Pediatric-modified Total Neuropathy Score Research Articles

MDB-48. A SINGLE INSTITUTION EXPERIENCE OF CIPN MEASURED BY THE PED-MTNS IN CHILDREN AND ADOLESCENTS WITH MEDULLOBLASTOMA TREATED ON A TRIAL USING SIMILAR DOSING OF VINCRISTINE AND CISPLATIN FOR ALL PATIENTS

Abstract BACKGROUND Standard treatment for medulloblastoma in patients >3 years of age consists of tumor resection, radiation and chemotherapy using vincristine, cisplatin, cyclophosphamide +/- CCNU. Vincristine and Cisplatin are known to cause chemotherapy induced peripheral neuropathy (CIPN). The prevalence of CIPN in children with non-CNS cancers can be measured using the pediatric-modified Total Neuropathy Score (ped-mTNS). The purpose of this observational, retrospective pilot design is twofold: to investigate the prevalence of CIPN in children with medulloblastoma receiving neurotoxic chemotherapy, and to examine the feasibility of using the ped-mTNS as a measurement tool in this population. METHODS Data was manually extracted from medical records and entered into a REDCap database for analysis. The percent of patients successfully tested and clinical inferences made from ped-mTNS testing results were used to determine feasibility and barriers to use. A total of 33 medulloblastoma patients >3 years of age were treated from 6/2013 - 6/2021 at Children’s Minnesota. Of those, 18 received testing using the ped-mTNS during chemotherapy treatment. RESULTS During cancer treatment, 54.5% of the cohort of patients received ped-mTNS testing. The average age of children tested was 10.26 (4.39) years with a majority being male (79%), and non-Hispanic white race/ethnicity (89%). Of the tested participants, 61.1% had more than one measurement. For those patients tested at multiple timepoints, 72.7% demonstrated worsening ped-mTNS scores while on chemotherapy treatment. Therapists recorded inferences relating to neuropathy in 88.1% of testing occurrences with questions of accuracy recorded in 31.3% of testing occurrences. Barriers to use of results included confounding impairments that may occur as a result of the primary tumor, post-surgical changes, and radiation. CONCLUSIONS Using the ped-mTNS is feasible in children and adolescents with medulloblastoma. The ped-mTNS scores indicated that children with medulloblastoma, treated with Vincristine and Cisplatin, experience worsening neuropathy while undergoing chemotherapy treatment.

Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis).

Vincristine is an integral component of treatment for children with cancer. Its main dose-limiting side effect is vincristine-induced peripheral neuropathy (VIPN). The VINCA trial was a randomized controlled trial that explored the effect of 1-hour infusion compared with push injection of vincristine on the development of VIPN in children with cancer. The short-term outcomes (median follow-up 9 months) showed that there was no difference in VIPN between the randomization groups. However, 1-hour infusion was less toxic in children who also received azoles. We now report the results of the final analyses (median follow-up 20 months), which includes treatment outcome as a secondary objective (follow-up 3 years). VIPN was measured 1-7 times per participant using the Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score. Poisson mixed model and logistic generalized estimating equation analysis for repeated measures were performed. Forty-five participants per randomization group were included. There was no significant effect of 1-hour infusion compared with push injection on VIPN. In participants receiving concurrent azoles, the total CTCAE score was significantly lower in the one-hour group (rate ratio 0.52, 95% confidence interval 0.33-0.80, p = 0.003). Four patients in the one-hour group and one patient in the push group relapsed. Two patients in the one-hour group died. 1-hour infusion of vincristine is not protective against VIPN. However, in patients receiving concurrent azoles, 1-hour infusion may be less toxic. The difference in treatment outcome is most likely the result of differences in risk profile.

Vincristine induced peripheral neuropathy in children undergoing chemotherapy for acute lymphoblastic leukaemia during induction

Background: Vincristine is an anticancer agent administered to all children with acute lymphoblastic leukemia (ALL), and peripheral neuropathy is the major dose-limiting toxicity of this therapy. As cure rates of childhood ALL exceeds 80%, therefore treatment-related toxicities need to be reduced. Thus, the aim of this study was to determine the prevalence and risk factors of vincristine-induced peripheral neuropathy (VIPN) in children with ALL undergoing induction chemotherapy. Methods: A case-control study was conducted from September 2017 to August 2018 in the Department of Paediatric Haematology and Oncology at Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Eighty newly diagnosed ALL and 35 acute myeloid leukemia (AML) cases aged 5 to 17 years with no pre-existing neurological abnormality were recruited. To assess the peripheral neuropathy, we used pediatric-modified total neuropathy score and National Cancer Institute- Common Terminology Criteria for Adverse Events (NCI-CTCAE), version-04 grade. Results: Among ALL patients, 29.2% developed peripheral neuropathy compared to 10% in AML control group (P=0.04). Higher proportion (57.1%) of peripheral neuropathy was found in age below 10 years (P<0.001). There was no significant association of peripheral neuropathy with sex and body mass index of the patients. Conclusion: Almost 3 in 10 patients developed VIPN during the induction therapy which is significantly higher in age below 10 years compared to ≥ 10 years.

Examination of the psychometric properties of pediatric-modified total neuropathy score in Turkish children with cancer

BackgroundEvaluation of chemotherapy-induced peripheral neuropathy has gained importance in symptom management of pediatric patients with cancer. This study aimed to perform the Turkish validity and reliability study of the Pediatric-Modified Total Neuropathy Score (Ped-mTNS). MethodsA methodological, descriptive, and cross-sectional design was used in the study. Forty children aged between 5 and 18 and were treated for cancer and 40 age- and gender-matched healthy children (control group) were included in the study. The mean scores of the items on the Ped-mTNS were compared, and item-total score correlations were evaluated. Cronbach's alpha coefficient of the Ped-mTNS was calculated for internal consistency. FindingsCronbach's alpha value of the scale was found as 0.709. The item-total correlations of the scale items ranged from 0.260 to 0.658. The mean score of cancer patients on the Ped-mTNS was found as 4.4 ± 3.8. DiscussionPed-mTNS scores of children with cancer indicated more deficits than those of the control group. In the evaluation of children in the patient and control groups, a difference was found in terms of light touch sensation, which is one of the sensory symptoms in the items of the Ped-mTNS, and pin sensibility and strength, which are among the clinical symptoms. Application to practiceThe Ped-mTNS was determined to be a valid and reliable measurement tool for children with cancer aged between 5 and 18 in the Turkish population.

Assessment of Pediatric Chemotherapy-Induced Peripheral Neuropathy Using a New Patient-Reported Outcome Measure: The P-CIN.

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is commonly experienced by children receiving neurotoxic chemotherapy. No validated pediatric CIPN patient-reported outcome (PRO) measures exist. Purpose: To test sensitivity, internal consistency reliability, content and convergent validity, and feasibility of the Pediatric Chemotherapy-Induced Neuropathy (P-CIN), an electronic PRO measure for assessing CIPN in children who received neurotoxic chemotherapy. Method: Five experts evaluated content validity of the 14-item P-CIN. Children 5 to 17 years old with CIPN (N = 79) completed the P-CIN via tablet computer; a subset (n = 26) also underwent neurological examinations using the Pediatric-Modified Total Neuropathy Score. Following preliminary analyses, one item was deleted and three others modified. The revised P-CIN was retested with patients (n = 6) who also completed the Bruininks-Oseretsky Test of Motor Proficiency motor function assessment. Means, item response ranges, standard deviations, content validity indexes, Cronbach's alphas, and correlation coefficients were calculated. Results: Mean participant age was 11.25 (SD = 4.0) years. Most had acute leukemia (62.5%) and received vincristine (98.7%). Content validity index coefficients ranged from .80 to 1.0 (p = .05). For 9 of 14 items, responses ranged from 0 to 4 or 5; response ranges for toe numbness, pick up a coin, and three of four pain items were 0 to 3. After deleting one item, Cronbach's alpha coefficient was .83. P-CIN scores were strongly associated with Pediatric-Modified Total Neuropathy Score (r = .52, p < .01) and Bruininks-Oseretsky Test of Motor Proficiency (r = -.83, p = .04) scores. Sixty-eight percent of children 6 to 17 years old completed P-CIN independently. Discussion: Preliminary evidence suggests that the 13-item P-CIN is internally consistent, is valid, and can be completed independently by children ≥ 6 years. However, we recommend additional testing.

Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology: A Randomized Controlled Trial Comparing Push Injections with One-Hour Infusions (The VINCA Trial).

Simple SummaryWe studied children with cancer who receive vincristine chemotherapy as a one-hour infusion and compared them to children who received vincristine as a push injection. We investigated if there was a difference in the development of vincristine induced peripheral neuropathy, the most common side effect of vincristine. We found that in general there were no differences between the two groups (one-hour group versus push group). However, in children using both vincristine and azole antifungals, we noticed that children who received vincristine as a one-hour infusion experienced less severe vincristine induced peripheral neuropathy compared to children who received vincristine as a push injection. Therefore, in children who require both azole antifungal medication as well as vincristine it might be beneficial to administer the vincristine as a one-hour infusion instead of a push injection. However, this finding needs to be confirmed in other studies as well.Vincristine (VCR) is a frequently used chemotherapeutic agent. However, it can lead to VCR-induced peripheral neuropathy (VIPN). In this study we investigated if one-hour infusions of VCR instead of push-injections reduces VIPN in pediatric oncology patients. We conducted a multicenter randomized controlled trial in which participants received all VCR administrations through push injections or one-hour infusions. VIPN was measured at baseline and 1–5 times during treatment using Common Terminology Criteria of Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score. Moreover, data on co-medication, such as azole antifungals, were collected. Overall, results showed no effect of administration duration on total CTCAE score or ped-mTNS score. However, total CTCAE score was significantly lower in patients receiving one-hour infusions concurrently treated with azole antifungal therapy (β = -1.58; p = 0.04). In conclusion, generally VCR administration through one-hour infusions does not lead to less VIPN compared to VCR push injections in pediatric oncology patients. However, one-hour infusions lead to less severe VIPN compared to push-injections when azole therapy is administered concurrently with VCR. These results indicate that in children treated with VCR and requiring concurrent azole therapy, one-hour infusions might be beneficial over push injections, although larger trials are needed to confirm this association.

Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients.

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1–5 occasions (1–8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (Cmax) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V2), and Cmax were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V2, and Cmax, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.

Long-term small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation

PurposeWe aimed at describing for the first time peripheral small-fiber neurotoxicity and pain sensitization in survivors of pediatric acute lymphoblastic leukemia after stem cell transplantation (SCT).MethodsIn a cross-sectional, retrospective, single-center study, we assessed 25 relapse-free long-term survivors (median age at SCT: 11 ± 4.9 years; median time between SCT and testing: 8.25 years, 19 males) using a reduced version of the pediatric-modified total neuropathy score for clinical assessment and Quantitative Sensory Testing (QST). Inclusion criteria: ge 6 years old at testing, le 18 years old at time of SCT, ge 1 year between SCT and testing.ResultsNine patients (36%) had peripheral neuropathy as defined by the clinical red-pmTNS (≥ 4). The QST parameters mechanical pain sensitivity, mechanical detection threshold, thermal sensory limen, vibration detection threshold and pressure pain threshold were significantly abnormal in the survivor cohort (p < 0.0038). Except for one, all survivors showed at least one abnormal QST parameter. When using QST, signs of small and large fiber dysfunction were present in 22 (88%) and 17 (68%) survivors, respectively. More than half of all survivors were found to experience pathologic sensitization to pain.Conclusions and implications for cancer survivorsSurvivors of pediatric acute lymphoblastic leukemia after SCT are at high risk for long-term peripheral neuropathy with a dominating small-fiber and pain sensitization pattern.

Measuring vincristine-induced peripheral neuropathy in children with cancer: validation of the Dutch pediatric\u2013modified Total Neuropathy Score

PurposeThe aims were to evaluate the construct validity and reliability of the Dutch version of the pediatric-modified Total Neuropathy Score (ped-mTNS) for assessing vincristine-induced peripheral neuropathy (VIPN) in Dutch pediatric oncology patients aged 5–18 years.MethodsConstruct validity (primary aim) of the ped-mTNS was determined by testing hypotheses about expected correlation between scores of the ped-mTNS (range: 0–32) and the Common Terminology Criteria for Adverse Events (CTCAE) (range: 0–18) for patients and healthy controls and by comparing patients and controls regarding their total ped-mTNS scores and the proportion of children identified with VIPN. Inter-rater and intra-rater reliability and measurement error (secondary aims) were assessed in a subgroup of study participants.ResultsAmong the 112 children (56 patients and 56 age- and gender-matched healthy controls) evaluated, correlation between CTCAE and ped-mTNS scores was as expected (moderate (r = 0.60)). Moreover, as expected, patients had significantly higher ped-mTNS scores and more frequent symptoms of VIPN compared with controls (both p < .001). Reliability as measured within the intra-rater group (n = 10) (intra-class correlation coefficient (ICCagreement) = 0.64, standard error of measurement (SEMagreement) = 2.92, and smallest detectable change (SDCagreement) = 8.1) and within the inter-rater subgroup (n = 10) (ICCagreement = 0.63, SEMagreement = 3.7, and SDCagreement = 10.26) indicates insufficient reliability.ConclusionThe Dutch version of the ped-mTNS appears to have good construct validity for assessing VIPN in a Dutch pediatric oncology population, whereas reliability appears to be insufficient and measurement error high. To improve standardization of VIPN assessment in children, future research aimed at evaluating and further optimizing the psychometric characteristics of the ped-mTNS is needed.

Switching to Bortezomib may Improve Recovery From Severe Vincristine Neuropathy in Pediatric Acute Lymphoblastic Leukemia

The purpose of this study was to evaluate the impact of switching patients being treated for acute lymphoblastic leukemia (ALL) from vincristine to bortezomib. A total of 20 patients with ALL were switched from vincristine to bortezomib (1.3 mg/m/dose) because of worsening neuropathy despite physical therapy interventions (n=18) or at increased risk of neuropathy (n=2). Relapse rates were compared with 56 vincristine-only patients matched by prognostic factors. Maintenance blood counts in bortezomib patients were compared with cooperative group data using vincristine during maintenance. In addition, 6 evaluable patients were assessed for neuropathy using the pediatric-modified total neuropathy score. Neuropathy scores were collected during treatment with vincristine and after switching to bortezomib. After a median follow-up of 3.5 years the relapse rate in patients switched to bortezomib was nonsignificantly different than those remaining on vincristine. Patients on monthly bortezomib had statistically significantly lower platelet counts that did not require transfusions or dose adjustment. Total neuropathy for all 6 cases decreased significantly when switched to bortezomib from vincristine (P=0.015), with motor neuropathy declines in 5 of 6 subjects. Bortezomib substitution for vincristine in ALL treatment is a potential strategy to mitigate severe vincristine neuropathy. These findings should be confirmed in a randomized clinical trial to further assess benefits and risks of this approach.

Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia.

Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7±3.5years at diagnosis, median 2.5 years after therapy; males: 28). ≥6 years of age, ≥3 months after last administration of Vincristine, and cumulative dose of Vincristine 12mg/m2. We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped-mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment ofsmall- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large-fiber neuropathy. Fifteen survivors (33%) had abnormal rPed-mTNS values (≥4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p<0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival.

The pediatric-modified total neuropathy score: a reliable and valid measure of chemotherapy-induced peripheral neuropathy in children with non-CNS cancers

Neurotoxicity is a common side-effect of cancer treatment, but no scales have been validated for the pediatric population. The objective of this study was to test the reliability and validity of the pediatric modified-Total Neuropathy Scale (ped-mTNS) to measure chemotherapy-induced peripheral neuropathy in school-aged children. Forty-one subjects aged 5-18 years undergoing chemotherapy with vincristine or cisplatin and 41 age- and gender-matched controls completed study measures. Subjects were tested with the ped-mTNS at a specified time during treatment. Standardized measures of balance and hand function were completed concurrently. Internal consistency of the ped-mTNS was evaluated using Chronbach's alpha. Validity was tested by comparing case and control ped-mTNS scores as well as testing the hypothesis that ped-mTNS scores would be associated with scores on tests of balance and manual dexterity. Inter-rater and test-retest reliability were each assessed in a subset of 10 subjects. Twenty-three subjects with acute lymphoblastic leukemia, six with lymphoma, and 12 with solid tumors completed measures along with 41 age- and gender-matched controls. Internal consistency was acceptable with a Chronbach's alpha of 0.76. Children undergoing treatment for cancer had significantly worse scores on the ped-mTNS compared to controls (subjects, 8.7 ± 4.2; controls, 1.4 ± 0.9; p < 0.001). As hypothesized, scores on the ped-mTNS were associated with measures of balance and manual dexterity. Inter-rater and test-retest reliability was acceptable (intraclass correlation coefficients >0.9 each). The ped-mTNS is a reliable and valid measure of chemotherapy-induced peripheral neuropathy in school-aged children that is associated with relevant functional limitations.