VOLUME

30

NUMBER

12

APRIL

20

2012

JOURNAL OF CLINICAL ONCOLOGY

O R I G I N A L

R E P O R T

Phase II Study of Weekly Vinblastine in Recurrent or

Refractory Pediatric Low-Grade Glioma
Eric Bouffet, Regina Jakacki, Stewart Goldman, Darren Hargrave, Cynthia Hawkins, Manohar Shroff,
Juliette Hukin, Ute Bartels, Nicholas Foreman, Stewart Kellie, Joanne Hilden, Michael Etzl, Beverly Wilson,
Derek Stephens, Uri Tabori, and Sylvain Baruchel
Eric Bouffet, Cynthia Hawkins, Manohar
Shroff, Ute Bartels, Derek Stephens,
Uri Tabori, and Sylvain Baruchel, Hospital for Sick Children, University of
Toronto, Toronto, Ontario; Juliette
Hukin, British Columbia Childrens
Hospital, Vancouver, British Columbia;
Beverly Wilson, University of Alberta
Hospital, Edmonton, Alberta, Canada;
Regina Jakacki, Childrens Hospital of
Pittsburgh, Pittsburgh, PA; Stewart
Goldman, Childrens Memorial Medical
Center, Chicago, IL; Nicholas Foreman,
The Childrens Hospital, Denver, CO;
Joanne Hilden, Peyton Manning Childrens Hospital at St Vincent, Indianapolis, IN; Joanne Hilden, The Childrens
Hospital at The Cleveland Clinic, Cleveland, OH; Michael Etzl, Phoenix Childrens Hospital, Phoenix, AZ; Darren
Hargrave, The Royal Marsden Hospital,
Sutton, United Kingdom; and Stewart
Kellie, The Childrens Hospital at Westmead, Westmead, New South Wales,
Australia.
Submitted January 6, 2011; accepted
January 11, 2012; published online
ahead of print at www.jco.org on
March 5, 2012.
Supported by the Ontario Institute for
Cancer Research (formerly the Ontario
Institute Research Network) through
funding provided by the Government of
Ontario (Grant No. 02-11-0261).
Authors disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Clinical Trials repository link available on
JCO.org.
Corresponding author: Eric Bouffet,
MD, FRCP(C), Hospital for Sick Children, 555 University Ave, Toronto,
Ontario, Canada M5G 1X8; e-mail:
eric.bouffet@sickkids.ca.
2012 by American Society of Clinical
Oncology
0732-183X/12/3012-1358/$20.00
DOI: 10.1200/JCO.2011.34.5843

1358

Purpose
To evaluate the efficacy of single-agent vinblastine in pediatric patients with recurrent or refractory
low-grade glioma.
Patients and Methods
Patients were eligible if they had experienced previous treatment failure (chemotherapy and/or
radiation) for incompletely resected or unresectable low-grade glioma (LGG). Vinblastine (6 mg/m2)
was administered weekly for 1 year unless unacceptable toxicity or progression (confirmed on two
consecutive imaging studies) occurred.
Results
Fifty-one patients (age range, 1.4 to 18.2 years; median age, 7.2 years) were prospectively enrolled
onto this phase II study. Fifty patients had previously received at least one prior regimen of
chemotherapy, and 10 patients had previously received radiation treatment. Fifty patients were
evaluable for response; 18 patients (36%) had a complete, partial, or minor response, and 31
patients completed 1 year of treatment. At a median follow-up of 67 months, 23 patients had not
experienced progression; three patients have died. Five-year overall survival was 93.2% 3.8%,
and 5-year progression-free survival was 42.3% 7.2%. Toxicity was manageable and mostly
hematologic, although a few patients needed transfusions.
Conclusion
Weekly vinblastine seems to be a reasonable alternative to radiation for pediatric patients with
LGG who have experienced treatment failure with first-line chemotherapy. The 5-year progressionfree survival observed in this phase II trial is comparable to results observed with first-line
chemotherapy in chemotherapy-naive patients. The role of single-agent vinblastine and other vinca
alkaloid in the management of pediatric LGGs deserves further investigation.
J Clin Oncol 30:1358-1363. 2012 by American Society of Clinical Oncology

INTRODUCTION

The management of pediatric low-grade gliomas

(LGGs) that cannot be completely resected has
evolved considerably during the last two decades.
Although radiation used to be the standard treatment for incompletely resected or unresectable
LGGs, chemotherapy and observation have now
progressively become the most commonly used options after initial diagnosis, depending on several
factors including tumor location, amount of residual tumor, age, and/or association with neurofibromatosis type 1 (NF1).1 Although no strict guidelines
have been implemented regarding first-line therapy,
many clinicians currently consider chemotherapy as
the first-line treatment option, particularly for the
younger population.1 The results of several protocols have been reported, with response rates varying

from 13% to 70%.2-8 However, event-free survival

(EFS), defined as the need to consider another intervention to control tumor progression, has been
consistently less than 50% at 5 years with these
regimens.3,5-9 This calls into question the exact benefit of these interventions, and more importantly,
this raises the need to better define long-term strategic options for these patients rather than limiting
reports to short-term results of initial management.
Few studies have evaluated the efficacy of interventions after failure of initial management. In 2000, a
pilot study of weekly vinblastine in patients with
recurrent LGG yielded promising results.10,11 The
choice of vinblastine was based on evidence of activity of vinca alkaloids in pediatric LGG in early chemotherapy studies.2,12 The objective of this phase II
study was to confirm the activity of vinblastine and
to evaluate its long-term benefit in patients who had

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Weekly Vinblastine in Pediatric Low-Grade Gliomas

previously experienced treatment failure with at least one line of standard therapy.
PATIENTS AND METHODS
The study was initiated in eight centers in four countries (Toronto in Canada;
Chicago, Pittsburgh, Cleveland, Phoenix, and Denver in the United States;
Sutton in the United Kingdom; and Weastmead in Australia). After an audit in
2004, the study was limited for budgetary reasons to three Canadian (Toronto,
Vancouver, and Edmonton) and two US (Chicago and Pittsburgh) centers.
Patients had to be younger than age 21 years at the time of diagnosis; eligible
histologicdiagnosesincludedlow-gradeastrocytoma(ie,grade1or2),pilomyxoid
astrocytoma, low-grade oligoastrocytoma, low-grade oligodendroglioma, mixed
LGG, and ganglioglioma. Histologic verification was required before entry onto
the study, except for patients with optic/hypothalamic glioma (OPG) with
or without NF1 who did not require biopsy confirmation. Patient had to
have evidence of measurable disease on contrast-enhanced magnetic resonance imaging (MRI) scan obtained within 3 weeks of study entry.
Prior treatment with chemotherapy, radiotherapy, or both was required.
Patients were eligible at the time of first, second, or subsequent recurrence of
tumor. Patients whose tumor did not respond to first-line therapy (refractory
tumor) were also eligible when there was radiographic evidence of progressive
disease (PD) on treatment. The study required a Lansky performance status
60. An interval of at least 8 weeks from prior radiotherapy or 2 weeks from
prior chemotherapy (4 weeks for nitrosoureas) was required. Corticosteroids
were allowed to control progressive symptoms, and antiepileptic medications
were permitted. Patients had to have adequate organ function defined as
absolute neutrophil count (ANC) more than 1,000/L, platelet count more
than 100,000/L, and serum creatinine 1.5 normal for age. The study was
approved by Health Canada (No. 9427-H1117-77C) and the Hospital for Sick
Children Research Ethics Board. The institutional review boards of each participating institution approved the protocol before initial patient enrollment,
and continuing approval was maintained throughout the study. Patients or
their legal guardians gave written informed consent, and assent was obtained
as appropriate at the time of enrollment.
Treatment
Vinblastine was given as an intravenous push at a dose of 6 mg/m2 (10
mg maximum) once a week for a total duration of 52 weeks. In children less
than 1 year of age or weighing less than 10 kg, doses were calculated according
to weight (0.2 mg/kg). Dose modifications were made for hematologic
toxicity. If the ANC was less than 750 but 500/L, the dose was reduced
to 5 mg/m2. If the ANC was less than 500/L, then vinblastine was withheld
until blood count recovery to ANC of 750/L, and vinblastine was resumed at 5 mg/m2. Patients who demonstrated persistent or recurrent
hematologic toxicity after a first dose reduction had their subsequent dose
decreased to 4 mg/m2. Once the dose was reduced, there was no dose
escalation, even when blood counts were satisfactory. The use of growth
factors was not allowed. Toxicities were graded according to Common
Terminology Criteria for Adverse Events (version 3).13 A limited pharmacokinetic study was conducted at the leading institution to confirm previous results in the pediatric population.14
Evaluation of Response
Preinclusion MRI of the tumor site was required in all patients. Neuroradiographic studies were requested after 10 weeks of vinblastine and then
every 3 months until completion of chemotherapy. Formal neurologic examination, including visual assessment for patients with OPG, was requested on
entrance to study and at 10 weeks and 6, 9, and 12 months.
MRI scans were centrally reviewed by two independent neuroradiologists. Responses were based primarily on the contrast-enhanced imaging results.15 For nonenhancing lesions, measurements were performed on T2 or
fluid-attenuated inversion recovery images. Response criteria for this study
were determined by changes in size using the maximal three-dimensional (3D)
cross-sectional tumor measurements. When only two measurements were
available, response was assessed by using the product of the largest two tumor
www.jco.org

Table 1. Definition of Response for the 2D and 3D Measurement Methods

Response

2D Method

3D Method

Complete
response

Complete disappearance of
tumor on imaging
studies
Reduction of at least 50%
in the sum of the
product of the 2 largest
perpendicular diameters
of all target lesions
Reduction of at least 25%
(sum of the product of
the 2 largest
perpendicular diameters
of all target lesions)
No change or a decrease/
increase of 25% (sum
of the product of the 2
largest perpendicular
diameters of all target
lesions)
25% increase (sum of
the product of the 2
largest perpendicular
diameters of all target
lesions)

Complete disappearance of
tumor on imaging
studies
Reduction of at least 65%
in the sum of the
product of the 3 largest
perpendicular diameters
of all target lesions
Reduction of at least 40%
(sum of the product of
the 3 perpendicular
diameters of all target
lesions)
No change or a decrease/
increase of 40% (sum
of the product of the 3
perpendicular diameters
of all target lesions)

Partial
response

Minor
response

Stable
disease

Progressive
disease

40% increase (sum of

the product of the 3
perpendicular diameters
of all target lesions)

Abbreviations: 2D, two dimensional; 3D, three dimensional.

diameters (two-dimensional [2D]). Response criteria are listed in Table 1.

However, because previous studies have shown that the time to best response
is generally long4,8 and some patients may even show early progression followed by stabilization or response,4 progression had to be confirmed by a
second scan at 6 to 12 weeks showing further increase in tumor size. Patients
who showed stabilization after initial progression were considered as having
PD for response purposes, but they were allowed to stay on study.
For patients who completed 1 year of vinblastine, MRI scans were requested every 3 months during the first year of follow-up and every 6 months
thereafter. Treatment failure was defined as the date of new clinical symptoms
or radiologic progression that required a change in management or initiation
of a new treatment.
Statistical Considerations
The primary end point was to estimate the response rate to vinblastine.
Estimate of EFS at 5 years was the secondary objective. The estimated number of
patients to be included in the study was based on previous reports on single agents
in LGGs. The best response rate reported was 29% after two courses of carboplatin,6 in a population where most patients were chemotherapy naive. The study
objective was to achieve a response rate at least similar to single-agent carboplatin.
Considering type I and type II errors of 5% and 20%, respectively, it was estimated
thatwithadjustmentforpotentialincompletedata,therequiredsamplesizeforthe
study would be 50. Other analyses included determination of EFS and overall
survival. Because some patients experienced transient progression while on vinblastine followed by sustained stabilization or tumor response, the length of EFS
was measured from the date of patient entry onto the study to the date of initiating
further therapy or last contact. Patients who discontinued treatment as a result of
unacceptable adverse effects were censored at that point. Distribution of survival
was calculated using the Kaplan-Meier method.

RESULTS

The study opened in December 2002, and enrollment was completed

in June 2006. Central radiology review was completed in 2009, and the
last follow-up analysis was conducted in January 2010. Table 2 lists the
characteristics of the 51 patients enrolled onto this study. Median age at
diagnosis was 3.5 years (range, 0.1 to 16.1 years), and median age at the
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of Clinical Oncology. All rights reserved.
129.215.149.92

1359

Bouffet et al

Table 2. Patient Demographics and Clinical Characteristics

Demographic or Clinical Characteristic
Sex
Male
Female
Neurofibromatosis type 1
Age at diagnosis, years
Median
Range
Age at beginning of vinblastine, years
Median
Range
Tumor site
Hypothalamic/chiasmatic
Brainstem
Other site
Pathology
Pilocytic astrocytoma
Low-grade glioma NOS
Ganglioglioma
Diffuse astrocytoma
Oligodendroglioma
No histology
Previous treatment
Radiation only
One line of chemotherapy
One line of chemotherapy and radiation
Two lines of chemotherapy
Two lines of chemotherapy and radiation
Three lines of chemotherapy

No. of Patients
24
27
9
3.5
0.1-16.1
7.2
1.4-18.2
34
6
11
23
7
7
1
1
12
1
32
5
7
4
2

Abbreviation: NOS, not otherwise specified.

*Other sites include spinal cord (n 2), temporal (n 2), hemispheric (n
1), thalamus (n 1), basal ganglia (n 1), tectal (n 1), anterior cranial fossa
(n 1), ventricle (n 1), and posterior fossa (n 1).

time of study enrollment was 7.2 years (range, 1.4 to 18.2 years). Most
patients had hypothalamic/chiasmatic tumors (34 of 51 patients). Thirtynine patients had a histologic diagnosis, and pathology was centrally reviewed in 33 patients. The most common histology was pilocytic
astrocytoma (n 23) followed by ganglioglioma (n 7). All but one
patient had received at least one line of chemotherapy, and 10 patients
were previously irradiated. The interval between radiation and initiation
of vinblastine was greater than 1 year in all but one patient (range, 11 to 99
months; median, 54 months). The number of prior chemotherapy treatments was one in 37 patients, two in 11 patients, and three in two patients.
Response to last treatment before vinblastine could be retrieved in 47
patients, with the majority having shown stable disease (SD; n 31),
whereas eight patients had PD and only eight patients had evidence of
response during their last treatment (one complete response, five partial
responses [PRs], and two minor responses [MRs]).

two techniques; one patient with PD on 3D was considered stable in

2D, and one patient with MR on 3D was considered stable in 2D. Four
patients who showed early progression on imaging continued treatment as per protocol, and two of these patients eventually showed MR
and PR, respectively (Fig 1). The response rate was slightly higher in
patients with NF1 (five of nine patients with NF1 v 13 of 42 patients
without NF1; P not significant). Histology has no significant influence on the response rate observed (data not shown). The median
time to best response was 12 months for responding patients.
Overall, 31 patients completed 1 year of treatment. Three patients
continued vinblastine beyond 1 year at the discretion of the investigator.
Three patients discontinued vinblastine transiently (n 2) or permanently(n1)becauseoftoxicity.Atamedianfollow-upof67months,23
patientshavenotrequiredanyfurthertherapy.Threepatientshavediedof
disease progression at 5, 35, and 60 months, respectively. Five-year overall
survival for the entire population was 93.2% 3.8%, and estimated
5-year EFS was 42.3% 7.2% (Fig 2), whereas 5-year progression-free
survival(whichtakesintoaccountearlypseudoprogression)was38.5%
7.3%. Five-year EFS was higher for patients with NF1 than patients without NF1 (75.0% 15% v 35.7% 7.6%, respectively; P .04; Fig 3). Age
and previous response to chemotherapy did not predict response to vinblastine. Five of 10 previously irradiated patients were free of progression
35to90monthsafterinitiationofvinblastine.Of34patientswithOPG,24
had a visual evaluation at week 10 and none showed deterioration.
Twenty-fourpatientswithOPGcompleted1yearoftherapy,including15
patients who had full visual evaluation; 12 of these patients showed stability, one showed improvement, and two (one with MR and one with SD)
showed slight deterioration.
Toxicities
Treatment was well tolerated. In a total of 2,020 treatments, 143
grade 3 to 4 adverse events were reported in 38 patients (Appendix Table
A1, online only). The main toxicity was hematologic. Eighteen patients
experienced grade 4 neutropenia requiring dose reduction. Thirteen episodes of fever and neutropenia occurred in 10 patients, and two patients
developed infection without neutropenia. Only five patients required
RBC transfusions, and no platelet transfusion was needed. Although hair
thinning was common, only three patients experienced mild to severe
alopecia. Three patients discontinued vinblastine at least temporarily because of clinical adverse events. Two patients with NF1 experienced grade
3 peripheral neuropathy at weeks 30 and 39, respectively. They both
resumed the treatment a few weeks later at a lower dose. One patient
presentedwithrecurrentcutaneousrash,andtreatmentwasdiscontinued
after 9 weeks. Pharmacokinetic studies confirmed previous findings,
showing triphasic elimination with a long terminal elimination half-life.
During the prolonged terminal half-life, plasma concentrations were consistent with those shown to have antiangiogenic activity in preclinical
studies (Appendix Fig A1, online only).16
DISCUSSION

Response
Response was assessable in 50 of 51 patients, and central review
was performed in 48 patients. After 10 weeks (first assessment), two
patients had PR, five patients had MR, 36 patients had SD, and five
patients had PD. The best responses observed were one complete
response, 10 PRs, and seven MRs. Nineteen patients has SD, and 13
patients experienced PD. Comparison of 3D and 2D assessments was
possible in 41 patients and showed only two discrepancies between the
1360

2012 by American Society of Clinical Oncology

This phase II study demonstrates that single-agent vinblastine has clinical

activity in pediatric patients with LGG who have experienced treatment
failure with at least one previous regimen of therapy. Thirty-six percent of
patients had an objective response, and EFS at 5 years was 42%. These
findings are significant in the context of a disease that increasingly seems
to be a chronic condition for which several regimens of treatment may
be required.17
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Weekly Vinblastine in Pediatric Low-Grade Gliomas

Fig 1. (A-C) Partial response and (D-F)

sustained tumor stabilization with disappearance of enhancement after transient increase
in tumor size and enhancement in two patients treated with weekly vinblastine. Both
patients are free of progression 68 and 60
months after initiation of vinblastine.

Over the last three decades, the role of chemotherapy in the

management of pediatric LGG has dramatically evolved. Chemotherapy was initially considered as a salvage treatment, and early reports
suggested some activity of vinca alkaloids and nitrosoureas.12,18 Progressively, chemotherapy was introduced as first-line treatment for
young children with unresectable LGG, in an attempt to postpone
or avoid the need for radiation.2,19 Several regimens have shown
activity and at least short-term benefit. Currently, the combination
of carboplatin and vincristine is the most widely used regimen.3,19
This regimen has a response rate in the range of 50% to 60% in
chemotherapy-naive patients and a 5-year EFS between 30%

and 40%.3,9 Other regimens have been described, such as the

thioguanine, procarbazine, lomustine, and vincristine (TPCV) regimen;
the etoposide-cisplatin combination; single-agent temozolomide;
single-agent carboplatin; and a six-drug combination (procarbazinecarboplatin/etoposide-cisplatin/vincristine-cyclophosphamide) used
by a French group4,5,7,20,21 (Table 3). Choice of treatment regimen is
largely based on physician preferences. The TPCV combination was
recently compared with the vincristine-carboplatin regimen in a study
conducted by the Childrens Oncology Group. TPCV showed a slight
advantage (P .11) in terms of 5-year EFS.9 However, other factors

1.0

Progression-Free Survival
(probability)

Progression-Free Survival
(probability)

1.0

0.8

0.6

0.4

0.2

0.8

0.6

0.4

0.2
NF1
Non-NF1

0
0

20

40

60

80

100

120

Time Since Initiation of Weekly

Vinblastine (months)
Fig 2. Progression-free survival in 51 patients treated with vinblastine.
www.jco.org

20

40

60

80

100

120

Time Since Initiation of Weekly

Vinblastine (months)
Fig 3. Progression-free survival in patients with and without neurofibromatosis
type 1 (NF1; P .04).
2012 by American Society of Clinical Oncology

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129.215.149.92

1361

Bouffet et al

Table 3. Objective Radiologic Response and EFS in Previous Clinical Studies Using Chemotherapy for Children With Newly Diagnosed and Recurrent
Low-Grade Glioma

Agent or Regimen

No. of
Patients

Central Radiology
Review

Carboplatin
Vincristine-carboplatin (first line)
SFOP
Temozolomide
Etoposide-cisplatin
TPCV
Vincristine-carboplatin (recurrent)
Temozolomide
Bevacizumab-irinotecan
Vinblastine

81
78
85
30
34
42
18
21
10
51

No
No
Yes
No
No
No
No
No
No
Yes

No. of Patients
Population
60
78
85
11
31
42
18
21
10
51

ND, 21 R
ND
ND
ND, 19 R
ND, 3R
ND
R
R
R
R

CR
2
4
0
0
1
0
0
1
1

PRMR

SD

PD

NE

21
40
51
3
23
15
12
1
6
17

46
29
23
11
10
25
5
10
2
19

11
5
11
12
0
2
6
9

13

1
1
1

EFS (%)
64
68
34
31
78
45

at
at
at
at
at
at

Study

3 years
3 years
5 years
4 years
3 years
3 years
NA
NA
NA
42 at 5 years

Gururangan et al6
Packer et al3
Laithier et al8
Gururangan et al7
Massimino et al4
Prados et al5
Packer et al19
Nicholson et al21
Packer et al21a

Abbreviations: CR, complete response; EFS, event-free survival; MR, minor response; NA, not available; ND, newly diagnosed; NE, not evaluable; PD,
progressive disease; PR, partial response; R, recurrent; SD, stable disease; SFOP, alternating courses of carboplatin-procarbazine, etoposide-cisplatin, and
vincristine-cyclophosphamide; TPCV, thioguanine, procarbazine, lomustine, and vincristine.

may influence treatment choices such as the short- and long-term

toxicity of these treatments. Carboplatin hypersensitivity reactions
occur in up to 40% of patients and limit the use of this regimen.22
Hearing loss is a serious concern with the use of cisplatin-containing
regimens, particularly among children with potential visual compromise such as those with OPG.4 Prolonged administration of alkylating
agents such as procarbazine, temozolomide, or even cyclophosphamide and platinum compounds is questionable in the context of a
chronic condition with excellent survival rates, and repeated exposure to etoposide is associated with a risk of leukemia.23 The
toxicity profile of vinblastine in this context is excellent and favorably compares with other treatment options. Vinblastine can be
administered over long periods of time with limited adverse effects.
The most common toxicity was hematologic, and 18 patients required dose adjustments. The need for transfusion was rare and
mostly seen in previously heavily treated patients.
The efficacy of single-agent vinblastine is well known in Hodgkins
disease24 and has recently been reported in patients with anaplastic largecell lymphoma.25 There is limited information on the penetration of
vinblastine in the CNS. Although this agent is lipophilic, animal studies
haveshownlowbrainpenetration,andCSFlevelsorbrainconcentrations
are negligible after systemic administration in monkeys.26,27 The mechanism of action of vinblastine in pediatric LGG is unknown. Preclinical
studies have suggested an antiangiogenic activity that might explain the
results observed in this study despite poor brain penetration.16 Plasma
concentrations observed were consistent with those shown to have antiangiogenic activity in preclinical studies.14,16 Such antiangiogenic activity
may explain observations of transient increase in tumor size followed by
progressive shrinkage, as seen in two patients who experienced sustained
tumor control after initial pseudoprogression. These observations raise
the issue of interpreting early tumor enlargement as progression and
overstating treatment failure in these slow-growing tumors. For this reason, the International Society of Pediatric Oncology group has agreed to
postpone the time of the first response evaluation to 24 weeks to avoid
early discontinuation of therapy in patients who may subsequently demonstrate benefit from chemotherapy.28 In the present study, progression
had to be confirmed on two consecutive MRIs. However, several investigatorsdidnotfollowthisrecommendation,andsixpatientsweretakenoff
study within 4 months of vinblastine initiation because of evidence of
progression on one imaging study only.
1362

2012 by American Society of Clinical Oncology

The response rate observed in this study was similar to that

reported with single-agent carboplatin in chemotherapy-naive patients and slightly inferior to the response rate reported with combinations such as carboplatin-vincristine or etoposide-cisplatin
(Table 3). However, the population of this phase II trial was different, because all patients had already received at least one line of
treatment. The results observed in terms of response rate and EFS
are encouraging and suggest that LGG may not develop resistance
to chemotherapy. The 42% EFS rate at 5 years is similar to that
observed in chemotherapy-naive patients. This observation is important, because in many institutions, the standard practice is still
to proceed to focal radiation when children have experienced
treatment failure with first-line chemotherapy. The evidence that a
proportion of patients can achieve sustained remission with
second-line chemotherapy may lead to a significant paradigm shift
and further delay the role of radiation in the management of
this condition.
The radiologic assessment used 2D and 3D evaluations and a
central radiology review. With one exception, prior large LGG
trials did not undergo central radiology review.8 This review
pointed out a number of challenges and, in particular, the issue of
interpreting early pseudoprogression that has also been observed
in other pediatric LGG trials.4 In pediatric brain tumors, 3D measurements are considered more accurate than one-dimensional or
2D assessments.29 Our experience suggested an excellent correlation between 2D and 3D measurements.
Seventy-five percent of the patients in this study had a histologic
diagnosis, with a large proportion of pilocytic astrocytoma. Still, a
significant number of patients with LGG are treated without histologic
diagnosis, accounting for up to 47% of all patients in published series.7
At the time this study was initiated, there were no known genetic
abnormalities identified in pediatric LGG. The recent identification of
a novel duplication in chromosome 7q34 in a large subset of pilocytic
astrocytomas30 and its potential prognostic value31 may have implications on the management of these patients. The impact of this finding
could be substantial and may contribute to revisiting the role of tissue
biopsies in pediatric LGGs. Future studies should prospectively evaluate the association between BRAF duplication and response to chemotherapy in pediatric LGGs when tissue is available.
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Weekly Vinblastine in Pediatric Low-Grade Gliomas

In conclusion, this phase II study showed that weekly vinblastine

holds promising activity in the management of recurrent pediatric LGG.
This may have significant implications in the management of this condition; vinblastine is cheap, has a low toxicity profile, and can be administered over prolonged periods. This may benefit a condition that
increasingly seems to be a chronic disease. To further establish the role of
this agent and other vinca alkaloids, the use of vinblastine32 and vinorelbine33 is currently being investigated in chemotherapy-naive patients
with LGG.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
The author(s) indicated no potential conflicts of interest.

REFERENCES
1. Reddy AT, Packer RJ: Chemotherapy for lowgrade gliomas. Childs Nerv Syst 15:506-513, 1999
2. Packer RJ, Sutton LN, Bilaniuk LT, et al:
Treatment of chiasmatic/hypothalamic gliomas of
childhood with chemotherapy: An update. Ann Neurol 23:79-85, 1988
3. Packer RJ, Ater J, Allen J, et al: Carboplatin and
vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 86:
747-754, 1997
4. Massimino M, Spreafico F, Cefalo G, et al: High
response rate to cisplatin/etoposide regimen in childhood low-grade glioma. J Clin Oncol 20:4209-4216, 2002
5. Prados MD, Edwards MS, Rabbitt J, et al:
Treatment of pediatric low-grade gliomas with a
nitrosourea-based multiagent chemotherapy regimen. J Neurooncol 32:235-241, 1997
6. Gururangan S, Cavazos CM, Ashley D, et al:
Phase II study of carboplatin in children with progressive low-grade gliomas. J Clin Oncol 20:2951-2958, 2002
7. Gururangan S, Fisher MJ, Allen JC, et al:
Temozolomide in children with progressive lowgrade glioma. Neuro Oncol 9:161-168, 2007
8. Laithier V, Grill J, Le Deley MC, et al:
Progression-free survival in children with optic pathway tumors: Dependence on age and the quality of
the response to chemotherapyResults of the first
French prospective study for the French Society of Pediatric Oncology. J Clin Oncol 21:4572-4578, 2003
9. Ater J, Holmes E, Zhou T, et al: Results of
COG protocol A9952: A randomized phase 3 study
of two chemotherapy regimens for incompletely
resected low-grade glioma in young children. NeuroOncology 10:451, 2008 (abstr)
10. Bouffet E, Hargrave D, Cairney E, et al: Weekly
vinblastine for recurrent/progressive low grade gliomas.
Neuro-Oncology 4:215, 2002 (abstr 6)
11. Lafay-Cousin L, Holm S, Qaddoumi I, et al:
Weekly vinblastine in pediatric low-grade glioma
patients with carboplatin allergic reaction. Cancer
103:2636-2642, 2005

AUTHOR CONTRIBUTIONS
Conception and design: Eric Bouffet, Darren Hargrave, Manohar Shroff,
Ute Bartels, Derek Stephens, Sylvain Baruchel
Provision of study materials or patients: Regina Jakacki, Manohar
Shroff, Juliette Hukin, Ute Bartels, Nicholas Foreman, Stewart Kellie,
Joanne Hilden, Michael Etzl
Collection and assembly of data: Eric Bouffet, Stewart Goldman,
Cynthia Hawkins, Juliette Hukin, Nicholas Foreman, Stewart Kellie,
Michael Etzl, Beverly Wilson
Data analysis and interpretation: Eric Bouffet, Regina Jakacki, Cynthia
Hawkins, Manohar Shroff, Ute Bartels, Joanne Hilden, Derek Stephens,
Uri Tabori
Manuscript writing: All authors
Final approval of manuscript: All authors

12. Rosenstock JG, Evans AE, Schut L: Response

to vincristine of recurrent brain tumors in children.
J Neurosurg 45:135-140, 1976
13. National Cancer Intitute: Common Terminology Criteria for Adverse Events. http://ctep.cancer
.gov/protocoldevelopment/electronic_applications/
docs/ctcaev3.pdf
14. Stempak D, Gammon J, Halton J, et al: A pilot
pharmacokinetic and antiangiogenic biomarker study of
celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol 28:720-728, 2006
15. Macdonald DR, Cascino TL, Schold SC Jr, et al:
Response criteria for phase II studies of supratentorial
malignant glioma. J Clin Oncol 8:1277-1280, 1990
16. Klement G, Baruchel S, Rak J, et al: Continuous
low-dose therapy with vinblastine and VEGF receptor2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 105:R15-R24, 2000
17. Qaddoumi I, Sultan I, Broniscer A: Pediatric
low-grade gliomas and the need for new options for
therapy: Why and how? Cancer Biol Ther 8:4-10, 2009
18. Lefkowitz IB, Packer RJ, Sutton LN, et al: Results
of the treatment of children with recurrent gliomas with
lomustine and vincristine. Cancer 61:896-902, 1988
19. Packer RJ, Lange B, Ater J, et al: Carboplatin and
vincristine for recurrent and newly diagnosed low-grade
gliomas of childhood. J Clin Oncol 11:850-856, 1993
20. de Haas V, Grill J, Raquin MA, et al: Relapses
of optic pathway tumors after first-line chemotherapy. Pediatr Blood Cancer 52:575-580, 2009
21. Nicholson HS, Kretschmar CS, Krailo M, et al:
Phase 2 study of temozolomide in children and
adolescents with recurrent central nervous system
tumors: A report from the Childrens Oncology
Group. Cancer 110:1542-1550, 2007
21a. Packer RJ, Jakacki R, Horn M, et al: Objective response of multiple recurrent low-grade gliomas to bevacizumab and irinotecan. Pediatr Blood
Cancer 52:791-795, 2009
22. Lafay-Cousin L, Sung L, Carret AS, et al: Carboplatin hypersensitivity reaction in pediatric patients with
low-grade glioma: A Canadian Pediatric Brain Tumor
Consortium experience. Cancer 112:892-899, 2008
23. Le Deley MC, Leblanc T, Shamsaldin A, et al:
Risk of secondary leukemia after a solid tumor in

childhood according to the dose of epipodophyllotoxins and anthracyclines: A case-control study by

the Societe Francaise dOncologie Pediatrique.
J Clin Oncol 21:1074-1081, 2003
24. Warren RD, Bender RA, Norton L, et al: The
treatment of combination chemotherapy-resistant
Hodgkin disease with single-agent vinblastine. Am J
Hematol 4:47-55, 1978
25. Brugie`res L, Pacquement H, Le Deley MC, et
al: Single-drug vinblastine as salvage treatment for
refractory or relapsed anaplastic large-cell lymphoma: A report from the French Society of Pediatric
Oncology. J Clin Oncol 27:5056-5061, 2009
26. Arboix M, Paz OG, Colombo T, et al: Multidrug
resistance-reversing agents increase vinblastine distribution in normal tissues expressing the P-glycoprotein but
do not enhance drug penetration in brain and testis.
J Pharmacol Exp Ther 281:1226-1230, 1997
27. Greig NH, Soncrant TT, Shetty HU, et al: Brain
uptake and anticancer activities of vincristine and vinblastine are restricted by their low cerebrovascular
permeability and binding to plasma constituents in rat.
Cancer Chemother Pharmacol 26:263-268, 1990
28. National Cancer Institute: Radiation therapy or
combination chemotherapy in treating patients with clinically or radiologically progressive low-grade gliomas.
http://www.cancer.gov/clinicaltrials/SIOP-LGG-2004
29. Warren KE, Patronas N, Aikin AA, et al: Comparison of one-, two-, and three-dimensional measurements of childhood brain tumors. J Natl Cancer
Inst 93:1401-1405, 2001
30. Pfister S, Janzarik WG, Remke M, et al: BRAF
gene duplication constitutes a mechanism of MAPK
pathway activation in low-grade astrocytomas. J Clin
Invest 118:1739-1749, 2008
31. Hawkins C, Walker E, Mohamed N, et al:
BRAF-KIAA1549 fusion predicts better clinical outcome in pediatric low-grade astrocytoma. Clin Cancer Res 17:4790-4798, 2011
32. National Cancer Institute: Weekly vinblastine
for chemotherapy naive children with progressive
low grade glioma (PLGGs). http://clinicaltrials.gov/
ct2/show/NCT00575796
33. Cappellano AM, Bouffet E, Silva F, et al: Vinorelbine in progressive unresectable low-grade glioma in
children. J Clin Oncol 29:591, 2011 (suppl; abstr 9524)

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