoms in the fingers (non-painful = 83.5%, painful = 76.5%) or toes (non-painful = 49.5%, painful = 41.2%) and characterized symptoms as numbness (non-painful = 54.1%, painful = 50%) or tingling (non-painful = 68.4%, painful = 82.4%). Self-reported CIPN functional limitations (n = 55) included difficulties with buttoning a shirt (38.2%) or walking (25.5%). Paclitaxel-related CIPN (n = 33) was frequently characterized as “continuous” (30.3%), whereas oxaliplatin-related CIPN (n = 51) was frequently characterized as “intermittent” (41.2%). Young adults (15-39 years old, n = 15) frequently reported moderate-severe non-painful CIPN (46.7%), painful CIPN (40%), and CIPN interference (33.3%). ConclusionsConsistent with qualitative research, participants frequently described CIPN as numbness and/or tingling in the fingers and/or toes.

Characterization of Patients With and Without Painful Peripheral Neuropathy After Receiving Neurotoxic Chemotherapy: Traditional Quantitative Sensory Testing vs C-Fiber and Aδ-Fiber Selective Diode Laser Stimulation

Painful chemotherapy induced peripheral neuropathy (CIPN) is a common complication of chemotherapy with drugs such as taxanes and platinum compounds. Currently, no methods are available for early detection of sensory changes that are associated with painful CIPN, nor are there biomarkers that are specific to painful CIPN. This study aimed to compare Diode Laser fiber type-selective stimulator (DLss), a method to selectively stimulate cutaneous C and Aδ fibers, to traditional quantitative sensory testing (QST) in determining psychophysical differences between patients with painful CIPN and a control group. Sensory testing was performed on the dorsal mid-foot of 20 patients with painful neuropathy after taxane- or platinum-based chemotherapy, and 20 patients who received similar neurotoxic chemotherapy, without painful CIPN. In a multivariable analysis, C-fiber to Aδ fiber detection threshold ratio, measured by DLss, was significantly different between the groups (P <.05). While QST parameters such as warmth detection threshold were different between the groups in univariate analyses, these findings were likely attributable to group differences in patient age and cumulative chemotherapy dose. PerspectiveIn this study, fiber-specific DLss test showed potential in identifying sensory changes that are specific for painful neuropathy, encouraging future testing of this approach as a biomarker for early detection of painful CIPN. Trial registrationThe study was approved by the Washington University Institutional Review Board (#201807162) and registered at ClinicalTrials.gov (NCT03687970).

Neuroendocrine Stress Axis-Dependence of Duloxetine Analgesia (Anti-Hyperalgesia) in Chemotherapy-Induced Peripheral Neuropathy

Duloxetine, a serotonin and norepinephrine reuptake inhibitor, is the best-established treatment for painful chemotherapy-induced peripheral neuropathy (CIPN). While it is only effective in little more than half of patients, our ability to predict patient response remains incompletely understood. Given that stress exacerbates CIPN, and that the therapeutic effect of duloxetine is thought to be mediated, at least in part, via its effects on adrenergic mechanisms, we evaluated the contribution of neuroendocrine stress axes, sympathoadrenal and hypothalamic-pituitary-adrenal, to the effect of duloxetine in preclinical models of oxaliplatin- and paclitaxel-induced CIPN. Systemic administration of duloxetine, which alone had no effect on nociceptive threshold, both prevented and reversed mechanical hyperalgesia associated with oxaliplatin- and paclitaxel-CIPN. It more robustly attenuated oxaliplatin CIPN in male rats, while it was more effective for paclitaxel CIPN in females. Gonadectomy attenuated these sex differences in the effect of duloxetine. To assess the role of neuroendocrine stress axes in the effect of duloxetine on CIPN, rats of both sexes were submitted to adrenalectomy combined with fixed level replacement of corticosterone and epinephrine. While CIPN, in these rats, was of similar magnitude to that observed in adrenal-intact animals, rats of neither sex responded to duloxetine. Furthermore, duloxetine blunted an increase in corticosterone induced by oxaliplatin, and prevented the exacerbation of CIPN by sound stress. Our results demonstrate a role of neuroendocrine stress axes in duloxetine analgesia (anti-hyperalgesia) for the treatment of CIPN.SIGNIFICANCE STATEMENT Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating dose-dependent and therapy-limiting side effect of many of the cytostatic drugs used to treat cancer (Argyriou et al., 2010; Marmiroli et al., 2017). Duloxetine is the only treatment for CIPN currently recommended by the American Society of Clinical Oncology (Hershman et al., 2014). In the present study, focused on elucidating mechanisms mediating the response of oxaliplatin- and paclitaxel-induced painful peripheral neuropathy to duloxetine, we demonstrate a major contribution to its effect of neuroendocrine stress axis function. These findings, which parallel the clinical observation that stress may impact response of CIPN to duloxetine (Taylor et al., 2007), open new approaches to the treatment of CIPN and other stress-associated pain syndromes.

Measurement properties of brief neuropathy screening items in cancer patients receiving taxanes, platinums, or proteasome inhibitors

BackgroundTimely detection of chemotherapy-induced peripheral neuropathy (CIPN) is critical to effectively tailor chemotherapy dose levels and offer supportive care. The purpose of this secondary analysis was to determine the reliability and validity of the two Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE™) numbness and tingling severity and interference items to screen for CIPN in patients receiving taxanes, platinums, or proteasome inhibitors.MethodsParticipants (N = 142) completed the two PRO-CTCAE items, a 0–10 numerical rating scale of worst CIPN pain intensity, and the Quality of Life Questionnaire–CIPN20 (QLQ-CIPN20) prior to three clinical visits (T1, T2, T3) during neurotoxic chemotherapy. Participants completed the two PRO-CTCAE items again following the T3 clinical visit (T4). In addition, study staff administered the modified Total Neuropathy Score–Clinical Version (TNSc©) at T3. We examined floor (i.e., no CIPN severity or interference) and ceiling effects, test–retest reliability, concurrent validity, longitudinal validity, construct validity of the response categories, and sensitivity and specificity of the two PRO-CTCAE items.ResultsAt T3, 29% of participants had PRO-CTCAE severity scores at the floor; 60.1% of participants reported interference item scores at the floor. Agreements between scores reported at T3 and T4 for PRO-CTCAE severity (ICC = 0.79) and interference (ICC = 0.73) were moderate to strong. The PRO-CTCAE severity and interference items correlated moderately-strongly with QLQ-CIPN20 sensory (Spearman’s ρ-range = 0.53–0.72) and motor (Spearman’s ρ-range = 0.50–0.58) subscale scores. The Cohen’s d from T1 to T3 for the PRO-CTCAE items were small (severity: d = 0.32, interference: d = 0.40) and comparable to the effect sizes for change observed with the QLQ-CIPN20. The PRO-CTCAE severity (0–3) and interference (0–2) response categories distinguished respondents with significantly different levels of QLQ-CIPN20 sensory and motor subscale scores (p < 0.001 via Jonckheere-Terpstra tests). The sensitivity and specificity of the PRO-CTCAE severity item (cutoff > 0) to detect probable sensory peripheral neuropathy were 95.83% and 65.22%, while the sensitivity and specificity of the PRO-CTCAE™ interference item (cutoff > 0) were 51.39% and 73.91%.ConclusionPreliminary evidence supports the reliability and validity of the PRO-CTCAE numbness and tingling items for CIPN screening, although there may be floor effects and limitations in the capacity of the PRO-CTCAE items to identify the full range of CIPN sensory and motor features beyond numbness and tingling.Trial Registration ClinicalTrials.Gov, NCT03514680. Registered 21 April 2018. https://clinicaltrials.gov/ct2/show/NCT03514680

Yoga for cancer survivors with chemotherapy-induced peripheral neuropathy: Health-related quality of life outcomes.

BackgroundYoga is a meditative movement therapy focused on mind‐body awareness. The impact of yoga on health‐related quality of life (HRQOL) outcomes in patients with chemotherapy‐induced peripheral neuropathy (CIPN) is unclear.MethodsWe conducted a pilot randomized wait‐list controlled trial of 8 weeks of yoga (n = 21) versus wait‐list control (n = 20) for CIPN in 41 breast and gynecological cancer survivors with persistent moderate to severe CIPN. HRQOL endpoints were Hospital Anxiety and Depression Scale (HADS), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). The Treatment Expectancy Scale (TES) was administered at baseline. We estimated mean changes and 95% confidence intervals (CIs) from baseline to weeks 8 and 12 and compared arms using constrained linear mixed models.ResultsAt week 8, HADS anxiety scores decreased −1.61 (−2.75, −0.46) in the yoga arm and −0.32 (−1.38, 0.75) points in the wait‐list control arm (p = 0.099). At week 12, HADS anxiety scores decreased −1.42 (−2.57, −0.28) in yoga compared to an increase of 0.46 (−0.60, 1.53) in wait‐list control (p = 0.017). There were no significant differences in HADS depression, BFI, or ISI scores between yoga and wait‐list control. Baseline TES was significantly higher in yoga than in wait‐list control (14.9 vs. 12.7, p = 0.019). TES was not associated with HADS anxiety reduction and HADS anxiety reduction was not associated with CIPN pain reduction.ConclusionsYoga may reduce anxiety in patients with CIPN. Future studies are needed to confirm these findings.Clinical Trial Registration Number: ClinicalTrials.gov Identifier: NCT03292328.

The role of PPARγ in chemotherapy-evoked pain

Although millions of people are diagnosed with cancer each year, survival has never been greater thanks to early diagnosis and treatments. Powerful chemotherapeutic agents are highly toxic to cancer cells, but because they typically do not target cancer cells selectively, they are often toxic to other cells and produce a variety of side effects. In particular, many common chemotherapies damage the peripheral nervous system and produce neuropathy that includes a progressive degeneration of peripheral nerve fibers. Chemotherapy-induced peripheral neuropathy (CIPN) can affect all nerve fibers, but sensory neuropathies are the most common, initially affecting the distal extremities. Symptoms include impaired tactile sensitivity, tingling, numbness, paraesthesia, dysesthesia, and pain. Since neuropathic pain is difficult to manage, and because degenerated nerve fibers may not grow back and regain normal function, considerable research has focused on understanding how chemotherapy causes painful CIPN so it can be prevented. Due to the fact that both therapeutic and side effects of chemotherapy are primarily associated with the accumulation of reactive oxygen species (ROS) and oxidative stress, this review focuses on the activation of endogenous antioxidant pathways, especially PPARγ, in order to prevent the development of CIPN and associated pain. The use of synthetic and natural PPARγ agonists to prevent CIPN is discussed.

Abstract PS9-19: Health-related quality of life (HRQOL) outcomes in arandomized controlled trial of yoga in breast and gynecological cancer survivors with chemotherapy-induced peripheral neuropathy

Abstract Background: Yoga is a meditative movement therapy that improves body conditioning, flexibility, and balance through mind-body awareness. We conducted a two-armed pilot randomized wait-list controlled trial in breast and gynecological (GYN) cancer survivors with persistent moderate to severe chemotherapy-induced peripheral neuropathy (CIPN) and found that yoga significantly reduced CIPN pain. Here we report on the HRQOL results. Patients and Methods: We randomized breast and GYN cancer survivors with persistent moderate to severe CIPN to eight weeks of yoga or usual care (UC). The HRQOL endpoints were Hospital Anxiety and Depression Score (HADS), Treatment Expectancy Scale (TES), Brief Fatigue Inventory (BFI), and Insomnia Severity Index (ISI). We estimated and compared the mean changes from baseline to weeks 8 and 12 along with 95% confidence intervals (CIs) between arms using linear mixed models. Results: From February 2018 to May 2019, we enrolled and randomized 41 female cancer survivors (93% breast, 7% GYN; mean (SD) age 61.7 (10.2) years; 56% white/non-Hispanic, 20% African American, 12% Asian, 12% other) to yoga (N=21) and UC (N=20) arms. The HADS anxiety score significantly reduced in the yoga arm compared to usual care at weeks 8 and 12. At baseline, the mean (95% CI) HADS anxiety score was 9.23 (7.42, 11.04) in the yoga arm, and 5.05 (3.19, 6.91) in the UC arm (p=0.002). At week 8, the mean (95% CI) HADS anxiety score decreased by -1.91 (-3.07, -0.76) points in the yoga arm, and by -0.02 (-1.10, 1.06) points in the UC arm (p=0.019). At week 12, in the yoga arm, the mean HADS anxiety score was 7.50 (5.62, 9.39), and a decrease of 1.73 (-2.88, -0.57) points; in the UC arm, the mean was 5.81 (3.94, 7.69) with an increase of 0.76 (-0.32, 1.84) points (p=0.002). There was no difference in HADS depression, BFI, and ISI scores between yoga and UC arms at baseline, week 8, and week 12. The TES at baseline was 14.9 (3.27) in the yoga arm, which was significantly higher than in the UC arm 14.9 (SD 3.27) vs. 12.7 (SD: 2.58), p= 0.019. The TES was not associated with HADS anxiety reduction, and HADS anxiety reduction was not associated with CIPN pain reduction. Conclusions: Our trial showed that a yoga intervention may be useful to reduce anxiety in patients with CIPN. We previously found that a yoga intervention reduced CIPN pain. CIPN pain reduction was not associated with anxiety reduction or TES. Future studies are needed to confirm our findings and to explore the mechanism of yoga in CIPN pain reduction. Citation Format: Wanqing Iris Zhi, Raymond Baser, Lillian Zhi, Lauren Piulson, Qing Li, Ting Bao. Health-related quality of life (HRQOL) outcomes in arandomized controlled trial of yoga in breast and gynecological cancer survivors with chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-19.

Abstract PS9-51: Secondary outcomes in a randomized controlled trial of acupuncture versus sham acupuncture and usual care in solid tumor survivors with chemotherapy-induced peripheral neuropathy

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is the most common and debilitating long-term adverse effect of neurotoxic chemotherapy and it significantly worsens cancer survivors’ quality of life. In a previously reported randomized controlled trial, we showed that real acupuncture is more effective in reducing persistent CIPN symptoms compared to usual care, with a trend of greater CIPN pain reduction compared to sham acupuncture (Bao et al, JAMA Netw Open, 2020). Here, we report secondary outcomes in this trial. Patients and Methods: Solid tumor survivors with persistent moderate to severe CIPN (symptoms of numbness, tingling, or pain rated ≥4 on a numeric rating scale [NRS]) were randomized to three arms: 1) Eight weeks of real acupuncture (RA); 2) eight weeks of sham acupuncture (SA); and 3) usual care (UC). The secondary endpoints were Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx), Hospital Anxiety and Depression Score (HADS), and Insomnia Severity Index (ISI). For each endpoint, the mean changes from baseline and 95% confidence intervals (CI) were estimated within each arm and compared between arms using linear mixed models.Results: We enrolled and randomized 75 solid tumor survivors (53% breast cancer) with moderate to severe CIPN to the study. Compared to baseline, at week 8, FACT/GOG-Ntx, HADS anxiety, and ISI scores significantly improved in both RA and SA arms, but not in the UC arm (Table 1). At week 8, FACT/GOG-Ntx scores significantly increased in both RA and SA arms when compared with UC (p=0.001 and 0.007), indicating improved CIPN related symptoms and quality of life. There was no statistically significant difference between RA and SA arms, p=0.498. When comparing RA and SA with UC, we found no statistically significant difference in changes from baseline in HADS anxiety and ISI. Conclusions: Our study showed acupuncture may be effective in improving CIPN symptoms and reducing anxiety and insomnia in cancer survivors with persistent CIPN. Further large sample size studies are needed to delineate possible placebo effects from SA. Table 1. Secondary Outcomes in RA, SA, and UC Arms and Changes From BaselineReal Acupuncture(n=27)Sham Acupuncture (n=24)Usual Care (n=24)OutcomeWeekMean (95% CI)Change from Baseline,Mean (95% CI)Mean (95% CI)Change from Baseline,Mean (95% CI)Mean (95% CI)Change from Baseline,Mean (95% CI)FACT/GOG-Ntx024.41 (21.38, 27.44)NA25.13 (21.91, 28.34)NA27.01 (23.80, 30.22)NA828.60 (25.52, 31.67)4.19 (2.39, 5.99)***28.42 (25.19, 31.66)3.30 (1.45, 5.15)***26.61 (23.32, 29.89)-0.40 (-2.35, 1.54)HADS Anxiety06.61 (4.98, 8.25)NA7.66 (5.93, 9.39)NA6.52 (4.79, 8.25)NA85.61 (3.95, 7.27)-1.00 (-1.99, -0.01)*6.64 (4.89, 8.38)-1.02 (-2.03, -0.01)*6.76 (4.99, 8.53)0.24 (-0.81, 1.29)ISI012.93 (10.24, 15.61)NA12.46 (9.61, 15.31)NA10.17 (7.32, 13.02)NA810.63 (7.88, 13.37)-2.30 (-3.99, -0.61)**10.20 (7.33, 13.07)-2.26 (-3.99, -0.53)*8.96 (6.05, 11.87)-1.21 (-3.01, 0.60)Table Symbols: *, p &amp;lt; 0.05; **, p &amp;lt; 0.01; ***, p &amp;lt; 0.001 Citation Format: Ting Bao, Ray Baser, Crystal Lin, Qing Li, Lauren Piulson, Iris Zhi. Secondary outcomes in a randomized controlled trial of acupuncture versus sham acupuncture and usual care in solid tumor survivors with chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-51.

Sexual dimorphism in the contribution of neuroendocrine stress axes to oxaliplatin-induced painful peripheral neuropathy.

Although clinical studies support the suggestion that stress is a risk factor for painful chemotherapy-induced peripheral neuropathy (CIPN), there is little scientific validation to support this link. Here, we evaluated the impact of stress on CIPN induced by oxaliplatin, and its underlying mechanisms, in male and female rats. A single dose of oxaliplatin produced mechanical hyperalgesia of similar magnitude in both sexes, still present at similar magnitude in both sexes, on day 28. Adrenalectomy mitigated oxaliplatin-induced hyperalgesia, in both sexes. To confirm the role of neuroendocrine stress axes in CIPN, intrathecal administration of antisense oligodeoxynucleotide targeting β₂-adrenergic receptor mRNA both prevented and reversed oxaliplatin-induced hyperalgesia, only in males. By contrast, glucocorticoid receptor antisense oligodeoxynucleotide prevented and reversed oxaliplatin-induced hyperalgesia in both sexes. Unpredictable sound stress enhanced CIPN, in both sexes. The administration of stress hormones, epinephrine, corticosterone, and their combination, at stress levels, mimicked the effects of sound stress on CIPN, in males. In females, only corticosterone mimicked the effect of sound stress. Also, a risk factor for CIPN, early-life stress, was evaluated by producing both stress-sensitive (produced by neonatal limited bedding) and stress-resilient (produced by neonatal handling) phenotypes in adults. Although neonatal limited bedding significantly enhanced CIPN only in female adults, neonatal handling significantly attenuated CIPN, in both sexes. Our study demonstrates a sexually dimorphic role of the 2 major neuroendocrine stress axes in oxaliplatin-induced neuropathic pain.

Non-Pharmacological Management of Painful Peripheral Neuropathies: A Systematic Review.

Peripheral neuropathic pain (PNP) is defined as the neuropathic pain that arises either acutely or in the chronic phase of a lesion or disease affecting the peripheral nervous system. PNP is associated with a remarkable disease burden, and there is an increasing demand for new therapies to be used in isolation or combination with currently available treatments. The aim of this systematic review was to evaluate the current evidence, derived from randomized controlled trials (RCTs) that assess non-pharmacological interventions for the treatment of PNP. After a systematic Medline search, we identified 18 papers eligible to be included. The currently best available evidence (level II of evidence) exist for painful diabetic peripheral neuropathy. In particular, spinal cord stimulation as adjuvant to conventional medical treatment can be effectively used for the management of patients with refractory pain. Similarly, adjuvant repetitive transcranial magnetic stimulation of the motor cortex is effective in reducing the overall pain intensity, whereas adjuvant static magnetic field therapy can lead to a significant decrease in exercise-induced pain. Weaker evidence (level III of evidence) exists for the use of acupuncture as a monotherapy and neurofeedback, either as an add-on or a monotherapy approach, for treatment of painful chemotherapy-induced peripheral neuropathy CONCLUSIONS: Future RCTs should be conducted to shed more light in the use of non-pharmacological approaches in patients with PNP.

Circadian regulation of chemotherapy-induced peripheral neuropathic pain and the underlying transcriptomic landscape

Growing evidence demonstrates circadian rhythms of pain hypersensitivity in various chronic disorders. In chemotherapy-induced peripheral neuropathy (CIPN), agents such as paclitaxel are known to elicit chronic neuropathic pain in cancer patients and seriously compromise their quality of life. Here, we report that the mechanical threshold for allodynia in paclitaxel-treated rats exhibited a robust circadian oscillation, reaching the nadir during the daytime (inactive phase). Using Per2::LucSV circadian reporter mice expressing a PER2::LUC fusion protein, we isolated dorsal root ganglia (DRG), the primary sensory cell body for peripheral nerve injury generated hypersensitivity, and monitored ex vivo reporter bioluminescence. We observed strong circadian reporter rhythms in DRG neurons which are highly entrainable by external cues. Paclitaxel treatment significantly lengthened DRG circadian periods, with little effects on the amplitude of oscillation. We further observed the core protein BMAL1 and PER2 in DRG neurons and satellite cells. Using DRG and dorsal horn (DH; another key structure for CIPN pain response) tissues from vehicle and paclitaxel treated rats, we performed RNA-sequencing and identified diurnal expression of core clock genes as well as clock-controlled genes in both sites. Interestingly, 20.1% and 30.4% of diurnal differentially expressed genes (DEGs) overlapped with paclitaxel-induced DEGs in the DRG and the DH respectively. In contrast, paclitaxel-induced DEGs displayed only a modest overlap between daytime and nighttime (Zeitgeber Time 8 and 20). Furthermore, paclitaxel treatment induced de novo diurnal DEGs, suggesting reciprocal interaction of circadian rhythms and chemotherapy. Our study therefore demonstrates a circadian oscillation of CIPN and its underlying transcriptomic landscape.

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update.

To update the ASCO guideline on the recommended prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathy (CIPN) in adult cancer survivors. An Expert Panel conducted targeted systematic literature reviews to identify new studies. The search strategy identified 257 new references, which led to a full-text review of 87 manuscripts. A total of 3 systematic reviews, 2 with meta-analyses, and 28 primary trials for prevention of CIPN in addition to 14 primary trials related to treatment of established CIPN, are included in this update. The identified data reconfirmed that no agents are recommended for the prevention of CIPN. The use of acetyl-l-carnitine for the prevention of CIPN in patients with cancer should be discouraged. Furthermore, clinicians should assess the appropriateness of dose delaying, dose reduction, substitutions, or stopping chemotherapy in patients who develop intolerable neuropathy and/or functional impairment. Duloxetine is the only agent that has appropriate evidence to support its use for patients with established painful CIPN. Nonetheless, the amount of benefit from duloxetine is limited.Additional information is available at www.asco.org/survivorship-guidelines.

The Therapeutic Efficacy of Acupuncture for Chemotherapy-Induced Peripheral Neuropathy: A Systematic Review and Meta-Analysis

Objective: This study aimed to report the therapeutic effect of acupuncture on chemotherapy-induced peripheral neuropathy (CIPN). Methods: The articles were sourced from databases including PubMed, EMBASE, Cochrane Library, CNKI, CiNii, WHO ICTRP, JSOM, KMBASE, KISS, NDSL, and OASIS as of July 2019. The main search keywords were peripheral neuropathy and acupuncture, and only randomized controlled trials using acupuncture for therapeutic purposes were included. Cochrane’s risk of bias was used to assess the risk of bias, and the Review Manager 5.3 program was used for meta-analysis. Results: Six studies with a total 394 participants were included. When combined treatment of acupuncture and usual care was compared with usual care alone, quality of life improved more significantly in the combination treatment group (SMD=-2.71, 95% CI: -5.01 to -0.41, P=0.02, I2=97%). The CIPN pain score was lower among the combination treatment group, but not to a significant degree (SMD=-2.55, 95% CI: -5.14 to 0.04, P<0.05, I2=98%). There were no severe side effects in any studies. Conclusion: Acupuncture combined with usual care may be considered to safely relieve CIPN pain and improve quality of life for cancer patients. However, as there are few randomized controlled trials studying the effect of acupuncture on CIPN, further well-designed research is needed. Keywords: CIPN, acupuncture, chemotherapy, peripheral nervous system diseases, neuropathy, cancer, systematic review, meta-analysis

Painful and non-painful chemotherapy-induced peripheral neuropathy and quality of life in colorectal cancer survivors: results from the population-based PROFILES registry

PurposeThis study aims to (1) examine the prevalence of painful versus non-painful chemotherapy-induced peripheral neuropathy (CIPN) among long-term colorectal cancer (CRC) survivors, (2) identify sociodemographic, clinical, and psychological factors associated with painful and non-painful CIPN, and (3) examine the associations of painful CIPN with health-related quality of life (HRQoL) in comparison with non-painful CIPN, i.e., numbness/tingling.MethodsAll CRC survivors diagnosed between 2000 and 2009 as registered by the population-based Netherlands Cancer Registry (Eindhoven region) were eligible for participation. Chemotherapy-treated survivors (n = 477) completed questions on CIPN (EORTC QLQ-CIPN20) and HRQoL (EORTC QLQ-C30).ResultsPainful CIPN was reported by 9% (n = 45) of survivors and non-painful CIPN was reported by 22% (n = 103). Time since diagnosis was related to painful CIPN, and time since diagnosis, a higher disease stage, osteoarthritis, and more anxiety symptoms were related to non-painful CIPN. Finally, survivors with painful CIPN reported a worse global quality of life and worse physical, role, cognitive, and social functioning compared to survivors with non-painful CIPN and those without any sensory CIPN. No differences were found between survivors with non-painful CIPN and those without sensory CIPN.ConclusionsIt seems that painful CIPN must be distinguished from non-painful CIPN, as only painful CIPN was related to a worse HRQoL. Future research is needed to examine whether painful CIPN must be distinguished from non-painful CIPN regarding predictors, mechanisms, and treatment.

Abstract P5-14-02: Yoga for chemotherapy-induced peripheral neuropathy and fall risk in breast and gynecological cancer survivors: A pilot study

Abstract Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating and dose-limiting side effect of neurotoxic chemotherapies that worsens quality of life and increases fall risk in cancer survivors. CIPN is painful and poorly managed with pharmacological agents.This pilot study assessed the preliminary effect of yoga on CIPN symptom severity and fall risk in cancer survivors.Methods: Breast and gynecological (GYN) cancer survivors with persistent, moderate-to-severe CIPN were randomized to yoga and usual care (UC) control arms. The yoga arm practiced Hatha yoga for 60 minutes daily via an in-person group class (2 times/week) and at home using a study-provided instructional video (5 times/week), and the UC arm received usual care for 8 weeks. Main study outcomes included a numeric rating scale (NRS) of CIPN pain, numbness and tingling (higher score indicates worse symptom); the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicitysubscale (FACT-GOG/Ntx) (higher score indicates improved symptoms); and functional reach (FR) test, an objective balance test used to evaluate fall risk (higher score indicates lower risk of fall). Mean changes from baseline to week 8 were calculated for each outcome measure and compared between treatment arms using two-sample t-tests. Results: From 2/2018 to 5/2019, 41 female cancer survivors (92.7% breast, 7.3% GYN; mean (SD) age 62.6 (10.2) years; 53.7% white/non-Hispanic, 19.5% African American, 12.2% Asian, 12.2% other) were enrolled and randomized to yoga (N=21) and UC (N=20) arms. At week 8, mean NRS pain decreased by 2.06 points (95% CI [-3.27, -0.86]) in the yoga arm, and 0.65 points [-2.08, 0.78] in the UC arm (p=0.12). No statistically significant change was observed in NRS numbness and tingling for yoga versus UC arms (both p&amp;gt;0.5). FACT-GOG/Ntx improved by 4.56 points [-1.84, 7.29] in the yoga arm, and 1.37 points [-0.51, 3.25] in the UC arm (p=0.05). FR improved by 3.08 inches [-1.43, 4.73] in the yoga arm, and decreased 0.59 inches [-0.51, 3.25] in the UC arm (p=0.003). Four yoga and 3 UC subjects reported a total of 11 adverse events deemed possibly related to the yoga intervention (all grade 1). Conclusion: Among breast and GYN cancer survivors with moderate-to-severe CIPN, yoga showed promising effects for improving neuropathy-related pain and quality of life, and for reducing fall risk. An adequately-powered and appropriately-controlled trial is warranted to confirm the specific and long-term effects of yoga on CIPN symptoms and fall prevention. Citation Format: Ting Bao, Madeline Hooper, Raymond Baser, Patricia Chen, Lauren Piulson, Clare Patterson, Tina Paul, Connie Chen, Qing Li, Katherine Panageas, Iris Zhi, Victoria Blinder, Mark Robson, Andrew Seidman, Jun Mao. Yoga for chemotherapy-induced peripheral neuropathy and fall risk in breast and gynecological cancer survivors: A pilot study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-02.

An Exploratory Randomized Trial of Physical Therapy for the Treatment of Chemotherapy-Induced Peripheral Neuropathy

Background. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxane treatment and cannot currently be prevented or adequately treated. Physical therapy is often used for neural rehabilitation following injury but has not been evaluated in this patient population. Methods. Single-blind, randomized controlled exploratory study compared standard care to a physical therapy home program (4 visits) throughout adjuvant taxane chemotherapy for stage I-III patients with breast cancer (n = 48). Patient questionnaires and quantitative sensory testing evaluated the treatment effect throughout chemotherapy to 6 months post treatment. Nonrandomized subgroup analysis observed effect of general exercise on sensory preservation comparing those reporting moderate exercise throughout chemotherapy to those that did not exercise regularly. Clinical Trial Registration. clinicaltrials.gov (NCT02239601). Results. The treatment group showed strong trends toward less pain (odds ratio [OR] 0.41, 95% confidence interval [CI] 0.17-1.01; P = .053) and pain decreased over time (OR 0.85, 95% CI 0.76-0.94; P = .002). Pain pressure thresholds (P = .034) and grip dynamometry (P < .001) were improved in the treatment group. For the nonrandomized subgroup analysis, participants reporting general exercise had preservation of vibration (Left P = .001, Right P = .001) and normal heat pain thresholds (Left P = .021, Right P = .039) compared with more sedentary participants. Conclusion. Physical therapy home program may improve CIPN pain in the upper extremity for patients with breast cancer, and general exercise throughout chemotherapy treatment was observed to have correlated to preservation of sensory function. Further research is required to confirm the impact of a physical therapy home program on CIPN symptoms.

Effect of serotonin-norepinephrine reuptake inhibitors for patients with chemotherapy-induced painful peripheral neuropathy

To compare the efficacy of serotonin-norepinephrine reuptake inhibitors (SNRIs) treatment for chemotherapy-induced peripheral neuropathy (CIPN) METHODS:: Two authors independently searched MEDLINE, Embase, Cochran Library, and Web of Science to identify and review articles published from January 1998 until December 2018 according to selection criteria. Outcomes were expressed as mean difference, the pooled odds ratio, or relative risk in a meta-analysis model. A total of 10 studies were included in this meta-analysis: 6 randomized-controlled studies and 4 observational studies. Meta-analysis showed that CIPN was improved after treatment with SNRI (standardized mean difference = 2.20; 95% confidence interval, 0.90-3.49; I = 93% in 3 randomized controlled studies). Somnolence and insomnia occurred in <15% of patients. Incidence of somnolence was lower than with pregabalin treatment, and insomnia was comparable to that in expectant management or pregabalin treatment. Incidence of nausea and vomiting was higher than in expectant management, but no significant difference was found when compared to expectant management. From the several available studies suitable for indirect comparison, SNRI shows excellent efficacy and tolerability to CIPN. SNRI could provide an important treatment option for CIPN.