Sensory Chemotherapy-induced Peripheral Neuropathy Research Articles

Assessment of proxy-reported responses as predictors of motor and sensory peripheral neuropathy in children with B-lymphoblastic leukemia.

Chemotherapy-induced peripheral neuropathy (CIPN), a common condition in children with acute lymphoblastic leukemia, can be challenging to diagnose. Using data from Children's Oncology Group AALL0932 physical function study, we sought to determine if parent/guardian proxy-reported responses from the Pediatric Outcomes Data Collection Instrument could identify children with motor or sensory CIPN diagnosed by physical/occupational therapists (PT/OT). Four variables moderately discriminated between children with and without motor CIPN (c-index 0.76, 95% confidence interval [CI]: 0.64-0.84), but sensory and optimism-corrected models had weak discrimination (c-index sensory models 0.65, 95% CI: 0.54-0.74). New proxy-report measures are needed to identify children with PT/OT diagnosed CIPN.

Persistence of Chemotherapy-Induced Peripheral Neuropathy Despite Vincristine Reduction in Childhood B-Acute Lymphoblastic Leukemia.

Children with B-acute lymphoblastic leukemia (B-ALL) are at risk for chemotherapy-induced peripheral neuropathy (CIPN). Children's Oncology Group AALL0932 randomized reduction in vincristine and dexamethasone (every 4 weeks vs 12 weeks during maintenance in the average-risk subset of National Cancer Institute standard-B-ALL (SR AR B-ALL). We longitudinally measured CIPN, overall and by treatment group. AALL0932 standard-B-ALL patients aged 3 years and older were evaluated at T1-T4 (end consolidation, maintenance month 1, maintenance month 18, 12 months posttherapy). Physical and occupational therapists (PT/OT) measured motor CIPN (hand and ankle strength, dorsiflexion and plantarflexion range of motion), sensory CIPN (finger and toe vibration and touch), function (dexterity [Purdue Pegboard], and walking efficiency [Six-Minute Walk]). Proxy-reported function (Pediatric Outcome Data Collection Instrument) and quality of life (Pediatric Quality of Life Inventory) were assessed. Age- and sex-matched z scores and proportion impaired were measured longitudinally and compared between groups. Consent and data were obtained from 150 participants (mean age = 5.1 years [SD = 1.7], 48.7% female). Among participants with completed evaluations, 81.8% had CIPN at T1 (74.5% motor, 34.1% sensory). When examining severity of PT/OT outcomes, only handgrip strength (P < .001) and walking efficiency (P = .02) improved from T1-T4, and only dorsiflexion range of motion (46.7% vs 14.7%; P = .008) and handgrip strength (22.2% vs 37.1%; P = .03) differed in vincristine and dexamethasone every 4 weeks vs vincristine and dexamethasone 12 weeks at T4. Proxy-reported outcomes improved from T1 to T4 (P < .001), and most did not differ between groups. CIPN is prevalent early in B-ALL therapy and persists at least 12 months posttherapy. Most outcomes did not differ between treatment groups despite reduction in vincristine frequency. Children with B-ALL should be monitored for CIPN, even with reduced vincristine frequency.

Colorectal Cancer Survivors Suffering From Sensory Chemotherapy-Induced Peripheral Neuropathy Are Not a Homogenous Group: Secondary Analysis of Patients' Profiles With Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin, a pivotal drug in the management of colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN) in a third of cancer survivors. Based on a previous cross-sectional study assessing oxaliplatin-related sensory CIPN in colorectal cancer survivors, a secondary analysis was designed to explore the possibility that different clusters of patients may co-exist among a cohort of patients with oxaliplatin-related CIPN. Other objectives were to characterize these clusters considering CIPN severity, anxiety, depression, health-related quality of life (HRQOL), patients’ characteristics and oxaliplatin treatments. Among the 96 patients analyzed, three clusters were identified (cluster 1: 52, cluster 2: 34, and cluster 3: 10 patients). Clusters were significantly different according to CIPN severity and the proportion of neuropathic pain (cluster 1: low, cluster 2: intermediate, and cluster 3: high). Anxiety, depressive disorders and HRQOL alteration were lower in cluster 1 in comparison to clusters 2 and 3, but not different between clusters 2 and 3. This study underlines that patients with CIPN are not a homogenous group, and that CIPN severity is associated with psychological distress and a decline of HRQOL. Further studies are needed to explore the relation between clusters and CIPN management.

Heart Rate Variability as a Non-invasive Objective Parameter for Predicting the Occurrence of Chemotherapy-induced Peripheral Neuropathy in Patients With Gastrointestinal Cancer.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most common chemotoxicities. However, no effective clinical CIPN screening methods have been reported. This study aimed to investigate whether changes in heart rate variability (HRV) could predict the development of CIPN for early symptom control in chemotherapy-prescribed patients with gastrointestinal (GI) cancer. Fifty-five GI cancer outpatients undergoing palliative chemotherapy including taxanes and/or platinum compounds were enrolled. CIPN was diagnosed using National Cancer Institute Common Toxicity Criteria for Adverse Event (NCI-CTCAE). HRV measures were derived from electrocardiogram signals. Twelve weeks after starting chemotherapy, 39 (70.9%) patients who complained of NCI-CTCAE grade 1-3 sensory changes were diagnosed with CIPN. Standard deviation of normal-to-normal R-R intervals (SDNN), high frequency (HF), low frequency (LF), and LF/HF ratio changed significantly during 3 assessment periods. Percentage changes in SDNN and HF were related to the occurrence of CIPN symptoms. A decision tree model indicated that patients with a rapid percentage change decrease in SDNN and HF were CIPN-positive. Using SDNN and HF, our decision tree predicted CIPN occurrence. The changes in HRV may occur earlier than sensory CIPN symptoms.

Prevalence of Chemotherapy-Induced Peripheral Neuropathy in Multiple Myeloma Patients and its Impact on Quality of Life: A Single Center Cross-Sectional Study.

Bortezomib is a pivotal drug for the management of multiple myeloma. However, bortezomib is a neurotoxic anticancer drug responsible for chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with psychological distress and a decrease of health-related quality of life (HRQoL), but little is known regarding bortezomib-related CIPN. This single center, cross-sectional study assessed the prevalence and severity of sensory/motor CIPN, neuropathic pain and ongoing pain medications, anxiety, depression, and HRQoL, in multiple myeloma patients after the end of bortezomib treatment. Paper questionnaires were sent to patients to record the scores of sensory and motor CIPNs (QLQ-CIPN20), neuropathic pain (visual analogue scale and DN4 interview), anxiety and depression (HADS), the scores of HRQoL (QLQ-C30 and QLQ-MY20) and ongoing pain medications. Oncological data were recorded using chemotherapy prescription software and patient medical records. The prevalence of sensory CIPN was 26.9% (95% CI 16.7; 39.1) among the 67 patients analyzed and for a mean time of 2.9 ± 2.8 years since the last bortezomib administration. The proportion of sensory CIPN was higher among patients treated by intravenous and subcutaneous routes than intravenous or subcutaneous routes (p = 0.003). QLQ-CIPN20 motor scores were higher for patients with a sensory CIPN than those without (p < 0.001) and were correlated with the duration of treatment and the cumulative dose of bortezomib (coefficient: 0.31 and 0.24, p = 0.01 and 0.0475, respectively), but not sensory scores. Neuropathic pain was screened in 44.4% of patients with sensory CIPN and 66.7% of them had ongoing pain medications, but none were treated with duloxetine (recommended drug). Multivariable analysis revealed that thalidomide treatment (odds-ratio: 6.7, 95% CI 1.3; 35.5, p = 0.03) and both routes of bortezomib administration (odds-ratio: 13.4, 95% CI 1.3; 139.1, p = 0.03) were associated with sensory CIPN. Sensory and motor CIPNs were associated with anxiety, depression, and deterioration of HRQoL. Sensory CIPN was identified in a quarter of patients after bortezomib treatment and associated with psychological distress that was far from being treated optimally. There is a need to improve the management of patients with CIPN, which may include better training of oncologists regarding its diagnosis and pharmacological treatment.

Moderate to vigorous physical activity effect on chemotherapy-induced peripheral neuropathy.

e24151 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common intractable side effect of oxaliplatin treatment that presents with numbness, tingling, and nerve pain in both hands and feet; and sometimes, weakness and impaired balance and quality of life. Moderate-vigorous (MV) physical activity (PA) may reduce CIPN by improving blood circulation, chemotherapy distribution, inflammation, oxidative stress, and neuroplasticity. This dose-response analysis aimed to explore the effect of different MVPA and total PA doses on CIPN severity among oxaliplatin-receiving gastrointestinal cancer survivors. Methods: The original pilot RCT tested an 8-week home-based brisk walking intervention versus PA education alone to reduce CIPN. This analysis focuses on the intervention group ( n = 29), which received MVPA motivational supports (e.g., a Fitbit Charge 2, walking plan, motivational interviewing). Participants completed self-report CIPN severity surveys at baseline (2nd oxaliplatin infusion) and 8 weeks. Fitbit-classified minutes of weekly MV and daily total (light-vigorous) PA were averaged over the 8 weeks. MVPA was dichotomized: met 225 weekly MVPA minutes ( n = 17) or not ( n = 19). Linear regression was used to analyze the effect of MVPA/total PA changes and effects on 8-week CIPN severity, controlling for oxaliplatin dose received and baseline CIPN levels. Results: Increases over the 8 weeks were observed in patients’ MVPA (mean difference [ MD] = 17.39 min/week; 95% CI 1.38, 33.40; p = .03) and total PA ( MD = 7.80 min/week; 95% CI 2.31, 13.29; p = .01). Total PA had no effect on the outcomes. However, averaging at least 225 MVPA minutes per week led to less severe sensory CIPN ( MD = -7.28; 95% CI -13.53, -1.03; p = .03), particularly tingling in the hands ( MD = -26.35; 95% CI -44.03, -8.68; p = .01). The models accounted for 37% and 44% of the variance in sensory CIPN ( p = .02) and tingling at 8 weeks ( p = .01), respectively. Conclusions: This pilot study provides preliminary evidence that increasing weekly MVPA, specifically, may lead to reduced CIPN severity among gastrointestinal cancer survivors receiving oxaliplatin. A larger study that utilizes stronger MVPA measurement and biomarker evaluation is needed. Clinical trial information: NCT03515356 .

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.

An observational study to evaluate the potential of Onlife to improve chemotherapy-induced peripheral neuropathy: Final results of the STEFANO trial.

e23143 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, long-term side effect of many antineoplastic agents and has a detrimental impact on patients (pts)’ quality of life and functional activities of daily living. Currently, preventive measures and treatment options for CIPN are quite limited. OnLife is a dietary supplement that contains a patented mixture of fatty acids with anti-inflammatory, neuroprotective and antinociceptive properties. Methods: The STEFANO study – an observational, prospective, two-cohort, multicenter study of dietary supplementation – was designed to evaluate the potential of OnLife to improve CIPN in adult pts with completed neo-/adjuvant chemotherapy and manifest CIPN (grade 1-3) (Cohort A: colon cancer, oxaliplatin-containing therapy; cohort B: breast cancer, paclitaxel therapy). Pts received OnLife for 3 months. The primary objective – assessment of changes in CIPN – was evaluated by comparing the severity of sensory and motor CIPN according to CTCAE v4.03 before, during and after treatment with OnLife. Secondary endpoints included patient-reported experience of symptoms and functional limitations related to CIPN. Descriptive statistics were used to analyze data. Results: In total, 75 breast cancer pts with paclitaxel-induced and 71 colon cancer pts with oxaliplatin-induced peripheral neuropathy, respectively, received OnLife. Based on physician-rated CTCAE grades, 21.3% of breast cancer pts and 12.7% of colon cancer pts had a sustained improvement of sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 12.0% and 9.9%, respectively. According to patient-reported outcomes, 45.3% of breast cancer pts and 23.9% of colon cancer pts had less symptoms and functional limitations related to sensory CIPN after OnLife treatment. Concerning motor CIPN, the proportions were 32.0% and 22.5%, respectively. Conclusions: STEFANO provides indications of the potential of OnLife to reduce severity of objective and subjective CIPN-related symptoms. Therefore, it is a promising agent to meet the unmet medical need of management options for patients with established CIPN. Clinical trial information: NCT03065478.

Long-term neurotoxicity in women with breast cancer.

e23089 Background: Taxanes (paclitaxel and docetaxel) are commonly administered as part of chemotherapy for breast cancer, but long-term data on chemotherapy-induced peripheral neuropathy (CIPN) are limited in this population. We aimed to assess CIPN approximately three years after an initial exposure to paclitaxel or docetaxel. Methods: In a cross-sectional observation study, which surveyed consented enrollees annually after receipt of care at Mayo Clinic for a new breast cancer diagnosis over age 18, we collected patient-reported EORTC CIPN20 data by mailed questionnaire at baseline and three years after a breast cancer diagnosis. We then confirmed patient-reported chemotherapy data by chart abstraction and only included those who had received a standard course of docetaxel-based or paclitaxel-based chemotherapy, but had not had other neurotoxic treatment for cancer. CIPN20 overall and sensory scale raw scores were converted to a 0-100 linear scale with lower scores indicating more severe symptoms. Results: 84 women who received a taxane for breast cancer completed the survey. 82 were treated in the adjuvant or neo-adjuvant setting, while 2 received a taxane for metastatic breast cancer. 67 women received paclitaxel, while 17 received docetaxel. The median age at diagnosis was 51.5 years (range 31-86). 37 had estrogen receptor (ER) and/or progesterone receptor (PR) positive and human epidermal growth factor receptor-2 (Her2) negative, 31 Her2 positive, and 16 triple negative breast cancer. The median CIPN20 score was 92.98 (range 33.33-100). The median sensory CIPN score was 92.59 (range 25.94-100). 81% of women had an overall CIPN20 score of less than 100, and 68% had a sensory score of less than 100. Conclusions: The majority of women who received a taxane based chemotherapy regimen for breast cancer reported at least mild neuropathic symptoms three years out from treatment. Additional research is needed to help tailor chemotherapy decisions to toxicity risks and to reduce the likelihood of long-term CIPN, which can impair quality of life.

Vitamin E for preventing chemotherapy-induced peripheral neuropathy

Sirs, Chemotherapy-induced peripheral neuropathy (CIPN) is currently acknowledged as a major and potentially doselimiting adverse event in patients exposed to commonly administered chemotherapeutic agents [1]. As a result, the prevention of CIPN remains a very challenging area broadly in the field. We read with great interest the results of a large phase III trial, conducted by the Mayo Clinic [2], on the neuroprotective effect of vitamin E against CIPN. The results of this study showed that vitamin E failed to reduce the incidence of grade 2+ sensory CIPN, thoroughly disputing our own and other previously published data, which were strongly supportive of its neuroprotective role against CIPN [3–5]. However, the methodology applied by the Kottschade study [2] raises a number of questions that, to our opinion, might hamper the general interpretability of results. To address the important clinical issue of CIPN prevention with vitamin E, the researchers enrolled patients with many different types of cancer who were treated with five different schedules, different combinations of drugs, and different doses. The cumulative dose for each drug was not reported, thoroughly suggesting that the two groups of patients have not been stratified for different dose intensities. Bearing in mind that oxaliplatin has a different pathogenetic mechanism to evoke peripheral nerve damage, e.g., channelopathy, and induces two clinically distinct forms of peripheral neurotoxicity, i.e., acute and chronic syndromes, it remains unclear why one third of the study sample (n=50) was composed of oxaliplatintreated patients. Although there are promising data on the prophylactic effect of vitamin E against cisplatinand paclitaxel-induced peripheral neuropathy [3–5], this is not the case for oxaliplatin-induced peripheral neuropathy. In our knowledge, the efficacy of vitamin E against CIPN has never to date been tested in oxaliplatin-treated patients. We might agree that the chronic neuropathy caused by oxaliplatin is not necessarily a channelopathy. Nevertheless, the rationale for neuroprotection with antioxidants in oxaliplatin-treated patients should be clarified. Moreover, the limited number of patients treated with cisplatin (n=8), carboplatin (n=2), or combination (n=20) certainly lacked the statistical power to detect significant differences between groups in outcome measures. Nonetheless, a significant proportion of the study sample (n=50) appears to be inappropriate, whereas the remaining number of patients already stratified in subgroups (n=30) was too small for being further divided into treatment and control arms. The effect of vitamin E supplementation on the incidence of CIPN was primarily assessed using the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3. Some standardized questions regarding neurotoxic symptoms, ranging the severity of CIPN in a visual analog scale, were also employed. One would expect a meaningful prophylactic agent for CIPN to reduce the incidence of grade II+ neuropathy in the NCI-CTC version 3 grading. However, this seems that might not be the case in the Kottschade et al. study [2]. Bearing in mind that CIPN is characterized by a great variability in symptom characterA. A. Argyriou (*) Department of Neurology, “Saint Andrew’s” General Hospital of Patras, 26335 Patras, Greece e-mail: andargyriou@yahoo.gr

Prospective assessment of chemotherapy-induced neurotoxicity in breast cancer (HOR 02) and questionnaire survey of physicians’ perspectives

6619 Background: Physician-based instruments (e.g., NCI-CTC) are widely used to assess chemotherapy-induced peripheral neuropathy (CIPN). However, current evidence suggests that physician-based assessments under-report the incidence and severity of CIPN. To overcome this limitation, a patient-based questionnaire, patient neurotoxicity questionnaire (PNQ) was developed, and a phase III randomized adjuvant trial of breast cancer (N-SAS BC 02; AC followed by PAC/DOC vs. PAC/DOC alone) has demonstrated that PNQ is reliable and sensitive and responsive instrument to assess CIPN (Shimozuma et al., SABCS 2004; #6037). We prospectively evaluated the reliability and sensitivity of PNQ in advanced or metastatic breast cancer treated by weekly administration of paclitaxel. Moreover, a questionnaire survey was conducted on physician perspectives regarding the assessment of CPIN in Japan. Methods: CIPN and QOL were prospectively assessed in thirty-five patients with advanced or metastatic breast cancer who received weekly paclitaxel (80–100 mg/m2/w). PNQ and FACT-Ntx subscale were compared to NCI-CTC. Assessments were conducted at baseline, 8 wk, 16 wk after starting treatments. A questionnaire was sent to physician who participated in N-SAS BC 02 to clarify their perspectives regarding the CPIN. Results: Average response rate of the instruments was 89%. Sensory PNQ scores correlated with sensory FACT-Ntx scores (r=0.51), and NCI-CTC scores (r=0.58). NCI-CTC scores mainly distributed between 0 and 1, while PNQ scores widely distributed. Follow-up study revealed that sensory CIPN assessed by PNQ appeared to be sensitive as compared to NCI-CTC. In clinician survey, 47 out of 61 physicians (77%) responded, and majority of them considered neurosensory symptoms as diagnostic hallmark for CIPN. However, for the justification for treatment delay, dose modification, or treatment cessation, most laid weight on functional impairment in patients with CIPN. Most (80%) rated PNQ is helpful in management of patients at risk for CIPN. Conclusions: This study confirmed that physicians tended to underestimate CIPN, and PNQ was a more reliable and valid instrument to assess CIPN with high acceptability in physicians. [Table: see text]