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Purpose Vincristine (VCR) is a chemotherapeutic agent used in the treatment of pediatric oncology patients, but its main toxicity is VCR‐induced peripheral neuropathy (VIPN). However, whether VIPN has an effect on health‐related quality of life (HR‐QoL) in children during treatment is unknown. Therefore, the aim of our study was to investigate the association between VIPN and HR‐QoL in children starting treatment for cancer. Methods Measurements of VIPN were performed using two tools: Common Terminology Criteria for Adverse Events (CTCAE) and pediatric‐modified Total Neuropathy Score (ped‐mTNS). Assessment of HR‐QoL was done with self‐ and proxy assessment of the Cancer and Generic module of the Pediatric Cancer Quality of Life Inventory™ (PedsQL). Results In total, N = 86 children were included. HR‐QoL of children with VIPN (n = 67%, 76%) was significantly lower in comparison with children without VIPN: estimated Total score of PedsQL Generic (proxy) 84.57; β = −8.96 and 95% confidence interval (CI) −14.48 to −3.43; p = 0.002, estimated PedsQL Generic Total score (self‐reported): 85.16, β = −8.38 (95% CI: −13.76 to −3.00); p = 0.003. Similar results were found in the Pain and Hurt domain of the PedsQL Cancer (pain: estimated score [proxy]: 85.28, β = −9.94 [95%CI: −16.44 to −3.45], p = 0.003; hurt: estimated score [self‐report] 97.57, β = −19.15 [95%CI: −26.82 to −11.48], p, This article reports on the association between vincristine‐induced peripheral neuropathy and health‐related quality of life in pediatric oncology patients. Our data show that health‐related quality of life is significantly lower in children who experience vincristine‐induced peripheral neuropathy compared to pediatric oncology patients without vincristine‐induced peripheral neuropathy.

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&ndash, 5 occasions (1&ndash, 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.

Purpose Vincristine (VCR) is frequently used for the treatment of pediatric cancer. However, it can lead to dose-limiting vincristine-induced peripheral neuropathy (VIPN). This study aimed to investigate if prolonging the duration of VCR administration (1-hour infusions instead of push injections) reduces VIPN in children with cancer during the first year of treatment. Methods The VINCA trial is an international multicenter randomized controlled trial. Participants were randomized to receive all VCR administrations through push injections or 1-hour infusions. Dose of VCR was 1.5-2 mg/m2 with a maximum of 2 mg. VIPN measurements were performed at baseline and 1-3 times during treatment, depending on the number of VCR administrations and the total treatment time, using 4 items of the common toxicity criteria of adverse events (CTCAE version 4.03): constipation, peripheral sensory neuropathy, peripheral motor neuropathy and neuralgia. Individual item scores range from zero (no complaints) to five (death). The primary outcome of this trial was total sum CTCAE score during first year of treatment. For the current analysis, patients treated for acute lymphoblastic leukemia (ALL) or Hodgkin's lymphoma were included. All included patients were analyzed according to the intention-to-treat principle. Besides VIPN measurements, data on all relevant co-medication during treatment were collected, including data of concurrent azole therapy (as azole treatment is known to interact with VCR treatment). Descriptive data were analyzed using either chi-square tests or t-tests. Longitudinal data were analyzed using repeated measures mixed model analysis for continuous outcomes (total CTCAE sum score) and generalized estimating equations for dichotomous outcomes (having VIPN yes or no, with VIPN defined as a CTCAE score of ≥ 2 on any of the 4 CTCAE items). Patients were considered to have been treated with concurrent azole therapy when azoles were used during the week before or following VCR administration and if ≥ 50% of VCR administrations between two succeeding measurements were given with concurrent azole therapy. Results were corrected for concurrent azole therapy, cumulative VCR dose, disease, age, gender, ethnicity and time since diagnosis. Results In total 90 children (n=45 one hour infusions group, n=45 push injections group) participated in the study, 58 (64%) with ALL and 18 (20%) with HL. Participants in the two randomization groups did not significantly differ regarding gender, age, ethnicity, diagnosis, or cumulative VCR dose. Overall results showed no effect of randomization on total CTCAE score (β=0.07, 95% confidence interval (CI) -0.42-0.56, p=0.78). However, concurrent azole treatment appeared to be an effect modifier in this analysis and therefore results are reported separately for measurements with (n=24) and without concurrent azole therapy (n=226). Among patients who received concurrent azole therapy, total CTCAE sum score was significantly higher in the push group compared to the 1-hour group (β=1.95, 95% CI 0.49-3.41, p=0.01), while among those without concurrent azole therapy, these CTCAE sum scores did not differ between the two randomization groups (β=-0.17, 95% CI: -0.67-0.34, p=0.52). The risk of developing VIPN (no/yes) did not significantly differ between both randomization groups, irrespective whether concurrent azole treatment was given or not (with azole: OR (95% CI)=4.92 (0.60-40.37), p=0.14; without azole: OR (95% CI)=0.97 (0.51-1.82, p=0.92). Conclusions Overall, administration method of VCR given as push injection or 1-hour infusion did not seem to affect the risk of developing VIPN in children treated for ALL or HL when using the current dosing regimen. However, when concurrent azole treatment is given, total CTCAE scores are significantly lower in children in the 1-hour infusion group compared to the push injection group, demonstrating less VIPN. These results indicate that for children treated with VCR and concurrent azole therapy for the prevention or treatment of fungal infections, administration of VCR by 1-hour infusions instead of push injections is recommended. Figure Disclosures Kaspers: Helsinn Healthcare: Consultancy; Boehringer Ingelheim Pharma: Other: Member of a DSMC. van der Sluis:medac: Consultancy; jazz farmaceuticals: Consultancy.

Purpose Vincristine (VCR) is a commonly used drug in the treatment of several pediatric cancers. Unfortunately, children suffer from dose-limiting vincristine-induced peripheral neuropathy (VIPN). We aimed to assess whether the administration of VCR by means of one-hour infusions, resulting in lower peak levels, leads to less VIPN than bolus injections in children having completed the induction phase of their treatment for acute lymphoblastic leukemia (ALL) or Hodgkin's lymphoma (HL). Methods The study is part of the VINCA trial, an international randomized controlled trial studying the effect of administration method of VCR on the development and severity of VIPN during treatment of several types of childhood cancer. Participants were measured 3-6 times (depending on the number of VCR administrations and the total treatment period) and one final measurement 6 months after cessation of therapy. VIPN was assessed using the pediatric modified total neuropathy scale (ped-mTNS) and four items of the common toxicity criteria of adverse events (CTCAE version 4.03) items: constipation, peripheral sensory neuropathy, peripheral motor neuropathy and neuralgia. For the current analysis two measurements were taken into account. The first measurement was performed before onset of VCR therapy and the second after induction at day 33 (after 4 VCR administrations) in case of ALL or in week 7 (after 6 VCR administrations) in case of HL. VIPN was defined as a CTCAE sum score of ≥ 2 and/or a total ped-mTNS score of ≥ 5, whereas severe PNP was defined as an individual CTCAE item score of ≥ 3 or a total ped-mTNS score of ≥ 10. Analysis were done using logistic regression or cox-regression. Results were corrected for age, gender and ethnicity. Results In total, 91 children participated in the study, 58 (64%) of whom were treated for ALL and 18 (20%) for HL. 15 (20%) dropped out of the trial or could not be included in the current analysis due to insufficient data (n=6 drop-out or no measurements available after induction, n=9 time between measurement was larger than 64 days). Of the remaining 61, 35 (57%) were randomized in the bolus group and 26 (43%) in the one-hour group. Overall, there was a mean increase of 2.77 for the CTCAE sum score and 7.81 for the ped-mTNS sum score in the bolus group, compared to 2.12 and 6.38, respectively, in the one-hour group (CTCAE: β=-0.71, CI: -1.7-0.44, ped-mTNS: β=-0.84, CI=-3.65-1.97). 27 (77%) children developed neuropathy in the bolus group and 19 (73%) in the one-hour group. Children in the bolus group had a slightly increased, but not significant, risk of developing VIPN compared to children in the one-hour group (hazard ratio=1.21; 95% CI: 0.66 - 2.20). The proportion of children with severe neuropathy was equal in both groups (42%). Conclusions Children treated for ALL or HL who receive VCR by means of one-hour infusions or bolus injections seem to be at equal or diminished risk of developing VIPN during induction therapy. Results of longer follow-up that includes the total treatment period should demonstrate whether VIPN occurs less frequently and/or is less severe in case VCR is administered through one-hour infusions compared to administrations by bolus injections. Figure. Figure. Disclosures No relevant conflicts of interest to declare.