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© 2003 American Society for Clinical Oncology CNS-Directed Therapy for Childhood Acute Lymphoblastic Leukemia: Childhood ALL Collaborative Group Overview of 43 Randomized Trials
Writing Committee: From the Clinical Trial Service Unit, Oxford, and Great Ormond Street Hospital, London, United Kingdom; Children’s Center for Cancer and Blood Disease, Los Angeles, CA; Clinica Pediatrica dell’ Università di Milano-Bicocca, Monza, Italy. Address reprint requests to Childhood ALL Collaborative Group secretariat, CTSU, Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom; email: all.overview{at}ctsu.ox.ac.uk.
Purpose: A collaborative meta-analysis was performed to clarify the relative effects on relapse and survival of different types of therapies directed at the CNS in childhood acute lymphoblastic leukemia. Materials and Methods: Data were sought for each individual patient in all trials started in or before 1993 that included unconfounded randomized comparisons of such treatments. Log-rank survival analyses were performed for each trial, and overall results for groups of trials addressing similar questions were obtained from the totals of the observed minus expected number of events and their variances. Results: Radiotherapy and long-term intrathecal therapy gave similar outcomes, with no significant difference in event-free survival despite random assignment of treatment to 2,848 patients, 1,001 of whom suffered relapse or death. Intravenous methotrexate reduced non-CNS rather than CNS relapses, and hence, the addition of intravenous methotrexate to a treatment regimen including radiotherapy or long-term intrathecal therapy improved event-free survival, with a 17% reduction in the event rate (95% confidence interval, 6% to 27%; P = .003). The event-free survival at 10 years in these trials was 61.9% without intravenous methotrexate and 68.1% with intravenous methotrexate. There was no significant difference in survival (14% death rate reduction; P = .09). There were insufficient randomly assigned patients to adequately address other questions, such as effect of different doses. No evidence was found of differences, between trials or between subgroups of different types of patients, in the relative effects of treatment. Conclusion: Radiotherapy can be replaced by long-term intrathecal therapy. Intravenous methotrexate gives some additional benefit by reducing non-CNS relapses.
ABREAKTHROUGH in the treatment of children with acute lymphoblastic leukemia (ALL) came with the introduction of treatments that could penetrate the CNS. Trials in the late 1960s and early 1970s1,2 established that children who received effective CNS-directed therapy had substantially superior event-free survival (EFS) and overall survival. The treatments used were initially craniospinal irradiation and then cranial irradiation, usually at a dose of 24 Gy, with short-term intrathecal therapy. However, with long-term follow-up of large numbers of children, it became apparent that there were late adverse effects, including growth and endocrine problems,3–6 an increased risk of developing secondary tumors,3,7–11 and possible neuropsychological sequelae.3,12–17 With the development of alternative CNS-directed strategies, including variations in the radiotherapy dose and combinations of intrathecal treatment and high-dose intravenous methotrexate, the question is now whether alternatives expected to have fewer such side effects might be as effective for disease control. Trials tend to be nonrandomly reported when differences are maximal, resulting in inflated estimates of treatment effects. Systematic meta-analyses using individual patient data, by obtaining additional follow-up information and including unpublished trials, reduce this bias and have many other advantages compared with reviews of the published literature.18 To review the effectiveness of different CNS-directed treatment strategies, the Childhood ALL Collaborative Group agreed to perform a meta-analysis of all relevant randomized trials worldwide, using data on each individual patient rather than just tabular or published results. Preliminary results were presented at a meeting of the Collaborative Group, at which the analyses to be done were discussed. After the completion of data checking and amendments, a draft manuscript was circulated to the group for comment before this final report was produced for publication.
Although systematic reviews of randomized trials provide the best evidence on treatment effects, they are still not totally immune to bias. Such biases have been minimized as far as possible by comprehensive searching for trials, including unpublished trials, collection of data on each patient, careful data checking, and the conduct of standard analyses for each trial. In this way, the biases of concentrating only on the results of a select subset of a few trials are avoided.
Trials Included
Data Checking
Events Analyzed
Grouping of Trials and Patient Characteristics
Statistics
Differences in event rates are given as proportional reductions or increases and are likely to be applicable to a wide variety of patient characteristics and background treatments. The descriptive curves and the EFS and survival values at 10 years show the treatment effects in these trials in terms of absolute differences. In circumstances for which a different background event rate applies, it may be preferable to estimate the absolute difference that a particular treatment would give by using the relevant background rate together with the proportional effect from the meta-analysis.
When the trials were grouped by the questions they addressed, there were at least three trials and at least 400 children in each group for six questions. A total of more than 9,000 children were included in these groups. Table 1  describes the CNS-directed therapies used in these trials. Some trials were for particular risk groups of patients. Table 2 shows the numbers by age, WCC and immunophenotype, and median length of follow-up within each trial. Data checking did not reveal any problems of imbalance between treatment arms.
Most of the trials for which data were not available were older trials. The usual reasons for the unavailability of data were difficulty in extracting the information from outdated computer systems and difficulty in contacting the responsible trialist.
Figure 1
Comparison A: Radiotherapy Plus Intrathecal Therapy Versus Extra Intrathecal Therapy There were eight trials in which all patients received some IT therapy and were randomly assigned to receive either cranial irradiation (XRT) or additional IT therapy. Data were available for seven of these trials, involving 2,848 children, and were only missing for one trial that involved about 350 children.21 The overall event rate was similar with XRT (34.3%) and with extra IT therapy (36.0%), and the proportional difference in the annual event rate was a nonsignificant 4.2% reduction (95% CI, 15% reduction to 8% increase; P = .50) with XRT (Fig 1A  ). There were fewer isolated CNS relapses with XRT (XRT, 4.9%; IT therapy, 7.1%; P = .03). However, the nonsignificant 22% proportional reduction in the annual rate of any CNS relapse was counterbalanced by a nonsignificant 5% increase in the annual non-CNS relapse rate (Table 3). Figure 2 shows that there was little difference in terms of either overall survival (XRT, 73.5%; IT, 75.3% at 10 years) or EFS (XRT, 64.0%; IT, 62.8%).
Comparison B: Addition of IV MTX to Long-Term IT Therapy or Radiotherapy With IT Therapy Eight trials randomized the addition of IV MTX, and data were available for all of these trials, which involved 3,189 children. All treatment arms included either irradiation and nine or more IT doses or at least 12 IT doses. The dose of IV MTX varied from 0.5 to 8 g/m2. The annual rate of non-CNS relapses was reduced by 17% with IV MTX (P = .02; Table 3 ). The CNS relapse rate was also reduced by 19%, but this was not significant (P = .08), and neither was the reduction in isolated CNS relapse (P = .1). This resulted in a significant reduction in the annual overall event rate of 17% (95% CI, 6% to 27%; P = .003) (Fig 1B), giving an improvement in EFS at 10 years of 6.2% (68.1% with IV MTX and 61.9% without IV MTX; Fig 3). There was a nonsignificant difference in survival (P = .09), with 10-year survival at 80.1% with IV MTX and 76.8% without IV MTX (Fig 3).
Comparison C: Radiotherapy Plus Short-Term IT Therapy Versus IV MTX Plus Short-Term IT Therapy Three trials (all available) randomly assigned children to XRT or IV MTX. All patients received some IT therapy. Analyses of the data on 958 children showed no significant difference in EFS, with a proportional reduction of 6.5% (95% CI, 23% reduction to 13% increase) with XRT (Fig 1C ). XRT reduced the CNS relapse rate by 62% (P < .00001; Table 3), and there was a 37%, nonsignificant reduction in deaths in first remission with XRT. In contrast, there was 67% increase in non-CNS relapse rate with XRT (P = .00005). Thus, there was little difference in either survival (XRT, 65.0%; IV MTX, 64.2% at 10 years) or EFS (XRT, 53.0%; IV MTX, 50.6%).
Comparison D: Higher Doses of Radiotherapy
Comparison E: Radiotherapy Plus Short-Term IT Therapy Versus IV MTX Plus Long-Term IT Therapy
Comparison F: Addition of IV MTX Plus IT Therapy to Radiotherapy Plus IT Therapy and/or IV MTX
Comparison G: Other Comparisons
For completeness, the EFS results for each trial for which data were supplied are shown in Fig 4
Effect of Radiotherapy in Modern Protocols Many physicians now accept that in the absence of XRT, long-term IT therapy substantially reduces CNS relapses, whereas short-term IT is insufficient.70 This view is supported indirectly by three pieces of evidence. First, in comparison C (XRT plus short-term IT therapy v IV MTX plus short-term IT therapy), in which short-term IT was used, the cumulative incidence of CNS relapse rate in the no-XRT group was 28%, which is high for this intermediate-risk group of whom only 9% had high WCC, although 22% were age 10 years or older. Second, in the CCG 101 trial,2 the isolated CNS relapse incidence was more than 35% in the no XRT arm, even though only 15% had high WCC and 16% were age 10 years or older. Third, in the trials in comparisons A (XRT plus IT therapy v extra IT therapy) and E (XRT plus short-term IT therapy v IV MTX plus long-term IT therapy), there were only 12% CNS relapses in the no-XRT arms, all of which used long-term IT, even though the patients included were relatively high risk (12% with high WCC and 27% age 10 years or older in comparison A, and 69% high WCC and 14% age 10 years or older in comparison E). Therefore, can XRT be replaced by long-term IT therapy for the prevention of CNS relapse? Comparison C (XRT plus short-term IT therapy v IV MTX plus short-term IT therapy) shows that the main effect of IV MTX is on non-CNS relapse. If we assume little effect of IV MTX on CNS relapse, comparisons A (XRT plus short-term IT therapy v extra IT therapy) and E (XRT plus short-term IT therapy v IV MTX plus long-term IT therapy) can be combined to determine the relative effects of XRT plus some IT therapy and long-term IT alone on CNS relapse. This shows that XRT may be a little more effective, with 8.4% cumulative CNS relapse in the XRT group compared with 11.8% in the long-term IT group, a difference of 3.4%. In fact, the number of additional cures may well be less than 3.4% because in comparison A (XRT plus short-term IT therapy v extra IT therapy), the 2.5% reduction in CNS relapses is counterbalanced by a 1.1% increase in non-CNS relapses, and some of the CNS relapses prevented by XRT might be curable, as there are 57 (63%) deaths among the 90 patients with CNS relapse in the XRT group, and only 54 deaths (46%) among the 117 patients in the long-term IT therapy arm. Thus, although there are more CNS relapses with long-term IT therapy, a larger proportion can be successfully re-treated. Although using long-term IT therapy with XRT might provide additional benefit, there are concerns about its adverse effects on the brain,71–73 and there is a lack of evidence in favor of the treatment. The CCG-162 trial47 (which included more than 1,000 children) and UKALL VII,39 both of which addressed the question of whether extra IT therapy should be added to XRT plus short-term IT, did not indicate additional prevention of CNS relapse and exhibited 1% more such relapses in the additional IT group.
Effect of IV MTX Does the addition of IV MTX to a schedule with adequate CNS-directed therapy also provide benefit, not in terms of CNS protection, but against non-CNS relapse? Comparisons B (addition of IV MTX to long IT therapy or XRT with IT therapy) and E (XRT plus short-term IT therapy v IV MTX plus long-term IT therapy) show that, among patients receiving standard CNS-directed treatment, IV MTX reduces the non-CNS relapse rate by 4.6%, with an incidence of 28.3% in the no–IV MTX arm compared with 23.8% in the IV MTX arm. Because it has no significant effect on CNS relapse, overall EFS is better with IV MTX than without it.
Investigation of Heterogeneity The only suggestion of heterogeneity was with respect to non-CNS relapse by age in comparison C (XRT plus short-term IT therapy v IV MTX plus short-term IT therapy; Phet = 0.01), but given the number of tests done, it is not surprising to find one with this level of significance as a result of chance alone. In addition, combining comparisons B (addition of IV MTX to long-term IT therapy or XRT with IT therapy) and E (XRT plus short-term IT therapy v IV MTX plus long-term IT therapy) does not show a different effect by age group for non-CNS relapse (Phet = 0.7). Thus, for patients receiving adequate CNS-directed therapy, IV MTX does not have a different effect on non-CNS relapses in the different age groups.
Analyses of survival have been included, as it is important to determine whether differences in EFS also translate into survival benefit. Although survival is dependent on both initial treatment and on salvage treatment for those who relapse, and the latter will have been variable in these trials, it is important to know the results for overall survival. For example, if a treatment improved EFS but overall survival was worse, we would want to be aware of this so that the reasons for it could be examined. Follow-up was generally more complete for trials with shorter median follow-up. The proportion of survivors lost to follow-up 3 or more years before the final follow-up date was less than 10% for trials with a median follow-up of less than 8 years, but varied from 0% to 40% for trials with longer median follow-up. This must be borne in mind when long-term effects are considered. The numbers at risk shown below the survival curves indicate how many patients remain in the analyses and, hence, how much confidence one can have in the right-hand ends of the curves. The most reliable results are those based on the largest numbers of events. Thus, we can be fairly sure, based on comparisons including more than 1,000 events, that XRT reduces CNS relapses slightly more than long-term IT therapy (about 3% absolute benefit) and that there is no evidence of particular benefit in any subgroup. From the trials included in this review, most of which used 18 or 21 Gy as the standard dose, there was no evidence that higher doses of XRT were of benefit. One of the advantages of systematic reviews is that, with the larger numbers available, false-negatives are less likely than with each individual trial. Adding IV MTX to regimens containing either XRT and short-term IT therapy or long-term IT therapies leads to improved EFS, and this result is based on almost 1,000 events. This is an example where the meta-analysis demonstrates a definite effect (P = .003) that was not clear from the individual trial results; only one of the eight trials addressing this question showed statistical significance at the P = .05 level. From the comparisons of XRT versus IV MTX, with some IT MTX used in both arms, it is clear that the principal effect of IV MTX is on non-CNS relapse; and other ways of intensifying treatment have been established that reduce bone marrow relapses and improve EFS.74 The EFS in the trials of the addition of IV MTX to adequate CNS-directed therapy was 65% at 10 years, and newer protocols using more intensive systemic treatment, particularly for high-risk patients, might be expected to produce a higher long-term EFS. Because, in general, the proportional effect of a treatment remains similar over different circumstances (unless there is a definite reason to expect an interaction between treatment components), the expected absolute increase in EFS with IV MTX for patients with a baseline EFS of 70% to 80% would be 4% to 5%, rather than the 6% seen in these trials. The IV MTX dose used varied from 0.5 to 8 g/m2, and from one to 33 courses, with the total cumulative dose varying from 1 to 32 g/m2. The dose was at least 5 g/m2 in the majority of cases. Most physicians currently do not believe that 0.5 g/m2 gives useful CNS levels, and many question whether even 5 g/m2 does so. There is little direct evidence on the effect of different doses, because only the French trials (FRALLE 8750 and FRALLE 8933), which also used extra IT therapy in the lower dose arm, and the German relapse trials (ALL-REZ-BFM-8549 and ALL-REZ-BFM-9051) compared different doses. Thus, there are insufficient data to demonstrate whether any additional benefit is accrued from higher doses. In addition, no suggestion of a trend in the effect was seen if an attempt was made to order the trials by intensity of IV MTX treatment (comparison B ordered by dose or by cumulative dose produced P values for trends of 0.7 and 0.3, respectively). There have been many suggestions that treatment effects differ in subgroups, such as high versus low WCC, T- versus B-cell lineage disease, and so on. These suggestions are not substantiated by the evidence in this review, although the limited data on immunophenotype, and in particular the small numbers involving T-cell lineage disease, mean that great uncertainty remains for this subgroup. All results need to be viewed in the context of other factors, including long-term side effects. Neuropsychological effects of the different treatments still require further evaluation to determine which treatments are damaging, how severe the long-term effects are, and which subgroups of children are most affected. Recent nonrandomized comparisons of children receiving chemotherapy regimens plus XRT with other children receiving chemotherapy alone, and with healthy controls, indicate that XRT causes learning problems.71–73 One retrospective comparison of children from a randomized trial of XRT versus intermediate-dose IV MTX showed poorer long-term psychosocial functioning with XRT.75 Further information will become available in due course, which may clarify lasting neuropsychological effects by age group and treatment, from the prospective studies attached to the randomized trial CCG-105 of continuing IT MTX versus XRT,76 and the UKALL XI trial of IT MTX plus high-dose IV MTX versus XRT or continuing IT MTX alone.77 In conclusion, XRT can be replaced by long-term IT therapy without detriment to EFS or overall survival. Intravenous MTX at doses of at least 0.5 g/m2 (and 5 g/m2 cumulative dose) improves EFS by a few percent but does not have much effect on overall survival. This review only provides information on the effects of treatment on events, and clinical decisions clearly need to also take into consideration other factors such as side effects and inconvenience.
The following trial organizations and associated trialists were involved in this overview: ALL-Berlin-Frankfurt-Münster (BFM) Study Group, Germany: M. Schrappe, M. Zimmermann. ALL-Rezidius (REZ) BFM Study Group, Germany: R. Hartmann, G. Henze, A. von Stackelberg. Associazione Italiana Ematologica Oncologia Pediatrica (AIEOP), Italy: G. Masera, V. Conter. Grupo Cooperativo Mineiro para Tratamento da Leucemia Aguda in Belo Horizonte (GCMTLA), Brazil: M.B. Viana. Bombay, India: P. Kurkure. Brazilian Cooperative ALL Group (GBTLI), Brazil: S.R. Brandalise. Cancer and Leukemia Group B (CALGB), United States: J.M. Boyett, M. Hancock. Children’s Cancer Group (CCG), United States: P. Gaynon, J. Nachman, H. Sather, M.E. Trigg. Cooperative Acute Lymphoblastic Leukemia Group (COALL), Germany: D. Harms, G. Janka. Dana-Farber Cancer Institute (DFCI), Boston, MA, United States: R.D. Gelber, S.E. Sallan, L.B. Silverman, V. Dalton, D.E. Levy, B. Staron. Dutch Childhood Leukemia Study Group (DCLSG), the Netherlands: W.A. Kamps, A. van der Does-van Berg. European Organization for Research on Treatment of Cancer (EORTC): J. Otten, S. Suciu, E. Vilmer. French ALL Cooperative Group (FRALLE), France: M.-F. Auclerc, A. Baruchel. Instituto Nacional de Enfermedades Neoplasicas (INEN), Peru: C. Perez, A. Solidaro. Israel National Study (INS), Israel: B. Stark, D. Steinberg. Japanese Children’s Cancer and Leukemia Study Group (JCCLSG), Japan: T. Fujimoto. S. Koizumi, M. Tsurusawa. Jena University, Germany: I. Schiller, F. Zintl. Medical Research Council (MRC), United Kingdom: J. Chessells, J. Durrant, O.B. Eden, I.M. Hann, F. Hill, S. Richards. Memorial and Sloan Kettering Cancer Center (MSKCC), United States: P.G. Steinherz. Naples University: D. Iarussi. Pediatric Oncology Group (POG), United States: S. Murphy. Programa para el Estudio de la Terapeutica en Hemopatia Maligna (PETHEMA), Spain: J.J. Ortega. St. Jude Children’s Research Hospital, Memphis, TN, United States:) J. Boyett, M.L. Hancock, C.-H. Pui. Tokyo Children’s Cancer Study Group (TCCSG), Japan: S. Nakazawa, M. Tsuchida. Vienna, St Anna Kinderspital, Austria: H. Gadner, G. Mann. Secretariat, Cancer Research UK/MRC Clinical Trial Service Unit, Oxford, United Kingdom. R. Alison, M. Clarke, C. Davies, H. Duong, P. Elphinstone, V. Evans, J. Godwin, G. Hall, H. Halls, G. Harrison, C. Harwood, C. Hicks, S. James, L. MacKinnon, R. Peto, S. Richards, and K. Wheatley.
Supported by the Imperial Cancer Research Fund, the Medical Research Council, the Biomed Programme of the European Union (grant no. PL-931247), and the Leukaemia Research Fund.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
10 years), WCC (< 50 x 109/L and 50 x 109/L or above), and immunophenotype (B-cell lineage and T-cell lineage). 
2 tests of heterogeneity and trend were used to examine differences in treatment effect both between trials and between different subgroups of patients. Clearly, differences in trial protocols and patient selection will result in differences in the true effects of treatment in different trials, even when a formal test for heterogeneity is not significant. However, this does not invalidate the fixed effect or assumption-free methods used.
