DISCUSSION
toxicity, cancer, toxic, PK/PD, weakness
CANCER, DISEASE
In this final analysis study, we assessed the long‐term effect of one‐hour administration of vincristine compared with push administration on the development of VIPN. We found that 1‐hour infusion of vincristine did not protect against VIPN compared with push injection, both during and 6 months after vincristine treatment. In an exploratory subgroup analysis, we found that one‐hour administration resulted was less toxic in children receiving concurrent azoles. More patients relapsed in the one‐hour group than in the push group, but this was most likely due to differences in disease risk profile.Although in previous studies multi‐day infusions with dosages up to 3.5–4.0 mg/mIn participants receiving concurrent azoles, one‐hour administration of vincristine resulted in less VIPN compared with push administration: the push group had a twice as high chance of having one point higher on the CTCAE scale. We confirmed this finding from the previously published study.We observed that more participants in the one‐hour group relapsed than in the push group. However, the number of participants with a high risk disease profile was higher in the one‐hour group than in the push group. Furthermore, we do not consider it biologically plausible that 1‐hour infusion of vincristine results in less overshoot of vincristine in the blood and thus lower therapeutic efficacy. All in all, we argue that it is unlikely that the duration of vincristine administration is the cause of the observed difference in treatment outcome between the push and one‐hour group.The results of this final analysis confirms those of the previously published one‐year analysis.The strength of this study is that we performed longitudinal VIPN assessments using sensitive measurement tools. We assessed the effect of administration duration on VIPN during and after treatment. A weakness of this study is that the study was not adequately powered to detect a difference in treatment outcome, which may hamper the interpretation of the clinical significance of the study. Another weakness of this study is that measurements were performed at different time points after a varying number of vincristine administrations. Since the timing of VIPN assessment in relation to the number and time of vincristine administrations affects VIPN, this likely influenced the results. We corrected for cumulative vincristine dosage and intra‐individual variability, but in this analysis, it was not possible to include the time between VIPN assessment and vincristine administrations. We are planning to investigate this in a follow‐up pharmacokinetic–pharmacodynamic (PK/PD) study. In addition, a median follow‐up of 20 months is relatively short to assess the long‐term effect of randomization on VIPN. However, studies have shown that there is little additional recovery from VIPN as the interval following vincristine administration increases.The VINCA trial assessed the effect of 1‐hour infusion of vincristine in comparison with push injection on the development of VIPN in children with cancer. We found that there was no long‐term effect of administration duration on VIPN. However, in participants receiving concurrent azoles, one‐hour administration was less toxic compared to push administration, suggesting that some children may benefit from one‐hour vincristine administrations. Future studies should aim to clarify the relationship between the PK and PDs of vincristine, including toxicity and efficacy. This will contribute to precision treatment of vincristine in children with cancer.