Vincristine-induced peripheral neuropathy in children with childhood cancer: comparing one-hour infusions with short-term infusions (the VINCA-study)

Vincristine (VCR) is a commonly used chemotherapeutic drug in the treatment of
for example pediatric acute lymphoblastic leukemia, nephroblastoma, low-grade
glioma, Hodgkin lymphoma and rhabdomyosarcoma. The main dose-limiting side
effect of VCR is peripheral neuropathy (PNP). PNP is often seen in the form of
weakness of lower limbs, areflexia, neuropathic pain, and/or sensory loss. The
quality of life of children who suffer from VCR-induced PNP is severely
affected.
There is a lack of information regarding the optimal therapeutic dosing and
method of administration of VCR for children with cancer. High peak plasma
concentrations seem to be correlated with PNP. However, the exact mechanism
underlying VCR-induced PNP is not clear.

This study aims to investigate whether the administration of VCR in children
with acute lymphoblastic leukemia, nephroblastoma, low-grade glioma, Hodgkin
lymphoma and rhabdomyosarcoma by one-hour infusions, resulting in lower peak
plasma concentrations, leads to less PNP compared to short-term infusions. In
addition, quality of life, (non-)medical costs, and treatment efficacy
associated with both administration methods will be evaluated. Moreover, it
will be investigated whether other factors, such as pharmacokinetics and
genetic susceptibility to drug-induced side-effects, also influence the degree
of PNP.

The study is a clinical intervention study, with a prospective,
randomized,controlled design. Participants will receive all VCR administrations
of their treatment either by short-term infusions (1-5 minutes) or by one-hour
infusions. Study measurements will be performed at 4 - 8 points in time: before
the first VCR administration, 1-7 times during treatment, at the end of
treatment, and 6 months after end of treatment.

Patients will be randomized into two groups. Patients will either receive all
VCR administrations during their treatment period by a one-hour infusion, or by
means of a short-term infusion of 1-5 minutes (or by injection).

The investigational medicinal product (IMP) that is studied is VCR, a drug
which is widely used. Moreover, the investigated methods of administration
(bolus injection/infusion and one hour infusion) are both being applied in
children in daily clinical practice. Which method is being used depends merely
on local center*s logistical/ practical considerations. Study measurements will
be performed at 7 points in time. At these time points patients are asked to do
the following: 1. undergo a physical neurological examination (3-7 measurements
in total, 20 minutes on average per measurement); 2. fill out questionnaires
(QoL: 2-6 measurements in total, 15-20 minutes on average per measurement;
costs: 0 - 3 measurements in total; 10 minutes on average per measurement); 3.
provide blood samples (1-4 pharmacokinetic measurements in total, 8 samples per
measurement). Clinical measurements and blood sampling will be performed on
days the patient has to visit the clinic for treatment purposes; questionnaires
will be given to the patients/guardians and can be filled out at home. Although
it is not the primary aim of this study, participants can benefit from the
effects of the intervention. The benefit could be less PNP, less use of
medication and lower costs, resulting in improved quality of life.

Whenever possible are pharmacokinetic measurements being performed at time
points at which the participants undergo general anesthesia, for example for a
bone marrow or lumbar puncture according to their treatment protocol. This
allows the insertion of an extra intravenous cannula (which is needed for the
PK measurements) without any extra burden for the patients. When this is not
possible, this part of the study becomes optional. Separate informed consent is
asked for participation of this part of the study.

The sampled blood volume is small (7 x 2 ml = 14 ml). As the average blood
volume of a 2-year old child weighing 12 kg is around 900 ml, the maximum
amount of blood sampled from the smallest eligible study participant concerns
1,6% of the total blood volume.

All in all, the risks associated with participation in the current study can be
considered negligible and the patient's and parent's burden can be considered
low to moderate. Given this low risk and low-moderate burden, and the fact that
this study has the potential to have major consequences for the improvement of
quality of life for all childhood acute lymphoblastic leukemia, nephroblastoma,
low-grade glioma, Hodgkin lymphoma and rhabdomyosarcoma patients, this study is
considered to have a favorable risk-benefit assessment.