Ellen M. Lavoie Smith

Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline

PURPOSE To provide evidence-based guidance on the optimum prevention and treatment approaches in the management of chemotherapy-induced peripheral neuropathies (CIPN) in adult cancer survivors. METHODS A systematic literature search identified relevant, randomized controlled trials (RCTs) for the treatment of CIPN. Primary outcomes included incidence and severity of neuropathy as measured by neurophysiologic changes, patient-reported outcomes, and quality of life. RESULTS A total of 48 RCTs met eligibility criteria and comprise the evidentiary basis for the recommendations. Trials tended to be small and heterogeneous, many with insufficient sample sizes to detect clinically important differences in outcomes. Primary outcomes varied across the trials, and in most cases, studies were not directly comparable because of different outcomes, measurements, and instruments used at different time points. The strength of the recommendations is based on the quality, amount, and consistency of the evidence and the balance between benefits and harms. RECOMMENDATIONS On the basis of the paucity of high-quality, consistent evidence, there are no agents recommended for the prevention of CIPN. With regard to the treatment of existing CIPN, the best available data support a moderate recommendation for treatment with duloxetine. Although the CIPN trials are inconclusive regarding tricyclic antidepressants (such as nortriptyline), gabapentin, and a compounded topical gel containing baclofen, amitriptyline HCL, and ketamine, these agents may be offered on the basis of data supporting their utility in other neuropathic pain conditions given the limited other CIPN treatment options. Further research on these agents is warranted.

The reliability and validity of a modified total neuropathy score-reduced and neuropathic pain severity items when used to measure chemotherapy-induced peripheral neuropathy in patients receiving taxanes and platinums

Background: Assessment of chemotherapy-induced peripheral neuropathy signs and symptoms has been hampered because of the lack of simple, reliable, and valid measures. Objective: The study objective was to examine the internal consistency and interrater reliability as well as the structural validity of a 5-component total neuropathy score-reduced (TNSr) variant and a chemotherapy-induced neuropathy-specific Neuropathic Pain Scale. Methods: One hundred seventeen outpatients receiving taxanes or platinums were assessed by a consistent nurse practitioner using the 2 instruments. Ten subjects participated in interrater reliability testing. Results: Mean scores and SDs for individual items were low. The strength item was deleted because of low interitem correlations and a floor effect. The reflex item was deleted because of low interitem correlations and its negative influence on Cronbach &agr;. Pin sensibility was deleted because of low factor loadings. The TNSr-short form and the chemotherapy-induced neuropathy-specific Neuropathic Pain Scale formed 2 distinct factors, providing evidence of structural validity. Cronbach &agr;s for the 2 instruments were .80 and .96, respectively. The TNSr interrater reliability results suggested acceptable rater concordance, but minor revisions could further improve scoring precision. Conclusion: Clinimetric evidence supports the use of 2 new instruments when monitoring taxane- and platinum-related neuropathy and pain. Further instrument modifications are recommended, followed by additional testing in diverse populations. Implications for Practice: With these new instruments, nurses can more easily incorporate prospective neuropathy assessment into daily clinical practice. The outcome will be improved symptom awareness by oncology clinicians and patients, leading to fewer chemotherapy-induced peripheral neuropathy-related devastating effects on functionality and quality of life.

Clinical Course of Oxaliplatin-Induced Neuropathy: Results From the Randomized Phase III Trial N08CB (Alliance)

PURPOSE Given that the clinical course of oxaliplatin-induced neuropathy is not well defined, the current study was performed to better understand clinical parameters associated with its presentation. METHODS Acute and chronic neuropathy was evaluated in patients receiving adjuvant FOLFOX (fluorouracil, leucovorin, and oxaliplatin) on study N08CB (North Central Cancer Treatment Group, Alliance). Acute neuropathy was assessed by having patients complete daily questionnaires for 6 days with each cycle of FOLFOX. Before each dose of FOLFOX and as long as 18 months after chemotherapy cessation, chronic neurotoxicity was assessed with use of the 20-item, European Organisation for Research and Treatment of Cancer quality-of-life questionnaire for patients with chemotherapy-induced peripheral neuropathy. RESULTS Three hundred eight (89%) of the 346 patients had at least one symptom of acute neuropathy with the first cycle of FOLFOX; these symptoms included sensitivity to touching cold items (71%), sensitivity to swallowing cold items (71%), throat discomfort (63%), or muscle cramps (42%). Acute symptoms peaked at day 3 and improved, although they did not always resolve completely between treatments. These symptoms were about twice as severe in cycles 2 through 12 as they were in cycle 1. For chronic neurotoxicity, tingling was the most severe symptom, followed by numbness and then pain. During chemotherapy, symptoms in the hands were more prominent than they were in the feet; by 18 months, symptoms were more severe in the feet than they were in the hands. Patients with more severe acute neuropathy during the first cycle of therapy experienced more chronic sensory neurotoxicity (P < .0001). CONCLUSION Acute oxaliplatin-induced neuropathy symptoms do not always completely resolve between treatment cycles and are only half as severe on the first cycle as compared with subsequent cycles. There is a correlation between the severities of acute and chronic neuropathies.

Patterns and severity of vincristine‐induced peripheral neuropathy in children with acute lymphoblastic leukemia

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine‐induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1–18 years who received vincristine at one of four academic childrens hospitals. VIPN assessments were obtained using the Total Neuropathy Score‐Pediatric Vincristine (TNS©‐PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©–Five (PNPS©‐5). Of children who provided a full TNS©‐PV score, 85/109 (78%) developed VIPN (TNS©‐PV ≥4). Mean TNS©‐PV, grading scale, and pain scores were low. CTCAE©‐derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8–12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2–3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.

Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia

Background: Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children. Objective: The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia. Interventions/Methods: Children (n = 65) aged 1 to 18 years receiving vincristine at 4 academic centers participated in the study. Baseline and pre–vincristine administration VIPN assessments were obtained using the Total Neuropathy Score–Pediatric Vincristine (TNS©-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES Pain Scale. The TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time points to quantify pharmacokinetic parameters. Results: Cronbach’s &agr; for a reduced TNS-PV scale was .84. The TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, P = 0.01), pharmacokinetic parameters (r = 0.41, P = 0.05), and grading scale scores (r range = 0.46–0.52, P = .01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; P = .01) and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (effect size = 0.65, P < 0.001). The TNS-PV scores were attainable in 95% of children 6 years or older. Conclusions: The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children 6 years or older. Implications for Practice: The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia.

The Validity of Neuropathy and Neuropathic Pain Measures in Patients With Cancer Receiving Taxanes and Platinums

PURPOSE/OBJECTIVES To assess the validity of neuropathy and neuropathic pain-measurement approaches. DESIGN Cross-sectional measurement study. SETTING Two comprehensive cancer centers in the northeastern United States. SAMPLE 117 patients with cancer in an outpatient setting. METHODS Participants were assessed using the five-component Total Neuropathy Score-reduced (TNSr), the TNSr short form (TNSr-SF), individual TNSr items, the Neuropathic Pain Scale for chemotherapy-induced neuropathy (NPS-CIN), and the National Cancer Institutes Common Toxicity Criteria™, version 3.0 (NCI-CTC). MAIN RESEARCH VARIABLES Neuropathy and pain measure scores, cumulative and per M2 chemotherapy dosage, comorbid risk factors, drug class, and the number of neurotoxic drugs received. FINDINGS TNSr, TNSr-SF, and tendon reflex scores were greater in patients receiving higher cumulative (z range = -2.2 to -3.6; p range = 0.01 to < 0.001) and per M2 (z range = -1.8 to -2.4; p range = 0.04 to < 0.001) chemotherapy doses. Scores from most neuropathy and pain measures were higher in patients with comorbid illnesses (z range = -1.79 to -3.51; p range = 0.03 to < 0.001). Sensory NCI-CTC scores were higher in patients receiving higher cumulative chemotherapy dosage (z = -2.1; p = 0.02). Only the sensory NCI-CTC correlated with other measures (r range = 0.22-0.63; p range = 0.05 to < 0.001). CONCLUSIONS Findings support the validity of the TNSr, TNSr-SF, tendon reflex item, NPS-CIN, and NCI-CTC sensory grading scale when measuring taxane and platinum-induced neuropathy. However, additional validity testing is warranted. IMPLICATIONS FOR NURSING Comprehensive neuropathy and pain measures mainly used by researchers and neurologists were simplified to more clinically useful tools for use by nurses when monitoring chemotherapy-induced peripheral neuropathy.

Preliminary assessment of a neuropathic pain treatment and referral algorithm for patients with cancer.

CONTEXT The purpose of this case series study was to pilot test an evidence-based neuropathic pain (NP) treatment and referral algorithm for use by oncology nurses when managing cancer-related NP. OBJECTIVES The primary study objective was to assess patient-reported outcomes (pain severity, changes in activities of daily living, and satisfaction) resulting from algorithm use. METHODS Outpatients (n=20) with cancer-related NP scores ≥4 on a 0-10 numeric rating scale participated in the study. NP assessment, treatment, and referral to ancillary providers were guided by an evidence-based NP algorithm that was implemented by oncology nurse practitioners. Based on efficacy evidenced through randomized clinical trials published at the time of study implementation, the following drugs were included in the algorithm: lidocaine patch, gabapentin, oxycodone, tramadol, morphine, methadone, duloxetine, pregabalin, and nortriptyline. Recommendations for starting dose, dose escalation, drug combinations, treatment duration, and contraindications were included for first-tier drugs. Patient-reported outcomes (pain severity, functional capacity, and satisfaction) were assessed monthly over 12 weeks. RESULTS Average NP severity (P=0.001), general activity (P<0.001), mood (P=0.002), walking ability (P=0.01), ability to perform normal work (P=0.002), relationships (P=0.002), sleep (P=0.01), life enjoyment (P<0.001), and patient satisfaction (P=0.003) all improved by 12 weeks. CONCLUSION Evidence from this pilot study suggests that NP evidence-based treatment may result in improved symptoms, function, and patient satisfaction. A randomized controlled trial is needed to further assess algorithm efficacy.

Measuring the quality of care related to pain management: a multiple-method approach to instrument development.

Background:Research to document the effects of nursing on patient outcomes such as pain has been limited by the inability to measure the quality of nursing care effectively. Objective:The purpose of this study was to establish content validity and to evaluate patient understanding of Pain Care Quality (PainCQ) survey items using cognitive interviewing. Method:In the development phase, 101 items representing four constructs were generated from the transcriptions of 33 qualitative interviews conducted with cancer patients in pain. In the judgment phase, items were reviewed systematically by two panels of pain experts. In the final phase, cognitive interviews were conducted with hospitalized cancer patients reporting pain. Results:Content validity was established if eight of nine (p < .05) experts agreed the item was relevant or very relevant. On the basis of the expert panel review, items were deleted, reworded, and added, and 73 items remained. These items were evaluated by cognitive interviews with 39 hospitalized patients with multiple types of cancer in three states. The mean age was 58.87 years, and 60.5% were women. Most were non-Hispanic White (94.7%), and education varied. On a 0 to 10 scale, worst pain during the past shift averaged 5.24 (SD = 2.43). Participant responses to the PainCQ survey items were summarized for each item using a matrix tool and evaluated in team meetings. Through an iterative process, items were revised and reduced to produce the PainCQ survey (v3) with 44 items. Discussion:Through this deliberative and iterative process, an instrument was produced that will contribute to the measurement of the quality of nursing and interdisciplinary care related to pain management. The items retained in the PainCQ were understood and judged by hospitalized patients with pain easily. Further psychometric testing of the PainCQ is indicated.

CALGB 170601: A phase III double blind trial of duloxetine to treat painful chemotherapy-induced peripheral neuropathy (CIPN).

CRA9013 Background: CALGB 170601 was a randomized, placebo-controlled phase III trial to determine whether duloxetine reduces painful chemotherapy-induced peripheral neuropathy (CIPN). The secondary study endpoint was treatment-related adverse events. METHODS The study used a double-blinded placebo-controlled crossover design with equally weighted randomization to one of two arms. Arm A participants received duloxetine followed by placebo. Arm B participants received placebo followed by duloxetine. The initial and crossover periods each consisted of six weeks of drug/placebo followed by one week of washout. Randomization was stratified by neurotoxic agent and high risk for developing painful CIPN. Eligible patients were 18 years or older with an average CIPN pain score > 4/10 attributed to prior single agent taxane or platinum treatment. Participants took one capsule daily (30mg) for one week, and then two capsules (60mg) daily for four additional weeks. Participants completed the Brief Pain Inventory-Short Form (BPI-SF) at baseline and then weekly. The primary study endpoint was the change in BPI-SF scores within the initial treatment period. Analysis of covariance with an intent-to-treat approach was used to test the effect of treatment on change in pain score. RESULTS The target accrual goal (N = 231) was met, of which 185 (80%) completed the initial treatment period. Oxaliplatin was the most commonly received neurotoxic agent (59%). Individuals receiving duloxetine over the initial treatment period had a larger average decrease in pain score (mean change score = -1.09; S.E. = 0.19) than those receiving placebo (mean change score = -0.33; S.E. = 0.18) (p = 0.004). There was no difference in duloxetine efficacy based on the specific neurotoxic agent received. Severe (Grade 3) non-hematologic toxicity was reported by 11%, and 41% reported moderate (Grade 2) toxicities. The incidence of Grade 2+ fatigue, the most commonly reported side effect, was significantly higher in the duloxetine arm as compared to placebo (11% vs. 3%, p = 0.029). CONCLUSIONS Duloxetine 60mg daily is an efficacious and well-tolerated intervention for the treatment of taxane or platinum-related painful CIPN.

Chronic Pain and Cognitive Behavioral Therapy: An Integrative Review.

Cognitive behavioral therapy (CBT) is often used to treat chronic pain; however, more information is needed about what are the most efficacious dose and delivery methods. The aims of this review were to determine (a) which CBT doses, delivery methods, strategies, and follow-up periods have been explored in recent intervention studies of individuals with chronic pain and (b) whether the outcomes described in the selected studies were consistent with recommendations by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials. The CINAHL, EMBASE, PubMed, PsycInfo, and SCOPUS databases were searched for randomized controlled trials published from 2009 to 2015 testing CBT for adults with chronic pain. Thirty-five studies were included in this review. Results revealed that CBT reduced pain intensity in 43% of trials, the efficacy of online and in-person formats were comparable, and military veterans and individuals with cancer-related chronic pain were understudied.