Vincristine: Can its therapeutic index be enhanced?

Pediatr Blood Cancer 2009;53:1180–1187

REVIEWVincristine: Can Its Therapeutic Index Be Enhanced?

Andrew Moore, MBBS1* and Ross Pinkerton, MD, FRCPCH

2

INTRODUCTION

Although first used successfully in adults and children as a

cytotoxic agent in 1962, vincristine has been known for its

medicinal properties since the 17th century. Extracts from the plant

Vinca rosea have been described in medicinal folklore as being

effective for the treatment of haemorrhage, scurvy, toothache,

wound healing, diabetic ulcers and hyperglycaemia [1]. Vincristine

exerts its cytotoxic effects via interference with microtubule

formation and mitotic spindle dynamics, disruption of intracellular

transport and decreased tumour blood flow, with the latter probably

as a consequence of anti-angiogenesis [1,2]. The ultimate result of

vincristine-mediated cellular disruption is apoptosis [1].

The most frequent and clinically important side-effect of

vincristine is neurotoxicity, characteristically resulting in an

autonomic and peripheral sensory-motor polyneuropathy. Central

nervous system toxicity is uncommon and can include the syndrome

of inappropriate anti-diuretic hormone (SIADH) secretion. Neurons

depend on microtubules for axoplasmic transport and when

disrupted by vincristine, axonal degeneration and demyelination

results. This occurs in a Wallerian-like and dying-back fashion and

is reversible, unless nerve degeneration reaches the perikaryon [1].

The most common clinical consequences of neurotoxicity include

loss of deep tendon reflexes, which may be associated with foot drop

and gait disturbance, jaw pain, constipation and ileus. Non-neural

side effects are markedly less common but can include alopecia and

myelosuppression [1].

The lack of myelosuppression at standard doses reflects the

inability to dose escalate due to neurotoxicity. The high level of

cytotoxicity is notable despite low doses, unlike most other agents

where myelosuppression is the dose limiting toxicity. On the basis

that in general, paediatric cancer regimens are most effective when

high dose intensity is achieved it seems probable that the effective-

ness of vincristine could be enhanced if neurotoxicity was reduced

or at least doses maintained. Moreover, dose individualisation could

lead to increased activity in some or reduced toxicity in others, thus

enhancing the therapeutic index.

Despite its widespread clinical use, much remains unknown

about such an important cytotoxic drug. Gidding et al. [1] published

an excellent and extensive review of vincristine in 1999 but in the

past decade, a number of studies have enhanced the understanding

of vincristine’s pharmacokinetics, pharmacodynamics and pharma-

cogenetics and could provide a basis for dose individualisation.

New clinical applications for vincristine and strategies to prevent

vincristine-related neurotoxicity have also been explored in recent

years.

CLINICAL USES

Adult and Paediatric Cancer

The role of vincristine in multi-modality chemotherapy

regimens remains almost unparalleled in both adult and paediatric

oncology practice. As with many drugs however, the precise role of

vincristine in combination chemotherapy has not been demon-

strated in randomised trials. There has, however, been debate as to

the benefit of vincristine and steroid pulses in maintenance therapy

for childhood acute lymphoblastic leukaemia (ALL), with a major

study by Conter et al. [3] showing that children with intermediate

risk ALL treated with intensive BFM chemotherapy did not benefit

from the addition of maintenance pulses of vincristine and

dexamethasone.

Use in Non-Malignant Disease

Vincristine has emerged as an effective agent in the treatment of

haemangiomas, (including haemangioendothelioma and Kaposi-

form haemangioendothelioma), particularly those complicated by

the Kasabach–Merritt syndrome (KMS) of thrombocytopaenia and

consumptive coagulopathy. The high tubulin content of endothelial

cells, together with the proliferating nature of haemangiomas makes

vincristine a logical agent to use for these lesions [2]. Since the first

two reported cases successfully treated with weekly vincristine

in 1995, there have been at least 22 case reports of successful

vincristine therapy for haemangioma and KMS described in the

literature [2,4–24].

The most frequent dose of vincristine described is 0.05 mg/kg/

dose or 1–1.5 mg/m2/dose given weekly initially with variable

tapering regimens. One of the largest retrospective international

studies involved 15 patients with haemangiomas and KMS

refractory to prior treatments. Vincristine therapy (1–1.5 mg/m2

or 0.05–0.065 mg/kg weekly with variable tapers) improved

thrombocytopaenia and fibrinogen levels in all patients and

significantly reduced the size of the lesions in 13 patients (87%)

[8]. All four patients (27%) who relapsed were successfully

Vincristine is one of the most widely used and more effectivedrugs in paediatric oncology. The dose-limiting toxicity of neuro-pathy, lack of proven neuroprotective measures and an incompleteunderstanding of the pharmacokinetics and pharmacogenetics ofvincristine have limited its therapeutic potential. Recent advances in

the understanding of vincristine pharmacokinetics and pharmaco-genetics, and potential methods of preventing neurotoxicity arereviewed which could enable dose escalation and dose individual-isation in order to enhance the therapeutic index. Pediatr BloodCancer 2009;53:1180–1187. � 2009 Wiley-Liss, Inc.

Key words: cancer pharmacology; chemotherapy neurotoxicities; pharmacogenetics; pharmacokinetics; vincristine

� 2009 Wiley-Liss, Inc.DOI 10.1002/pbc.22161Published online 8 July 2009 in Wiley InterScience(www.interscience.wiley.com)

——————1Section of Paediatric Oncology, The Institute of Cancer Research,

Sutton, United Kingdom; 2Queensland Children’s Cancer Centre,

Royal Children’s Hospital, Brisbane, Queensland, Australia

*Correspondence to: Andrew Moore, Clinical Research Fellow,

Section of Paediatric Oncology, The Institute of Cancer Research, 15

Cotswold Rd, Sutton, Surrey SM2 5NG, United Kingdom.

E-mail: [email protected]

Received 16 February 2009; Accepted 26 May 2009

retreated with additional vincristine [8]. Gowans et al. [25] have also

described the case an infant with a potentially malignant

haemangiopericytoma successfully treated with vincristine

(0.05 mg/kg), doxorubicin, actinomycin-D and cyclophosphamide.

PHARMACOKINETICS

Despite a number of pharmacokinetic studies over the past

decade, the dosing strategy of vincristine, including the dose-

capping at 2 mg, largely remains empirical. Pharmacokinetic

research during the past 10 years has involved both the paediatric

and adolescent population. In a study of 32 children with a median

age of 4.6 years (range 0–16) receiving weekly vincristine for ALL,

non-Hodgkin lymphoma (NHL) or Wilms tumour, there was wide

inter- and intra-patient variability in distribution and elimination

half-life (t1/2), clearance, volume of distribution at steady state

and area under the concentration-time curve (AUC). The median

clearance of vincristine based on all 169 doses in the 32 children was

333 ml/min/m2 (range 34–830). Although vincristine clearance in

infants less than 1 year of age was lower compared to older children,

the study could not demonstrate any significant influence of age

above 1 year on vincristine clearance. On multivariate analysis,

diagnosis was the only statistically significant factor affecting

vincristine clearance with ALL/NHL patients receiving concom-

itant steroids having faster clearance rates compared to patients with

Wilms tumour (mean, 381� 140 ml/min/m2 vs. 258� 120 ml/min/

m2; P¼ 0.0092) [26].

A Nordic study of 98 children with newly diagnosed ALL also

failed to demonstrate any correlation between vincristine pharma-

cokinetics and age, sex, body surface area (BSA), body mass index,

dosage per m2 or biochemical variables [27]. Children were found to

reach a BSA of 1 m2 at 8–9 years of age and since the dose in the

protocol was 2.0 mg/m2 with a maximum dose of 2.0 mg, several

teenage patients only received approximately 1.0 mg/m2. As a

consequence, the vincristine AUC negatively correlated with age,

but when corrected for BSA, this correlation was lost. Likewise,

there was no difference in median total body clearance for patients

older (n¼ 26) or younger (n¼ 72) than 10 years of age (371 versus

353 ml/min/m2, respectively) [27]. Six patients with Down

syndrome were included in the study, although no pharmacokinetic

differences were detected between Down syndrome and non-Down

syndrome patients [28]. Long term follow-up (median 10.5 years,

range 7.3–12) of this patient cohort demonstrated that patients with

standard risk precursor B cell ALL had a significantly higher relative

risk (RR) of relapse if their vincristine clearance was above the

median (RR 5.2; P¼ 0.036) or AUC below the median (RR 5.8;

P¼ 0.025) [29]. Although there was a similar trend overall, no

significant difference in relapse risk was detected for patients with

intermediate or high risk precursor B cell ALL. The authors suggest

the significant relationship between relapse risk and vincristine

pharmacokinetics for standard risk patients is likely due to the

homogenous nature of this patient group and the increased relative

importance of vincristine in standard risk protocols compared to

intermediate and high risk protocols that utilise more intensive

multi-agent chemotherapy strategies [29].

Studies assessing high doses of vincristine are limited. In 1994,

Haim et al. [30] reported the results of a trial administering full dose

vincristine (1.4 mg/m2 with no limit to the first dose) to 104 adults

with Hodgkin disease and NHL (median age 52 years, range 18–72)

and acceptable performance status (median WHO score 1, range

0–3). Patients received multi-agent chemotherapy with vincristine,

vinblastine, prednisone, methotrexate, calcium leucovorin, doxor-

ubicin, cyclophosphamide, etoposide, mechlorethamine, procarba-

zine and bleomycin, usually as part of ProMACE/MOPP, CHOP and

MOPP/ABV regimens. Overall, the average dose of vincristine was

2.55 mg for men and 2.29 mg for women, with 90% of patients

receiving a first dose >2 mg, but only 7/23 (30%) receiving >2 mg

with the eighth course of vincristine, due to toxicity-related dose

reductions [30]. Symptoms of vincristine neuropathy in this adult

cohort were almost universal; 92% reported at least one symptom,

with 78% experiencing paraesthesia/dysaesthesia (13% grade 2–3),

59% constipation (10% grade 3–4), 45% muscle cramps, 38%

motor weakness (13% grade 3, none grade 4), 24% jaw pain, 23%

muscle/bone pain, 15% of males erectile/ejaculatory dysfunction,

14% postural hypotension and 9% taste disturbance [30]. Despite

the frequency of symptoms, the authors reported vincristine

neuropathy as being mostly reversible, with significant symptom

improvement occurring within weeks of vincristine cessation or

dose reduction and concluded that full dose vincristine was still

feasible in patients older than 65 years [30].

Only one study reporting the use of high-dose vincristine has

been published in the past decade. Kellie et al. adopted a schedule

used in high dose therapy prior to autologous marrow rescue

[31], administering cyclophosphamide (65 mg/kg) on day 1, then

vincristine as a 1.5 mg/m2 bolus on day 2, followed immediately by

a continuous vincristine infusion of 0.5 mg/m2 per 24 hr for 96 hr to

16 children (median age 4.8 years, range 1.7–15.8 years) with

central nervous system tumours [32]. Fifteen patients received two

courses of treatment at 21–28 day intervals. Such a continuous

infusion of vincristine achieved a steady state after 1 hr and the mean

total-body clearance following the infusion of 203 ml/m2/min was

similar to an earlier study of vincristine monotherapy in leukaemia

patients [32,33]. The total dose of 3.5 mg/m2 delivered over 4 days

was reported as being well tolerated, with 61% of treatment courses

resulting in grade 1 or 2 neurotoxicity and only 1 patient (6%)

experiencing grade 3 neurotoxicity. A single dose of cyclo-

phosphamide (65 mg/kg) was administered on the day prior to each

vincristine infusion and, not surprisingly, the majority of patients

experienced neutropaenia (75% �0.5� 109/L; 63% �0.5� 109/L)

[32]. The authors highlight the potential therapeutic benefit of

having vincristine present when cell replication is occurring within

tumours composed of heterogenous cell populations [32]. Whether

this justifies the expense and resource demands of prolonged

vincristine infusions requires further evaluation.

The cytochrome P450 3A4 (CYP 3A4) enzyme system is heavily

involved in the metabolism of vincristine and is induced by

corticosteroids [34–36]. The induction of CYP3A4 by steroids

likely accounts for the faster clearance rates in patients receiving

concomitant steroids compared to patients who do not receive high

dose steroids as part of multi-agent chemotherapy as demonstrated

by Gidding et al. [26]. In a window study of vincristine monotherapy

in 70 children over 1 year of age with untreated ALL, Groninger

et al. [33] demonstrated a median vincristine clearance of 228 ml/

min/m2 (interquartile range 128–360) which is markedly slower

than rates reported by studies where patients received concomitant

steroids for ALL. Interestingly, vincristine clearance was faster in

patients whose leukaemic blasts had >50 chromosomes compared

to patients with diploid or hyperdiploid (46–50 chromosomes)

leukaemia [33]. Further analysis of this patient group however,

failed to detect any correlation between the antileukaemic effect of

Pediatr Blood Cancer DOI 10.1002/pbc

Vincristine: Can Its Therapeutic Index Be Enhanced? 1181

vincristine and vincristine clearance, elimination half-life or peak

plasma concentration [37].

Published studies have in general utilised high performance

liquid chromatography (HPLC) assays. The use of mass spectrom-

etry which permits the clear separation of parent drug from

metabolite should provide more accurate information about

pharmacokinetics and in particular shed more light on the relevance

of metabolites to toxicity and efficacy.

PHARMACOGENETICS

A number of in vitro studies have highlighted the complex

pharmacogenetics involved in vincristine metabolism. Vincristine is

predominantly metabolised to one metabolite, M1, in the liver by the

cytochrome P450 (CYP) enzymes CYP3A4 and CYP3A5. CYP3A5

is up to 14 times more efficient than CYP3A4 and has a number

of common genetic polymorphisms, including CYP3A5*1,

CYP3A5*3, CYP3A5*6 and CYP3A5*7 [38–41]. CYP3A5 produc-

tion is heavily dependent on the presence of at least one functioning

CYP3A5*1 allele, without this very little CYP3A5 is produced and

vincristine metabolism will be largely dependent on CYP3A4.

Conversely, the presence of one or two active CYP3A5*1 alleles

results in high expression of CYP3A5, accounting for approxi-

mately 40% of all CYP3A protein activity and significant vincristine

metabolism [41,42]. The CYP3A5*3 allele is most common in

Caucasians (allele frequency 89–94%) and encodes abnormal

splicing resulting in an absence of CYP3A5 enzyme [34].

The expression of CYP3A5 varies considerably according to

race, with 75% of African-Americans being high expressors,

compared to 47% of East Asians and 19% of Caucasians [38].

African-American children have been shown to have inferior

survival compared to Caucasian children with ALL [43,44]. It is

possible the high expression of CYP3A5 in African-Americans and

East Asians results in increased clearance of vincristine and may

contribute to this disparity in survival. In light of the finding that

African-American children with intermediate risk ALL treated on

the CCG-1891 protocol had a markedly inferior event-free survival

(EFS) at 6 years compared to Caucasian children (54% vs. 82%,

respectively) [43], Aplenc et al. [45] performed a retrospective

analysis of relapse and CYP3A genotype. CYP3A variants were not

found to be associated with an increased risk of relapse and,

inexplicably patients with CYP3A5*3 genotypes had a reduced risk

of peripheral neuropathy [45]. This result is counter-intuitive if

neurotoxicity is related to PK of parent drug since as there is no

CYP3A5 enzyme activity with CYP3A5*3 vincristine metabolism

would be expected to be less rapid.

Evidence for a racial difference in vincristine pharmacokinetics

was demonstrated by Renbarger et al. [46] in a retrospective study of

92 non-Hispanic Caucasian and 21 African-American children with

ALL. When compared to Caucasian children, African-American

children had lower average neurotoxicity grades (1 vs. 2.72, P¼< 0.0001), less vincristine-related neurotoxicity (4.8% vs. 34.8%,

P¼ 0.007), fewer vincristine doses reduced due to vincristine-

related neurotoxicity (0.1% vs. 4.0%, P¼ < 0.0001) and fewer

vincristine doses omitted due to vincristine-related neurotoxicity

(0.1% vs. 1.2%, P¼ 0.01). Patients were treated on various

protocols and although the authors report there was no significant

difference in cumulative vincristine dose, there was a trend toward

lower doses in African Americans (42.44� 11.62 mg/m2 vs.

48.52� 14.25 mg/m2; P¼ 0.07) and it was not stated whether

individual vincristine doses were capped. Although the African-

American children were significantly older than the Caucasian

children (mean age 8.2� 4.80 years vs. 4.95� 3.08; P¼ 0.0002),

the authors acknowledged this difference and did not believe it

impacted on the overall findings. As discussed above, a body surface

area of 1.0 m2 is reached at approximately 8–9 years of age [27] so

it is possible that the impact of relative under-dosing in these

older African-American children may have been underestimated.

Furthermore, race was used as a retrospective surrogate marker of

CYP3A5 genotype. Despite these potential confounders however,

the difference in vincristine related toxicity in the Renbarger et al.

study is compelling.

The syndrome of inappropriate anti-diuretic syndrome (SIADH)

resulting in hyponatraemia is a rare, but well recognised side effect

of vincristine [47]. A retrospective review of a pharmaceutical

company’s (Eli Lilly and Company, Indianapolis, IN) global safety

database revealed a marked over-representation of Asian patients

with SIADH and/or hyponatraemia (90% Asian, 8% Caucasian,

2% Black). Major limitations of this study include its retrospective

analysis of a spontaneously reported adverse event register and the

finding that two thirds of the cases were reported from Japan.

However, when the cases of SIADH reported from the United States

(US) were analysed, 75% of cases where race was reported involved

Asian patients. If all the US cases where race was unknown were

assumed to be non-Asian, Asian patients would still have accounted

for 41% of SIADH cases reported from the US [47]. A biological

explanation for the apparent predisposition of Asian patients to

SIADH was not investigated and further research is warranted.

The multi-drug resistance MDR1 gene (also called ATP-binding

cassette subfamily B, ABCB1) encodes for Permeability-glycopro-

tein (P-glycoprotein), a transmembrane efflux pump transporting

drugs from the intracellular to the extracellular compartment and

implicated in the resistance and pharmacokinetics of many drugs,

including vincristine [48,49]. P-glycoprotein is found on a variety of

cells including hepatocytes, renal tubular cells, enterocytes, various

blood cells including haematopoietic stem cells and cells lining

blood-tissue barriers including the brain, cerebrospinal fluid, testes,

ovaries and placenta (reviewed in Ref. [48]). Preclinical models

using P-glycoprotein inducers and inhibitors have demonstrated a

role for P-glycoprotein in the biliary excretion and renal clearance of

vincristine [50–52].

A number of functional single nucleotide polymorphisms

(SNPs) have been identified for MDR1, raising the possibility that

genetic variations in this gene may contribute to inter-patient

variation in vincristine pharmacokinetics, treatment response and

toxicity [48,49]. Few clinical studies have tested these hypotheses

however. When SNPs of the MDR1 gene were retrospectively

analysed for 52 children with ALL treated with vincristine

monotherapy, no association was found between the SNPs

C3435T or G2677T and vincristine pharmacokinetics or toxicity

[49]. Furthermore, when assessed prospectively, MDR1 gene

expression in childhood ALL blasts at diagnosis did not correlate

with levels of minimal residual disease at the end of induction [53].

STATEGIES TO REDUCE TOXICITY

Liposomal Vincristine

Liposomal formulations of drugs, ranging from cosmetics to

cytotoxics and antifungal agents have been used in attempt to

optimise drug delivery to target tissues and minimise toxicity, with


1182 Moore and Pinkerton

liposomal doxorubicin and daunorubicin being the most extensively

studied anti-cancer drugs [54]. Vincristine has been encapsulated

in both sphingomyelin/cholesterol liposomes (sphingosomal vin-

cristine) and the more permeable distearoylphosphatidylcholine/

cholesterol (DSPC/Chol) liposomes [54]. An early phase I trial

of sphingosomal vincristine reported a maximum tolerated dose

(MTD) of 2.4 mg/m2 and recommended phase II dose of 2.0 mg/m2,

with pain and constipation being the dose-limiting toxicities [55].

Boehlke and Winter [54] reviewed the use of sphingosomal

vincristine in seven trials involving patients with solid tumours,

ALL, Hodgkin disease and NHL. They concluded that sphingoso-

mal vincristine had a favourable side effect profile, responses were

demonstrated in heavily pre-treated patients and excellent outcomes

were seen in studies that used sphingosomal vincristine as part of

CHOP or R-CHOP multi-agent therapy for NHL [54].

Bedikian et al. [56,57] have subsequently reported the use of

vincristine sulphate liposome infusion (VSLI) in 27 patients with

metastatic melanoma. At doses to provide 2.0 mg/m2 vincristine

without an upper dose cap, VSLI was reportedly well tolerated,

although approximately 65% of patients developed VSLI-associ-

ated fever within 48 hr of infusion [57]. Other frequent toxicities

included constipation in 48% of patients (grade 3 in 15%), muscle

cramps in 30%, anxiety/psychiatric disorders in 30% (grade 3 in

7%) and paraesthesia in 22% (grade 3 in 4%). Grade 3 arthralgia and

infection occurred in 1 patient each (4%) but no grade 4 toxicities

were reported. Grade 1–2 neutropaenia was the most common

haematological toxicity although its frequency was not quantified

[57]. Disease control was achieved in 31% of patients with

a median time to progression of 1.9 months (95% CI: 1.8–

2.2 months). One patient with two isolated pulmonary metastases,

arising from a previously treated and enucleated uveal primary,

achieved a complete response after 9 months of therapy (VSLI given

every 2 weeks). At the time of Bedikian et al.’s [57] report,

almost 3 years after completing 24 cycles of VSLI, he remained

disease-free.

Currently there are three active (two recruiting) phase II trials

registered on ClinicalTrials.gov, investigating the use of VSLI

in relapsed ALL (NCT00495079), metastatic malignant uveal

melanoma (NCT00506142) and relapsed/refractory NHL (NCT

00006383) [58].

Charcot-Marie-Tooth Disease

The association between severe vincristine-related neurotoxicity

and underlying neuropathies such as Charcot-Marie-Tooth disease

(CMT) is well established [1]. Numerous case reports in the past

decade have highlighted the potential for previously undiagnosed

CMT (including type 2 CMT) being unmasked by vincristine

[59–67]. Despite the strong association with type 1A CMT,

Ajitsaria et al. [68] recently reported the successful administration

of vincristine to a 5-year-old boy with Wilms tumour and previously

diagnosed x-linked type 1 CMT. The complex relationship between

neuropathy and vincristine pharmacology is highlighted in Porter

et al.’s [69] report of vincristine-induced neuropathy in a child with

previously undiagnosed x-linked type 1 CMT receiving concom-

itant voriconazole. Although the unmasking of CMT with vincris-

tine often occurs in the absence of a family history, the need for

taking a thorough family history prior to vincristine therapy remains

paramount.

Important Drug Interactions

Drugs know to potentiate vincristine-induced neurotoxicity

through inhibition of CYP3A enzymes or inhibition of P-glyco-

protein, include nifedipine, cyclosporine, itraconazole, voricona-

zole and possibly posaconazole and CYP3A4-inducing highly

active antiretroviral therapy (HAART) [69–80]. Important vincris-

tine drug interactions are summarised in Table I. The list of drugs

in Table I is by no means exhaustive. Physician and pharmacist

vigilance for potential drug interactions with vincristine and

appropriate dose reduction or the avoidance of concomitant dosing

is of obvious importance.Despite numerous case reports of

increased neurotoxicity in the setting of concomitant azole and

vincristine therapies, there are currently no evidence-based guide-

lines addressing this potential drug interaction, nor the need for

vincristine dose adjustment following an episode of severe neuro-

toxicity. Specific recommendations are therefore based upon expert

opinion and available case reports. Moreover, withholding or

reducing doses of vincristine may not result in a rapid improvement

of neurotoxicity symptoms such as foot drop, and it is important to

not risk effectiveness for what are often reversible symptoms [30].

For patients receiving itraconazole, voriconazole or posaconazole it

may be prudent to withhold these agents from the day prior until

the day after the planned vincristine dose if the antifungal agent is

being used for prophylaxis or empiric therapy. Alternatively, a

substitute antifungal agent from another class may be administered.

For patients with proven, probable or possible invasive fungal

infection where azole therapy is required and alternative antifungal

therapies are contraindicated or not appropriate, dose-reduction of

vincristine should be considered on an individual basis [81].


TABLE I. Clinically Important Drug Interactions With Vincristine

Drug

Effect on vincristine

concentration Mechanism of interaction References

Aprepitant Variable CYP3A4 Inhibition then Induction [82]

Azole antifungals Increase CYP3A inhibition [69-79,81]

Nifedipine Increase CYP3A and P-glycoprotein inhibition [70,71]

Cyclosporin A Increase CYP3A and P-glycoprotein inhibition [70]

Erythromycin Increase CYP3A inhibition [70]

HAART Variable CYP3A inhibition and induction [80]

Corticosteroids Decrease CYP3A induction [34-36]

Carbamazepine Decrease CYP3A4 induction [83]

Phenytoin Decrease CYP3A induction [83]

CYP, cytochrome P450; HAART, highly active antiretroviral therapy; VCR, vincristine.


Neuroprotective Agents

Gidding et al. [1] reviewed the use of neuroprotective agents for

vincristine-related neurotoxicity including folinic acid, vitamin B1,

B6 and B12, isaxonine, glutamic acid, gangliosides, adrenocortico-

tropin hormone (ACTH) analogues, insulin-like growth factor 1

(IGF-1) and nerve growth factor (NGF) and concluded there was

insufficient evidence to recommend the use of any of these agents

outside the experimental setting. Over the past decade, research in

this area has continued with preclinical investigation of the effect of

agents such as FK506, verapamil, amiloride, pralidoxime, brady-

kinin receptor antagonists, mexiletine and propentofylline [84–88].

There has also been interest in understanding the protective effect of

the gene for slow Wallerian degeneration (Wlds) which could have

clinical implications [89–91].

There have been few recent major clinical trials of neuro-

protective agents. Koeppen et al. [92] investigated the effect of the

ACTH (4–9) analogue Org 2766 on the neuropathy-free interval in

150 patients being treated with vincristine as part of multi-agent

chemotherapy for NHL or Hodgkin disease. Adult patients (mean

age 46.6 years) expected to receive a cumulative vincristine dose of

at least 8 mg were randomised to receive placebo or Org 2766 before

and after each vincristine dose and 3 to 4 weeks after cessation

of vincristine therapy. No significant differences were observed

between the placebo and treatment groups and for the 80 patients

treated uniformly with CEBOPP chemotherapy, Org 2766 had no

influence on tumour response [92].

Three NIH-registered clinical trials aimed at minimising

vincristine neuropathy are currently open and recruiting patients

[58]. All three trials are recruiting patients with both solid and

haematological cancers. A randomised, placebo-controlled, single-

centre phase II trial (NCT00365768) of glutamine in children and

adolescents (5–21 years, estimated enrolment 100 patients) with

established grade I peripheral neuropathy, is administering oral

placebo or oral glutamine twice daily for 21 days following a dose of

vincristine [58]. A larger multi-centre, randomised phase III study

(NCT00369564, ACCL0731) of glutamic acid in children and

adolescents (3–20 years, estimated enrolment 208 patients) is

administering oral placebo or oral glutamic acid three times daily

from before the first dose of vincristine until either 5 or 10 weeks

with the primary objective being to compare the reduction in

neurotoxicity as measured by a scored neurological examination.

For this study, patients are not permitted regular prophylactic

laxatives or itraconazole [58]. Finally, vitamin B6 and B12 are being

assessed in a randomised, phase III study of adults (NCT00659269,

age over 18 years, estimated enrolment 228 patients) being treated

with heavy metals, taxanes or vinca alkaloids. Patient stratification

for this study is based on treatment and the presence of pre-existing

neuropathy, however there is no true placebo arm, since the

experimental arm involves intramuscular injections of vitamin B12

(1 mg) plus oral pyridoxine (50 mg tid), whilst the active comparator

arm gives a multivitamin containing no more than 10 mg of

pyridoxine or 10 mg of vitamin B12 [58].

CONCLUSIONS

Vincristine continues to be an invaluable agent in the treatment

of cancer. The narrow therapeutic window and apparent dose-

limiting toxicity of neuropathy has limited its potential and led to

largely empiric dose capping at 2 mg. Such dose-restriction results

in many patients receiving a suboptimal dose and in adolescents, this

may contribute to poorer prognosis for diseases where vincristine

plays an important role in upfront therapy such as ALL and sarcoma.

Maximal doses of 2.5 mg have been successfully used in paediatric

ALL protocols without an increase in toxicity, although the

influence of steroids in ALL protocols may increase the toxicity

threshold of vincristine in this setting [27,93]. Suboptimal dosing of

chemotherapy has been known to produce inferior outcomes for

children with cancer since the 1960s [94]. Despite the results of

numerous pharmacokinetic studies of vincristine over the past

decade, clinical trials of multi-agent chemotherapy have not

addressed vincristine dosing. This is likely due to patient numbers

limiting the number of possible hypotheses to test, as well as a focus

on other components of chemotherapy, such as anthracycline dose

reduction and asparaginase dose optimisation. Since there is a real

potential for vincristine under-dosing, especially in adolescents,

future clinical trials should specifically address vincristine dosing.

Research on the pharmacokinetics and pharmacogenetics

of vincristine is ongoing. The authors have recently completed a

study examining the relationship between vincristine pharmaco-

kinetics, CYP3A genotype and toxicity. The Children’s Oncology

Group is currently undertaking a similar study of vincristine and

actinomycin D (NCT00674193, ADVL06B1) [58]. Although

pharmacogenetics offers the hope of providing ‘personalised

chemotherapy’, the challenge remains to incorporate pharmacoge-

netically guided dosing for individual drugs in the context of multi-

agent clinical trials such as those for ALL in children and

demonstrate an improvement in survival [95]. Furthermore, the

results of multi-agent trials with pharmacogenetically guided

dosing for an individual drug may be protocol specific and not

broadly applicable [95]. More reasonable objectives for favourable-

risk diseases might be to maintain survival but with reduced

vincristine-related toxicity. The results of current trials investigating

neuroprotective agents such as glutamic acid may increase the

therapeutic window of vincristine. Taking into account age, race,

CYP genotype and utilising effective neuroprotectants the aim is

ultimately to anticipate toxicity and pre-emptively modify dose

accordingly or enable dose escalation to maintain or maximise

effectiveness.

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Vincristine: Can its therapeutic index be enhanced?