Pediatr Blood Cancer 2013;60:185–195
Systematic Review and Meta-Analysis of Randomized Trials of Central Nervous
System Directed Therapy for Childhood Acute Lymphoblastic Leukemia
Sue Richards, PhD,1* Ching-Hon Pui, MD,2and Paul Gayon, MD3on behalf of the Childhood Acute
Lymphoblastic Leukemia Collaborative Group (CALLCG)y
Pre-symptomatic treatment of the central nervous system
(CNS) is an indispensable component of the successful therapy
of childhood acute lymphoblastic leukemia (ALL) . Historical-
ly, pre-symptomatic cranial or craniospinal irradiation was a stan-
dard component of treatment for all patients. As concerns about
the long-term consequences of radiation increased , irradiation
was first limited to the brain, then decreased in dose, and finally
largely replaced by effective intrathecal and systemic chemother-
apy, but retained for patients with high-risk disease or leukemic
blasts identifiable in the cerebrospinal fluid at diagnosis. In some
contemporary clinical trials, irradiation has been omitted for all
patients [3,4]. To successfully prevent the progression or recur-
rence of leukemia in the CNS, optimal systemic and intrathecal
therapy is necessary . In 2003, we performed a collaborative
meta-analysis of randomized trials addressing issues of pre-
symptomatic CNS therapy that initiated accrual prior to 1994 .
In this study, we update this work, and include additional trials
that commenced before 2000 to allow adequate follow-up time.
CNS-directed interventions include cranial or craniospinal
irradiation, intrathecal drugs, intravenous methotrexate at a dose
of ?0.5 g/m2plus leucovorin, or intravenous mercaptopurine.
This study focuses on newly diagnosed patients and excludes
those who received craniospinal irradiation, a strategy no longer
in use. Intravenous mercaptopurine will be reported separately.
Other drugs, which also have an effect on CNS control, in
particular type of steroid [6–8] will be addressed in a future study,
but a summary of steroid use in the current set of trials has been
recorded. Thioguanine also appears to influence CNS control, but
is not currently in use in most protocols because of concerns
about toxicity .
Trials were identified following detailed search of electronic
databases including MEDLINE and EMBASE. Additional hand-
searching of review articles, meeting abstracts, reference lists of
published trials, and the content lists of major cancer and general
medical journals was undertaken. Members of the Childhood
ALL Collaborative Group and other experts were consulted to
ensure the completeness of the resulting list of trials. For all trials,
ethical committee review and individual/family informed consent
were obtained as per national standard. Data collected on each
trial included period of recruitment, eligibility criteria, random-
ized treatment elements and timing, and any CNS-directed treat-
ment given in addition to the randomized question.
For all trials the following information was sought for each
patient aged 21 years or younger at random assignment to treat-
ment: date of diagnosis, age or date of birth, gender, white blood
count (WBC) at diagnosis, immunophenotype, date of random
assignment to treatment and treatment allocation, site of any first
relapse, as well as time of first remission, relapse, death, or last
contact. In addition, the date and type of any secondary tumor
were sought. Data were checked for internal consistency, balance
between treatment groups by initial features, randomization dates,
and length of follow-up, and consistency with published results.
All first event outcomes were measured from date of randomi-
zation. Primary outcomes were event-free survival (EFS) and
overall survival (OS). Any induction failure, relapse or death
was counted as an adverse event. As many trials did not record
secondary tumors, these events were not included in analyses.
Secondary outcome measures were no remission (defined as death
without remission achievement), isolated CNS relapse, any CNS
relapse (isolated CNS relapse plus combined relapses with CNS
involvement), non-CNS relapse, and death in remission, which
included death due to secondary tumor. Relapse data were
obtained only for first relapse. Survival from relapse was also
Treatment of the central nervous system (CNS) is an essential
therapy component for childhood acute lymphoblastic leukemia
(ALL). Individual patient data from 47 trials addressing 16 CNS
treatment comparisons were analyzed. Event-free survival (EFS)
was similar for radiotherapy versus intrathecal (IT), and radiothera-
py plus IT versus IV methotrexate (IV MTX) plus IT. Triple intrathe-
cal therapy (TIT) gave similar EFS but poorer survival than
intrathecal methotrexate (IT MTX), but additional IV MTX improved
both outcomes. One trial resulted in similar EFS and survival with
IV MTX plus IT MTX versus TIT alone. Radiotherapy can generally
be replaced by IT therapy. TIT should be used with effective sys-
temic therapy such as IV MTX.Pediatr Blood Cancer 2013;60:185–
? 2012 Wiley Periodicals, Inc.
childhood leukemia; CNS; leukemia; meta-analysis; triple intrathecal therapy
Additional Supporting Information may be found in the online version
of this article.
1University of Oxford, Oxford, UK;
Hospital, Memphis, Tennessee;
Los Angeles, California
2St. Jude Children’s Research
3Children’s Hospital Los Angeles,
Conflicts of interest: Nothing to declare.
ySee Supplemental Appendix for list of CALLCG members.
*Correspondence to: Dr. Sue Richards, PhD, Clinical Trial Service
Unit, Richard Doll Building, University of Oxford, Old Road
Campus, Roosevelt Drive, Oxford OX3 7LF, UK.
Received 10 April 2012; Accepted 16 May 2012
? 2012 Wiley Periodicals, Inc.
Published online 12 June 2012 in Wiley Online Library
Standard statistical meta-analysis methods were used. Within
trials, analyses examined time from randomization to any
event, with the observed minus expected (o ? e) number of
events and its variance (v) obtained by the log-rank method.
These o ? e values were then added over all trials to produce
a total (T), with variance (V) equal to the sum of the separate
variances. These were used to calculate an overall odds ratio
(OR), or ratio of event rates, and its 95% confidence interval
(CI) equal to exp(T/V ? 1.96/HV). Results are presented as
forest plots with a square representing the point estimate of
the OR and a horizontal line showing the 99% CI for each trial.
The size of the square is proportional to the number of events,
not patients. Overall estimates are shown by a diamond with
the width representing the 95% CI. All P values given are
two-sided. Heterogeneity between the effects in different trials
or subgroups was tested with X2
S is the sum of (o ? e)2/v from each of n trials or n subgroups
T and V obtained by summing o ? e and v from log rank
analyses restricted to each one year time period were used to
estimate the log OR, b, for each year. The estimated overall
event rate in each time period, r, equals the number of events
divided by the number of person years, and the probability
of surviving event-free during that year is P ¼ exp(?r). Descrip-
tive survival curves were drawn from the separate probability
estimates P þ 0.5p(p ? 1)b for one treatment group, and
p ? 0.5p(p ? 1)b for the other treatment group .
Trials were categorized a priori and the results combined
according to the treatment comparisons and background CNS-
directed treatments. We examined conventional pre-specified
subgroups by gender, age group (<10 and ?10 years), WBC
(<10, 10–19, 20–49, 50–99, and ?100 ? 109/L), and immuno-
phenotype (B-lineage and T-lineage).
n-1equal to S ? T2/V, where
Data were available for 47 trials, ten of which were not
included in the previous analyses. Forty-five trials had a median
follow-up of at least 5 years. Studies were grouped into 11 cate-
gories by randomized comparison. Table I gives details of the
CNS-directed treatments [11–56]. Steroid use is given in supple-
mentary Table S1. Supplementary Tables S2 and S3 show the
distribution of patient and disease characteristics and median
follow-up for each trial.
Grouping of Trials
A: Triple intrathecal therapy (TIT) with methotrexate, hydro-
cortisone and cytarabine versus intrathecal (IT) methotrexate
(IT MTX) therapy. One new trial, involving 2,029 NCI standard-
risk (age <10 years and WBC <50 ? 109/L) patients, addressed
B: Radiotherapy plus IT therapy versus extra IT therapy. Nine
trials, including one new trial, addressed this question. Data were
available for eight of these trials, involving 2,995 patients, which
compared treatment regimens with either 18 or 24 Gy cranial
irradiation (CRT) plus some IT treatment with the same regimen
without CRT but with additional doses of IT MTX or TIT,
the use of double IT (DIT) in place of IT MTX, or TIT in place
of double IT.
In the light of the results of the comparison of TIT versus
IT MTX therapy, this group of trials was split post hoc into
three subgroups: (a) CRT þ IT versus extra IT, (b) CRT þ IT
MTX versus DIT or TIT, and (c) CRT þ DIT versus TIT.
We found heterogeneity among subgroups for CNS relapse
(P ¼ 0.01).
C: Addition of IV methotrexate (IV MTX) (doses ? 500 mg/
m2) to long-term IT therapy or radiotherapy with IT therapy. Ten
trials with 4,140 patients addressed this question, including two
new trials. One trial (CCG-163d) previously included was discov-
ered to be confounded, with other chemotherapy differences be-
tween the arms with and without IV MTX, and so it has now been
excluded in the analysis. One trial (POG9005), which was previ-
ously in the ‘‘other comparisons without data’’ category, is now
included because most protocols specified some additional low
dose oral MTX in the control arm and this is considered not an
important confounding factor.
Again, in the light of the IT MTX versus TIT results, this
comparison of the addition of IV MTX was split into three
groups according to the background treatment: (a) TIT therapy,
sometimes plus IV mercaptopurine (MP) and/or some IV
MTX, (b) IT MTX, and (c) CRT plus IT MTX or TIT therapy.
Heterogeneity of effect between subgroups was seen for EFS
(P ¼ 0.01). Excluding group c, heterogeneity was seen between
groups a and b for both CNS (P ¼ 0.06) and non-CNS relapse
(P ¼ 0.008).
D: IV MTX plus IT MTX therapy versus triple IT therapy.
Data were newly available for one trial, previously included in the
‘‘other comparison’’ group, involving 1,159 patients.
E: Addition of IT therapy to treatment including radiotherapy
and short-term IT therapy. Data were available for 1,174 patients
in two trials out of the four addressing this, previously included in
the ‘‘other comparisons group’’.
F: Radiotherapy plus IT therapy versus IV MTX plus IT
therapy. Trials comparing CRT with IV MTX were grouped to-
gether on the assumption that small differences in IT therapy do
not have a major impact. Data for eight trials (including one new
trial), involving 1,635 patients, were available.
G: Higher dose of IV MTX. Two new trials, both including
TIT therapy for all patients and totally involving 1,071 patients,
addressed this treatment.
H: Higher doses of radiotherapy. Data were available for all
eight trials, including one previously without data (GBTLI-80),
involving 905 patients. Comparisons were of 24 Gy versus 21 or
18 Gy, except for one trial comparing 18 Gy versus 12 Gy.
I: Addition of radiotherapy. Data, involving 664 patients, were
available for three of the eight trials addressing this question,
including one new trial (CCG-123). These were previously in-
cluded in the ‘‘other comparison’’ group. Significant heterogene-
ity was found for the effect on CNS relapse between (a) CCG
trials, which used only IT therapy, and (b) the EORTC 58,832
trial, which included IV MTX in both arms (P ¼ 0.0003). There-
fore this comparison was split.
J: Higher dose of IV MTX versus more IT therapy. Two trials,
involving 700 patients, previously included in ‘‘other compari-
sons’’ are grouped here. One used double IT and the other IT
K: Addition of IV MTX plus IT therapy to radiotherapy plus
IT therapy and/or IV MTX. Three trials involving 511 patients
186Richards et al.
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