A randomized controlled trial published in Cancer Medicine in September 2023 examined whether administering vincristine as a 1-hour infusion versus a push injection affected rates of vincristine-induced peripheral neuropathy (VIPN) in children with cancer. The study, known as the VINCA trial, was conducted by researchers in the Netherlands and Belgium and funded by the Netherlands Organization for Health and Development and the Belgian Health Care Knowledge Centre.
Vincristine is a chemotherapy drug commonly used to treat various pediatric cancers, including acute lymphoblastic leukemia (ALL), lymphoma, and nephroblastoma. However, VIPN is a major dose-limiting side effect that can significantly impact patients' quality of life both during and after treatment. This study aimed to determine if altering the administration method could reduce VIPN incidence and severity without compromising treatment efficacy.
The multi-center, open-label trial enrolled 90 pediatric cancer patients between ages 2-18 years who were newly diagnosed and had not previously received vincristine. Patients were randomized 1:1 to receive vincristine as either a push injection (n=45) or a 1-hour infusion (n=45). Stratified block randomization was used, with patients stratified by age (2-10 years vs 11-18 years), sex, and country.
Eligible diagnoses included ALL, Hodgkin's lymphoma, nephroblastoma, rhabdomyosarcoma, low-grade glioma, and medulloblastoma. Patients with pre-existing peripheral neuropathy were excluded. The majority of participants were white (over 80% in both groups) and diagnosed with ALL (64.4% in both groups). The median follow-up time was 20 months.
VIPN was assessed longitudinally using two validated measurement tools: the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and the pediatric-modified Total Neuropathy Score (ped-mTNS). Assessments were conducted at predefined time points during treatment and 6 months after completing vincristine therapy. The primary outcome was development of VIPN over time based on total CTCAE scores.
The results showed no significant difference in overall VIPN incidence or severity between the push and 1-hour infusion groups. According to CTCAE criteria, 57.8% of patients in the push group and 55.6% in the 1-hour group developed VIPN. Rates of severe VIPN (grade 3 or higher) were 15.6% and 13.3% in the push and 1-hour groups, respectively. Analysis of total CTCAE scores over time found no statistically significant effect of administration method (rate ratio 0.92, 95% CI 0.67-1.26, p=0.59).
However, a pre-specified subgroup analysis revealed that for patients receiving concurrent azole antifungal medications, 1-hour infusion resulted in significantly lower total CTCAE scores compared to push injection (rate ratio 0.52, 95% CI 0.33-0.80, p=0.003). This finding persisted after adjusting for potential confounders. Additionally, there was a trend toward lower risk of severe VIPN with 1-hour infusion in azole-treated patients, though this did not reach statistical significance (OR 0.26, 95% CI 0.06-1.20, p=0.09).
Results were similar when analyzing ped-mTNS scores, with no significant differences between administration methods in the overall cohort. The study was not powered to detect differences in treatment efficacy, but exploratory analysis found more relapses in the 1-hour infusion group (4 vs 1 patient). However, the authors noted this was likely due to differences in underlying disease risk profiles rather than administration method.
Some key limitations of the study include the relatively short median follow-up time of 20 months for assessing long-term VIPN effects. The authors acknowledged that VIPN measurements were performed at different time points after varying numbers of vincristine doses, which may have influenced results despite attempts to correct for cumulative dosage. Additionally, while two measurement tools were used, the authors noted these still provide an imperfect representation of the clinical reality of VIPN.
The researchers concluded that overall, 1-hour infusion of vincristine does not appear to reduce VIPN incidence or severity compared to push injection in pediatric cancer patients. However, they emphasized that patients receiving concurrent azole antifungals may benefit from 1-hour infusion, as this subgroup showed significantly lower VIPN scores with the longer administration time.
These findings have potential clinical implications for optimizing vincristine administration in certain patient populations. For children requiring azole antifungals during cancer treatment, clinicians may consider using 1-hour infusion of vincristine to reduce neurotoxicity risk. However, the lack of overall benefit means a widespread change in administration practices is likely not warranted based on these results alone.
The study adds valuable data to the ongoing effort to mitigate VIPN in pediatric oncology while maintaining treatment efficacy. The authors called for future research to further elucidate the pharmacokinetic and pharmacodynamic relationships between vincristine administration methods, toxicity, and anticancer activity. Additional studies with larger sample sizes and longer follow-up periods may help clarify any potential differences in long-term outcomes or rare adverse events.
This trial also highlights the challenges of studying supportive care interventions in pediatric cancer populations. The heterogeneity of diagnoses, treatment protocols, and patient characteristics can make it difficult to isolate the effects of a single intervention. Multi-center collaborations like this one are crucial for accruing adequate sample sizes to address these important clinical questions.
The finding of a potential benefit for azole-treated patients underscores the complexity of drug interactions in cancer care. As supportive medications like antifungals are frequently used alongside chemotherapy, considering their impact on toxicity profiles is an important aspect of personalized medicine approaches. This subgroup analysis, while exploratory, provides a basis for further targeted studies in this patient population.
From a practical standpoint, the feasibility of implementing 1-hour vincristine infusions is an important consideration. While longer than push injection, a 1-hour administration time is likely manageable for most oncology units without major workflow disruptions. This makes it a reasonable option to consider for high-risk patients if future studies continue to show a benefit.
The use of both physician-reported (CTCAE) and more comprehensive neuropathy-specific (ped-mTNS) outcome measures is a strength of this study's design. However, the authors' note that even these tools provide an imperfect clinical picture highlights the need for continued refinement of VIPN assessment methods, particularly those appropriate for younger pediatric patients.
In summary, this well-designed randomized trial provides important data on a common supportive care question in pediatric oncology. While the primary analysis did not show an overall benefit to 1-hour vincristine infusion, the potential reduction in neurotoxicity for patients on concurrent azoles warrants further investigation. As research continues to optimize chemotherapy administration and minimize long-term toxicities, studies like this contribute valuable evidence to guide clinical decision-making and future trial designs.
References
Uittenboogaard A, van den Berg MH, Abbink FCH, et al. Randomized controlled trial on the effect of 1-hour infusion of vincristine versus push injection on neuropathy in children with cancer (final analysis). Cancer Med. 2023;12(19):19480-19490. doi:10.1002/cam4.6550
