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1. Introduction

Vincristine (VCR) is a frequently-used chemotherapeutic agent in pediatric oncology since many decades^[1][2] [1,2]. VCR inhibits the mitotic spindle in the cell, thereby blocking cell division^[3][4] [3,4]. In the liver, it is metabolized into M1 by the cytochrome P450 (CYP) 3A enzymes^[5] [5]. A major adverse effect of VCR is neurotoxicity, which is characterized by autonomic and peripheral sensory-motor neuropathy and reported in 12–87% of VCR-exposed children^[1][6][7][8] [1,6,7,8]. Symptoms of VCR-induced peripheral neuropathy (VIPN) include paresthesia, muscle weakness, areflexia, pain, and diminished sensibility^{[9][10][11][12]} [9,10,11,12]. It usually starts after a few administrations and symptoms often reside several months after treatment cessation^[1][2] [1,2]. VIPN can lead to suboptimal treatment due to dose reductions or omissions of VCR^[10][13] [10,13]. VIPN is dose-dependent, with single administration doses exceeding 2.0 mg/m²  leading to intolerable VIPN in children^[14] [14]. Children of older age or Caucasian ancestry seem more vulnerable. Furthermore, genetic predispositions and pharmacokinetics (PK) of VCR influence VIPN development^{[1][6][14][15][16][17][18][19][20][21]} [1,6,14,15,16,17,18,19,20,21]. Moreover, multiple studies have shown that concurrent azole antifungal and VCR treatment leads to more and severe VIPN in children, due to competitive interaction by the CYP enzyme^[22][23][24] [22,23,24]. This is clinically relevant, since azole antifungals are frequently used to prevent or treat invasive fungal infections in pediatric cancer^[25] [25]. Although VIPN is dose-limiting^[1][14] [1,14], prolongation of VCR administration showed that the single administration dose can be increased without leading to intolerable VIPN in children. In two studies using continuous VCR infusion up to five days, cumulative VCR doses of 4.0 mg/m²  were well tolerated^[26][27] [26,27]. This could be due to lower peak-plasma concentrations that are related to longer lasting infusions, which seem associated with less VIPN^[28] [28]. Yet, multiple day VCR infusions are costly and cumbersome. Therefore, in clinical practice VCR is usually administered intravenously (iv) through a short-term push injection or infusion (up to 15 min). Sometimes it is administered through a one-hour infusion. Both push and one-hour administrations use standardized VCR doses of 1.5–2.0 mg/m²  (maximum 2.0 mg) [29]. However, the effect of prolonging VCR infusion on VIPN using standardized dosing regimens, is unknown.

2. High Therapeutic Effectiveness of VCR

In the current study, in which 90 pediatric oncology patients were randomized to receive VCR administrations through iv push injections or one-hour infusions, overall VIPN did not differ between the two groups. However, when VCR was administered concurrently with azole antifungals, children in the one-hour group had a significantly lower total CTCAE score than those in the push group. When VIPN was assessed by ped-mTNS scores or by dichotomized outcomes (having VIPN or not), no significant differences were found between push administrations and one-hour infusions, irrespective of concurrent azole treatment, although a trend in the same direction as CTCAE results was shown.

VIPN is a debilitating toxicity with symptoms still present in adult survivors of childhood cancer^[30] [30]. Therefore, the overarching goal of this trial was to study an intervention possibly resulting in reduced VIPN during treatment of childhood cancer. To the best of our knowledge, this is the first RCT studying the effect of administration duration of VCR on VIPN, either in children or adults. During this trial we evaluated VIPN prospectively and longitudinally with repeated measurements. At each hospital uniformly trained assessors evaluated VIPN using two different instruments (CTCAE and ped-mTNS) including standardized physical examination^[31] [31]. Especially the ped-mTNS has been systematically reviewed and is currently recommended for the assessment of VIPN in children^[32] [32].

Our results show that one-hour infusions result in lower total CTCAE scores when VCR is concurrently used with azole antifungals. In general, this concurrent treatment is associated with increased incidence and severity of VIPN ^[22][23][24][22,23,24]. In our study, estimated CTCAE score was 1.41 (95%CI: 1.19 to 1.64) for measurements without concurrent azole treatment and more than twice as high (2.87 (95%CI: 2.15 to 3.58)) for measurements with concurrent azole treatment (p < 0.001). However, when these scores of VIPN with concurrent azole antifungal use were evaluated for patients in each randomization group separately, estimated CTCAE score of patients in the one-hour group was 1.97 (95%CI: 0.92 to 3.01) vs. 3.64 (95%CI: 2.67 to 4.62) in the push group for measurements with concurrent azole treatment. These results show that concurrent treatment of azole antifungals and VCR has a smaller impact on VIPN when VCR is administered through one-hour infusions. This could also well be true for concurrent use with other strong CYP3A inhibitors, such as anti-retroviral drugs or carbamazepine.

Since concurrent use of azole antifungals and VCR are generally avoided, alternative treatment for invasive fungal infections (IFI) must be used, such as echinocandins or (liposomal) amphotericin B. However, these agents have several disadvantages including high costs, iv administration only, and lack of evidence of superior efficacy over azole antifungals in children^[33][34][35] [33,34,35]. Therefore, in clinical practice IFI are frequently treated with azole antifungals irrespective of concurrent VCR treatment^[36][37] [36,37]. Although in clinical practice treatment with azole antifungals is sometimes discontinued 24 hours before VCR administration, this interval is too short, based on the half-life of azole antifungals, to have an impact on this drug-drug interaction^[38] [38]. It should be noted, that the absolute number of patients with concurrent VCR and azole treatment was small in our study (n  = 19, 21%). Therefore, future studies should be undertaken to replicate our results and indisputably confirm the favorable effect of one-hour infusions over push injections regarding VIPN development. Furthermore, due to low patient numbers, we were not able to study the effect of azole type, such as itraconazole, fluconazole, voriconazole, and posaconazole. This could very well be of importance as itraconazole is a stronger inhibitor of CYP3A4 than for instance fluconazole or voriconazole^[39] [39]. Finally, diagnostic indication for treatment with azole antifungals, such as prophylaxis or treatment of diagnosed mycoses, on the relation between administration method and VIPN should be considered as well in a future study.

Although VIPN is a serious toxicity, high therapeutic effectiveness of VCR is of utmost importance. Regarding administration method, it is not expected that one-hour infusions of VCR are associated with a worse therapeutic outcome than push injections. It might even be the contrary. In general, longer lasting infusions of chemotherapy may improve therapeutic efficacy of a drug with a short half-life and an action mechanism of the drug that is related to the cell cycle, both of which are true for VCR^[26] [26]. While it is conceivable, that one-hour infusions are too short to benefit from this cell-cycle dependence or prolonged half-life, it underlines the unlikeliness of lower therapeutic effectiveness of one-hour infusions of VCR. In our study we also did not find any differences regarding relapse or mortality between the two groups.

Our study had some limitations. First of all, we included a heterogeneous group of patients with multiple diseases, varying VCR dosing regimens and co-medications. These different co-medications could theoretically alter pharmacokinetics and thus VCR exposure and VIPN development. In order to further investigate the true effect of VCR administration duration on the development of VIPN, future studies including more uniform diagnostic study groups are needed. Furthermore, in treatment protocols for ALL and Hodgkin’s lymphoma, the use of glucocorticoids is common practice^[29][40] [29,40]. Adverse effects of these agents could mimic symptoms of VIPN not attributed to VCR. However, we see a similar distribution of disease types in our two randomization groups, thereby ensuring similar distribution of co-medication. Secondly, the assessment of VIPN in children in general is difficult. Children of younger age are not able to verbally express their complaints. Therefore, for children aged <5 years VIPN assessment often relies on parent reports^[31][41] [31,41], which could introduce bias. The CTCAE lacks extensive physical examination, such as manual strength testing, vibration sense or assessment of sensibility, whereas the ped-mTNS cannot be used in younger children. As a consequence, both tools might not measure the same aspects of VIPN in the same population. Nevertheless, currently they represent the best available methods for VIPN assessment in children.

Furthermore, assessors of VIPN in this study, although frequently unaware of randomization status of the patients, were not strictly blinded to the randomization status. This could have introduced bias in the VIPN results reported.

Finally, VIPN is a multifactorial phenomenon, also influenced by PK of VCR and single nucleotide polymorphisms^[1] [1]. It would be beneficial to study the impact of administration duration on VIPN while also considering these factors. Data on VCR PK and SNP’s were also collected as part of this trial, but analyses of these data was beyond the scope of this paper. Data of this trial regarding administration duration related to PK were published separately^[42] [42]. Potentially, infusion of VCR in one-hour could lead to an increased risk of extravasation, which is dangerous in VCR treatment. However, in all our patients, VCR was administered using a central venous catheter, therefore, extravasation was not a potential risk factor.

Reference (we'll rearrange the references after you submitted it)

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