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© 1999 American Society for Clinical Oncology Metastasis Stage, Adjuvant Treatment, and Residual Tumor Are Prognostic Factors for Medulloblastoma in Children: Conclusions From the Children's Cancer Group 921 Randomized Phase III StudyFrom the University of California at Irvine Medical Center, Orange, Neurosurgical Institute, Cedars Sinai Medical Center, Los Angeles, and Childrens Hospital, Los Angeles, CA; St. Jude Children's Research Hospital, Memphis, TN; Memorial Sloan-Kettering Cancer Center, Beth Israel Medical Center, and New York University Medical Center, New York, NY; Children's Hospital of Pittsburgh, Pittsburgh, and Children's Hospital of Philadelphia, Philadelphia, PA; Children's Hospital and Medical Center, Seattle, WA; Doernbecher Children's Hospital, Portland, OR; Childrens Hospital of Denver, Denver, CO; Department of Pediatrics, University of Iowa, Iowa City, IA; Cleveland Rainbow Babies Hospital, Cleveland, OH; and Children's National Medical Center, Washington, DC. Address reprint requests to Paul M. Zeltzer, MD, Children's Cancer Group, PO Box 60012, Arcadia, CA 91066-6012.
PURPOSE: From 1986 to 1992, "eight-drugs-in-one-day" (8-in-1) chemotherapy both before and after radiation therapy (XRT) (54 Gy tumor/36 Gy neuraxis) was compared with vincristine, lomustine (CCNU), and prednisone (VCP) after XRT in children with untreated, high-stage medulloblastoma (MB). PATIENTS AND METHODS: Two hundred three eligible patients with an institutional diagnosis of MB were stratified by local invasion and metastatic stage (Chang T/M) and randomized to therapy. Median time at risk from study entry was 7.0 years.
RESULTS: Survival and progression-free survival (PFS) ± SE at 7 years were 55% ± 5% and 54% ± 5%, respectively. VCP was superior to 8-in-1 chemotherapy, with 5-year PFS rates of 63% ± 5% versus 45% ± 5%, respectively (P = .006). Upon central neuropathology review, 188 patients were confirmed as having MB and were the subjects for analyses of prognostic factors. Children aged 1.5 to younger than 3 years had inferior 5-year estimates of PFS, compared with children 3 years old or older (P = .0014; 32% ± 10% v 58% ± 4%, respectively). For MB patients 3 years of age or older, the prognostic effect of tumor spread (M0 v M1 v M2+) on PFS was powerful (P = .0006); 5-year PFS rates were 70% ± 5%, 57% ± 10%, and 40% ± 8%, respectively. PFS distributions at 5 years for patients with M0 tumors with less than 1.5 cm2 of residual tumor, versus
CONCLUSION: VCP plus XRT is a superior adjuvant combination compared with 8-in-1 chemotherapy plus XRT. For patients with M0 tumors, residual tumor bulk (not extent of resection) is a predictor for PFS. Patients with M0 tumors,
MEDULLOBLASTOMA (MB) was first reported in 1925 by Bailey and Cushing,1 who described 25 patients with densely cellular brain tumors of the posterior fossa that were fatal if radiation therapy (XRT) was not administered after surgery.2 MB was named after a still-unidentified "indifferent" cell thought to be a precursor for both glia and neurons.3 In 1973, Hart and Earle4 described a series of mostly adult patients who had small, round, blue cell tumors of the supratentorial fossa that did not fit into the current classification; they were called primitive neuroectodermal tumors (PNETs). This controversy in nosology5 was later extended by the combining of the histopathologically similar supratentorial PNETs with MB into the revised World Health Organization childhood brain tumor classification6 of all intracranial childhood embryonal brain tumors. On the basis of that World Health Organization revision, the term posterior fossa PNET was formally introduced, although MB has continued in use. Five-year survival rates of 50% to 80% have been reported with different treatment approaches over the past 25 years. These results occurred after the introduction of craniospinal radiotherapy with local boost and, later, chemotherapy.7-14 Clinical trials and reports, however, used different definitions of high- and low-risk patients.11-21 Thus, conclusions are difficult to draw in regard to relative efficacy of newer treatments, such as lower neuraxis XRT,8,13,14 or the risk/benefit of intensive chemotherapy for "high-risk" patients.16,22 Prospective clinical trials by the Children's Cancer Group (CCG; CCG-942) and the International Society for Pediatric Oncology (SIOP; SIOP I) concluded that young age and advanced tumor stage were associated with inferior survival and that vincristine (VCR), lomustine (CCNU), and prednisone (VCP) chemotherapy in addition to XRT could improve survival in higher-stage patients.11,12 However, there was no clear benefit of three-drug chemotherapy in improving survival for all patients. The reasons for inferior survival, biologic or therapy-related, were not established. These data, however, were confounded: (a) Chang metastasis (M) staging21 was not universally performed11; (b) treatment was not stratified for all "risk" groups11,12; (c) few M1+ patients were studied11; (d) the lower-stage, "better-risk" group could have been contaminated with higher-stage patients; and (e) the risk groups were created retrospectively.11,12 Between 1986 and 1992, the CCG undertook a series of treatment trials for all patients with intracranial PNETs. In contrast to previous multi-institutional group trials, eligibility for study entry required stratification for the known probable risk factors, ie, tumor size and extension, site (Chang tumor [T] stage),21 M stage,21 age,23 and complete postoperative assessment of residual tumor. Patients with "low-stage" T1/2 M0 MB with less than 1.5 cm2 of residual tumor (and stage T3a between 1988 and 1992) were enrolled onto a different study, CCG-923, and were randomized to receive either 23.4 Gy or 36 Gy neuraxis XRT plus 54 Gy to the tumor and no chemotherapy.24 CCG-921 included patients with "higher-stage" and/or residual disease MB, all other PNETs, and malignant ependymal tumors. Patients who were 1.5 years of age or older were randomized to receive either the VCP regimen11 or the "eight-drugs-in-one-day regimen" (8-in-1) in addition to XRT to the primary tumor site and neuraxis. The 8-in-1 regimen was chosen on the basis of encouraging phase II response and survival data.25 Infants younger than 1.5 years of age were not randomized and were assigned to receive 8-in-1 chemotherapy and delayed XRT. The major study question was a comparison of survival between the two therapy regimens. Subsidiary study aims were to evaluate (a) the impact of therapy on patterns of relapse in MB (posterior fossa PNET), (b) the role of M and T stage on prognosis in MB, (c) the effect of (chemotherapy) toxicities before and after XRT on delivery of XRT, and (d) early disease control and survival in infants who received chemotherapy alone. The survival, treatment, and prognostic factors for infants with PNET and ependymoma26 and for older randomized patients with supratentorial PNET have been reported.27-30 Clinical variables associated with XRT,31 patterns of relapse in MB,32 and selected survival-related interactions with neurosurgical treatment variables also were reported for MB and supratentorial PNET.27,28,30 We report here the patient, tumor, and treatment-related factors that influenced tumor progression and survival for patients on CCG-921 with MB.
Between 1986 and 1992, 203 patients with institutional diagnoses of MB or "posterior fossa PNET" were eligible for and randomized onto CCG-921. Eligibility criteria for randomization included the following: (a) age 1.5 to less than 21 years, (b) Chang M stages 1 to 4 or Chang T stage T3b-T4 (and stage T3a from 1986 to 1988), and (c) more than 1.5 cm2 of residual tumor on postoperative computed tomography (CT)/magnetic resonance imaging (MRI).
Surgical Treatment and Staging
Therapy
Radiation Therapy Guidelines The posterior fossa volume extended from the C1-C2 interspace to 1 cm superior to the midpoint between the foramen magnum and the cranial vertex. For other primary sites, the tumor volume as defined on the preoperative CT scan was to be treated with a minimum margin of 2 cm. The craniospinal axis volume comprised the whole brain, spinal cord, and theca to the inferior border of S2. Divergent, individually shaped blocks were recommended to shape the cranial field at the base of the skull and eyes. Specific attention was paid to ensure that the cribriform plate was not blocked. The large cranial field was to be rotated so that the inferior border was parallel to and was matched with the diverging superior edge of the spinal field.35,36 This junction was to be moved 1 cm after each 12.6 Gy, to smooth out any dose inhomogeneity occurring at the junction. Inferiorly, the spinal field was flared to include the cauda equina nerve roots. Treatment records and diagnostic scans and myelograms used to establish XRT fields were centrally reviewed and evaluated by radiation oncologists (K.R.S. and J. Cherlow, MD). Compliance with XRT protocol guidelines (volume and dose) was evaluated for the primary tumor, brain, and spinal cord treatment for each patient.27
Statistical Considerations and Methods
Durations of progression-free survival (PFS) and survival were measured from the date of randomization to the first date of progressive disease or death for children who failed or to the date of last contact for children who survived without failure. The Kaplan-Meier method was used to estimate the distributions of PFS and survival.37 SEs of the Kaplan-Meier estimates were calculated as suggested by Peto et al38,39 and appear in the text following estimates for specific points in time (estimates ± SE). Comparisons of PFS distributions were made using the stratified Mantel-Haenszel statistic.40 The Cox life-table regression model41 was used to generate estimates of relative risk. The traditional and exact
Study Population Two hundred twelve patients with an institutional diagnosis of MB and who were at least 1.5 years of age were registered and randomized. Nine (4.2%) were found to have inadequate documentation of eligibility or staging criteria. Thus, 203 met eligibility criteria, ie, had "high-stage" posterior fossa PNET and MB (T3b-T4, or M1+, or > 1.5 cm2 of residual tumor). Of these, 155 were registered as having MB and 48 as having posterior fossa PNET. The latter group, on neurosurgical review, had primary tumors in the posterior fossa, were diagnosed as having MB upon histopathologic review (described below), and were similarly distributed on both treatment regimens; they are included in the total MB group in this article. Sixty-five percent of patients with MB were male. Other demographics are summarized in Table 2. All patients received either three-drug (VCP) or 8-in-1 chemotherapy in addition to XRT. Patients were evenly distributed between the two treatment regimens.
Survival and PFS
The major question of this therapeutic study was whether 8-in-1 chemotherapy was superior to VCP chemotherapy for MB. There is a clear survival advantage for VCP over 8-in-1 therapy (stratified as randomized, P = .006). Five- year estimates of PFS were 63% ± 5% compared with 45% ± 5% for VCP and 8-in-1 chemotherapy, respectively (Fig 3).
Analyses of Patients With Centrally Reviewed Neuropathology
Histomorphologic evidence of cellular differentiation (performed at the institution of diagnosis) was found in 53 (28%) of 188 patients. No specific differentiation was observed in 135 patients; astrocytic differentiation was seen in 20 patients, neuronal in 17, ependymal in eight, oligodendroglial in five, and mixed in three. No correlation between absence or presence of cellular differentiation and PFS was found (P > .9; data not shown). The use of and variation in staining techniques precludes firm conclusions.
Analyses of Prognostic Factors
Chang T/M Stage
An ordered effect of lower M stage and improved PFS for patients with confirmed MB who were
For evaluation of T stage and pre-entry residual disease, CT/MRI scans and neurosurgical reports were submitted for 167 (99%) of 169 patients. There was no statistical evidence of a relationship between T stage and PFS (Fig 7): Neither T1/2 versus T3/4 (stratified by treatment and M stage; P > .4) nor T1/2 versus T3a versus T3b comparisons (stratified by treatment and M stage; P > .6) were significant.
Surgical Resection
Confirmation of Residual Tumor
The neurosurgical assessment of residual tumor mass could be confirmed by CT/MRI scan in 162 (96%) of 169 patients, and 121 (75%) of 162 patients
Toxicity Data
Effect of Chemotherapy on Delivery of XRT and Outcomes
Our results demonstrate the superiority of XRT and standard VCP over 8-in-1 chemotherapy plus XRT for high-stage patients with MB. The latter therapy, previously thought to be very aggressive, produced significant and promising results in phase II trials for recurrent childhood brain tumors25 and other selected brain tumors.43,44 These data again confirm the important role for prospective, adequately controlled, randomized clinical trials using appropriate statistical methods to evaluate the efficacy of new treatments. There are several possible explanations for the inferiority of the adjuvant 8-in-1 therapy regimen. The treatment arms differed in at least three ways: (a) by timing of chemotherapy with XRT, (b) by delay in XRT administration for 8-in-1 chemotherapy, and (c) by VCR dose-intensity. Two courses of neoadjuvant 8-in-1 chemotherapy were intended to treat the postsurgical tumor prior to any XRT-induced decreased perfusion. Although VCR was applied soon after surgery, only two doses of VCR were given and none was administered during the 6 weeks of XRT (compared with eight doses given in standard VCP therapy); 8-in-1 chemotherapy had one third of the VCR total dose during maintenance therapy. Thus, the decreased dose-intensity of both proven-effective agents for MB, VCR and lomustine in the 8-in-1 regimen, could have been responsible for the decreased survival rate. The lack of peripheral neurotoxicity in the 8-in-1 group corroborates the lack of VCR dose-intensity. The children on 8-in-1 chemotherapy received cisplatin, which is effective against MB,13 yet its addition in the 8-in-1 regimen did not affect a better survival. Reasons for this are speculative and are not easy to dissect. As well, the 1-month delay in initiating XRT could have had a role in the decreased survival of the 8-in-1 group. Future clinical trials using more intensive chemotherapy for MB need to assess true improvement in survival against VCP and XRT; the latter represents the best-studied treatment regimen to date. Over the last 30 years, there has been variability in assigning risk and prognostic factors to patients with MB. Both tumor11,12,17,23,45 and treatment-related factors7-10,13,18-20,31,46 have been proposed (T stage, tumor size, location and invasion47; metastasis stage in the neuraxis11,21; extent of surgical resection10,19,47,48; histopathology45,49; age4,18,23,50,51; treatment/hospital site20,46,52; and a combination of the above53). These inconsistent conclusions most likely resulted from multiple factors, including patient selection bias, small patient populations, surgical philosophy, tumor detection methods, changes in imaging techniques, extent of residual tumor evaluation, and variation in XRT dosage. Prospective risk factor assignment was a methodologic feature of this study. The CCG-921 study confirmed prospectively the unequivocal impact of neuraxis dissemination at diagnosis (M1+ stages) on early tumor progression or relapse for both MB (this study and in Cohen and Duffner52) and related supratentorial PNET.27,28 Even patients with small primary posterior fossa tumors, if accompanied by dissemination at diagnosis, experienced relapse earlier, and these relapses were often extraprimary recurrences.32 Of 16 patients with small primary T1/2 tumors and M1+ disease, 10 had cranial or spinal lesions requiring boosts that would have been missed without staging. Although the presence of a positive CSF cytology alone (M1) lacked statistical power, the progression from M1 to M2 and M3 was an ordered one for PFS, and M0 versus M1+ comparisons were significant. Extra-axial spread to the bone marrow at diagnosis was rare, as we documented only two patients with M4 disease in our study. For this reason, the role of routine marrow assessment at diagnosis is probably unwarranted as a staging strategy for MB. The role of residual tumor mass vis-a-vis the neurosurgeons' reports of extent of resection also has been clarified. A residual tumor mass of less than 1.5 cm2 is statistically associated with improved survival only in the subset of CT/MRI scan-confirmed M0 patients 3 years of age or older at diagnosis. Why would CT/MRI scan-detectable disease be related to survival, while neurosurgeons' observations were not? The absolute residual tumor burden, most likely in the range of 109 cells (1 cm3), is critical for the chemotherapy/XRT effect rather than the percentage of tumor removed. We favor this explanation, because generally the neurosurgeons' reports and scans correlated well; there was no correlation between residual tumor and PFS in patients with M1+ disease (who had more bulk disease remaining before XRT and chemotherapy). Recently, Ayan et al54 reported that patients with M0 stage who had local subarachnoid invasion at the time of resection, ie, more residual disease, also had decreased PFS compared with those without invasion. This advantage in PFS of about 25% for patients with "total-body" minimal residual tumor is an association also reported for ependymoma55 and supratentorial PNET.56 These results suggest a future strategy to improve survival: suspected or proven PNET and MB brain tumors should have pretherapy extent-of-disease staging, including neuraxis evaluation,27-30 so as to offer tailored neurosurgical treatment with maximal tumor cytoreduction when possible. This trial has clarified the relationship between age as a prognostic factor and outcome. Children aged 1.5 to 2.9 years had inferior survival compared with older age groups, yet we do not consider age a prognostic factor in this context. It is tempting to conclude that PNETs in these younger children are somehow different. Recent molecular and cytogenetic analyses of MB demonstrating higher frequencies of specific chromosomal abnormalities in younger patients support this conclusion.57,58 The caveat is that planned reductions in neuraxis and posterior fossa XRT dosages were administered to all these young children and there is a known dose response with "shoulder" effect at 50 Gy.59 Previous reports of reduced survival in young children did not emphasize the effect of lower XRT dosage on survival.12,18,23,49,50 Our evidence for this conclusion is that there were no demonstrable differences in PFS between the 1.5- to 2-year-old group versus the 2- to 3-year old group (all received reduced XRT), nor between the 3- to 4-year-olds and the older patients, all of whom received optimal tumor and neuraxis XRT dosage and surface-area proportional chemotherapy.31 The clear cutoff in PFS was between groups who received less than 50 (45) Gy tumor dose and 36 (23.4) Gy neuraxis dose. Even older children who had decreased tumor XRT volume or 5% to 15% dose reduction or more than 120% time to administer XRT did not have a statistically different survival outcome.31 These latter differences were smaller than the planned 30% reduction in dosage received by 1.5- to 2.9-year-olds on study. Hence, the probable explanation for the poorer survival of these young children is that they received a lower therapeutic XRT dosage rather than that their tumors possessed different biologic characteristics. The importance of T stage has been clarified by our study design, using complete pretherapy T/M staging, which previously was correlated with survival when XRT was the sole therapy.21,47 In the group clinical trials that tested the association of T stage and adjuvant chemotherapy and XRT, the CCG found only a weak correlation,11 whereas the SIOP study found a significant survival advantage with low T stage.12 Up to one half of patients on previous CCG and SIOP trials did not have CSF cytology or myelography,11,12 so the T3/4 group was composed of both M0 and M1+ patients. These data again underscore the necessity of prospective staging as the diagnostic standard for all PNETs and stratification in planning of randomized trials. It was our hypothesis that patients with tumors involving the floor of the fourth ventricle or invading the brainstem (T3b by Chang staging) would fare worse.21 In fact, when data were corrected for M stage, we found no independent effect of any T stage or interaction of extent of surgical resection with T3a/3b stage on PFS. Additionally, no significant association with PFS was noted in T1/2/3a–stage patients with no residual tumor on the CCG-923 study, which did not use chemotherapy.24 We conclude that when patients are completely staged and stratified, there is no univariate effect of T stage on PFS. The use of XRT and VCP chemotherapy in high-stage patients was based on the CCG-942 study of 19 M1+-staged patients in which there were no stage T3/4 M1+ survivors who received XRT alone, compared with 46% 5-year PFS in patients who received XRT and chemotherapy.11 Our data confirm this result but do not indicate whether chemotherapy was additionally helpful for patients with M0 disease and more than 1.5 cm2 of residual tumor. An important conclusion from our data relates to the survival implications of more complete tumor resections. Five-year survival for one fourth of the children with MB on this study (stage M0 and residual mass > 1.5 cm2) could be enhanced by about 25% solely by application of a neurosurgical philosophy/technique designed to increase near total and total resections; this survival enhancement would occur independently of any improvements in adjuvant therapies. This strategy should be generally applicable, as there were no differences in amount of residual tumor between patients operated upon at affiliate versus full-member institutions (data not shown).
The optimal, least toxic therapy for high-stage MB remains to be determined. Future therapy trials need to be constructed with the idea of uniform risk assignment as proposed by ourselves, Laurent and Cheek,53 and Jenkin et al.60 The conclusion that patients 3 years of age or older who are stage M0 with less than 1.5 cm2 of residual tumor can achieve a 78% PFS was based on a retrospective statistical construct. This finding suggests future testing of a lessening-of-toxicity hypothesis with lower neuraxis XRT dosage and increased intensity of chemotherapy.13 It is hoped that this treatment will spare the long-term neuropsychologic61,62 and endocrine costs62,63 of therapy without compromising PFS.
Supported in part by grant no. CA 21765 from the National Cancer Institute, the American Lebanese Syrian Associated Charities (J.M.B., H.L.), and grant no. CA 13539 from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. Children's Cancer Group investigators, institutions, and grant numbers are listed in the Appendix.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
1.5 cm2 of residual tumor by scan, were significantly different (P = .023; 78% ± 6% v 54% ± 11%, respectively). 
1.5 cm2 residual tumor, had a 78% ± 6% 5-year PFS rate. Children younger than 3 years old who received a reduced XRT dosage had the lowest survival rate. 
2 tests were used to assess imbalance in potential risk factors between the two treatment arms. The median follow-up period of patients remaining at risk for failure was 7.0 years. 
