Role of Radiotherapy in Supratentorial Primitive Neuroectodermal Tumor in Young Children: Results of the German HIT-SKK87 and HIT-SKK92 Trials
Publication: Journal of Clinical Oncology
Abstract
Purpose
To assess the outcome of young children with supratentorial primitive neuroectodermal tumor (stPNET) treated by intensive postoperative chemotherapy alone compared with treatment with chemotherapy and delayed radiotherapy (RT).
Patients and Methods
From 1987 to 1992, children younger than 3 years of age with stPNET were enrolled in the HIT-SKK87 trial in Germany and Austria. After surgery, low-risk patients received maintenance chemotherapy before RT. In high-risk patients, intensive induction chemotherapy was followed by maintenance chemotherapy until delayed RT was initiated. In the following trial, HIT-SKK92 methotrexate-based chemotherapy was applied. In children with complete remission after three cycles, therapy was finished without irradiation. Otherwise, radiotherapy or salvage chemotherapy was administered.
Results
Twenty-nine children were eligible (age, 3.0 to 37.0 months). All children received chemotherapy. In 15 children, no RT was administered. Four children had tumor progression during chemotherapy and underwent irradiation. In 10 patients, RT was given after chemotherapy. Overall survival (OS) and progression-free survival (PFS) rates after 3 years were 17.2% and 14.9%, respectively. Twenty-four children relapsed (13 at the tumor site only, three at distant site, and eight at both local and distant sites). Positive impact on survival was observed in children with complete resection but without statistical significance. Administration of RT was the only significant predictive factor for OS and PFS. Only one child not having RT survived.
Conclusion
Outcome of infants and babies with stPNET is unsatisfactory. Omission of RT jeopardizes survival, even if intensive chemotherapy is applied. We suggest to limit any delay of RT to a maximum of 6 months even in young children.
Introduction
So far, the standard of care for medulloblastomas, supratentorial primitive neuroectodermal tumor (stPNET), and pineoblastomas in childhood comprises surgery, irradiation, and chemotherapy.1-4 In children older than 3 years with medulloblastoma, this approach led to survival rates of 60% to 80% after 3 years.5,6 StPNETs are less frequent and survival rates did not reach 50% after 3 years.7-9 Unfortunately, stPNETs occur predominantly in infants and babies.10 Multiple trials aimed to delay or omit radiotherapy (RT) for these young children to reduce severe adverse effects after therapy.11-14 Delaying RT in infants and babies with medulloblastomas, by administering immediate postoperative chemotherapy, was shown to be successful; in some children, RT could be avoided completely.11,13,15,16 However, stPNET is known to be more aggressive and is considered high risk regardless of stage. Unfortunately, only a few larger series have been reported because of the rarity of this tumor.
We report on young children with stPNET that were treated in two consecutive multicenter trials administering intensive postoperative chemotherapy and postponing or even omitting RT.
Patients and Methods
In 1987, the German Society for Pediatric Oncology and Hematology initiated a cooperative multi-institutional trial in Germany and Austria to delay or omit radiation therapy in young children with stPNET and other malignant brain tumors by administering intensive chemotherapy after surgery. The study’s objective was to reduce the potential for injury to the developing CNS. The study plan was tested in the pilot trial, HIT-SKK87, from March 1987 to October 1992 and continued in the HIT-SKK92 trial through December 1997. However, children were treated according to this protocol until August 2000.
Patient Eligibility
Children younger than 3 years of age with newly diagnosed malignant brain tumors were accrued. Diagnosis was made by institutional pathologists according to the WHO classification of brain tumors.17 Central review for histology was also recommended. Patients with stPNET only were included in this analysis.
Assessment of Disease
Before surgery, computed tomography or magnetic resonance imaging scans of the brain and the entire spine were recommended. Additional imaging was obtained after surgery and every 10 weeks during therapy course. Neurologic examinations and assessment of CSF were also recommended. After completion of therapy, neuroradiologic imaging was performed every 6 months.
Treatment Protocol
Surgery.
Best safe resection was performed. Histologic examination was mandatory. The extent of resection, either subtotal or complete, was estimated from operative reports and postoperative imaging.
Chemotherapy.
Two to 4 weeks after surgery, all children received chemotherapy according to the HIT-SKK87 or 92 trial (Fig 1).
HIT-SKK87.
Low-risk patients (complete resection, no dissemination) received a maintenance chemotherapy until RT was applied at 3 years of age or progression.
High-risk patients (subtotal resection or metastases) as well as children between ages of 2.5 and 3.0 years received postoperative chemotherapy after surgery in two cycles (Fig 2). Subsequently, maintenance chemotherapy was administered until RT at 3 years of age. In case of progression or tumor recurrence, chemotherapy was interrupted and RT was administered immediately.
HIT-SKK92.
Three cycles, each consisting of four elements, were given with intervals of 3 weeks (Fig 3). In case of complete remission, no RT was recommended. In case of progression or tumor recurrence before 18 months of age, an experimental chemotherapy was recommended to follow; whereas, RT was recommended for children older than 18 months.
RT.
Prescribed treatment volume for all children with stPNETs was the neuraxis (CSI) followed by a boost to the tumor bed.
Prescribed total dose for the CSI covering the whole subarachnoidal space was 35.2 Gy (1.6 Gy per fraction, five times per week). The tumor bed was to receive a boost dose of 20.0 Gy (2.0 Gy per fraction, five times weekly). For children without residual disease or dissemination, the total dose to the CSI was allowed to be reduced to 24.0 Gy. The choice was at the discretion of the local radiotherapist.
At the time of onset of the HIT-SKK87 trial, no further detailed guidelines for RT were integrated. In 1991, guidelines were specified as described.5
Statistical Considerations
Data of children with stPNET, as diagnosed by institutional pathologists, included in the HIT-SKK87 and 92 trials, served as the basis for statistical assessment of prognostic factors and survival. These patients were treated in 20 centers between 1987 and 1997.
Documentation of disease was performed by treating centers. Clinical data was monitored at the Children’s Hospital, University of Würzburg (Würzburg, Germany). Additional data on RT was collected and monitored by the Department of Radiation Oncology, University of Tübingen (Tübingen, Germany).
The follow-up period was calculated from date of surgery to the last patient contact or last event. The length of survival was calculated from date of surgery. Terminal events were defined as date of death from any cause (overall survival [OS]) or date of progression or relapse (progression-free survival [PFS]). For all patients alive without events, length of survival was censored for the statistical analysis at the last date of documented contact with the patient. Data for patients who died without evidence of progression were censored.
The Kaplan-Meier method was used to estimate OS, and the log-rank test was applied for statistical comparison of survival estimates. Data are presented with nominal two-tailed P values and 95% CIs. Differences in survival among subgroups were defined to be statistically significant if P < .05. All analysis was performed on SAS system, version 8 (SAS Institute, Cary, NC).
Results
Patient Population
Thirty children with stPNET were registered. One child was excluded from analysis because histopathologic review revealed a plexus carcinoma. Twenty-nine children with stPNET were eligible (16 females and 13 males; age range, 3.0 to 37.0 months; median age, 23.0 months). Pathologic findings were centrally reviewed in 17 children (58.6%). In two patients (6.9%), the tumor site was pineal; in 27 children (93.1%), the tumor site was supratentorial nonpineal.
In 24 patients, leptomeningeal dissemination was assessed by CSF cytologic studies at presentation. Six children had positive CSF cytologic findings (20.7%). Craniospinal imaging revealed solid metastases to the CNS in three children (10.3%), two of them also had dissemination of tumor cells in CSF (Table 1).
Treatment
Surgery.
All children underwent surgery. The extent of resection was considered to be macroscopically complete in six children and incomplete in 23 children (79.3%).
Chemotherapy.
In HIT-SKK87 trial, 13 children and, in HIT-SKK92, 16 children were treated. All children received postoperative chemotherapy.
RT.
Fifteen children did not receive any RT (51.7%). In 14 children with progressive disease, either parents refused treatment or responsible clinicians stated that general condition contradicted further treatment. One child was irradiated at the tumor site only. Thirteen children received craniospinal irradiation with additional boost to the tumor (44.8%). The median cumulative total dose to the tumor was 54.4 Gy (range, 45.0 to 55.2 Gy). Median total dose to the CSI was 30.6 Gy (range, 24.0 to 36.0 Gy). In six children, total dose to the CSI was limited to 24 or 25.2 Gy. The median dose per fraction was 1.6 Gy (range, 1.4 to 2.0 Gy). In 10 children, RT was given immediately after completion of chemotherapy, even without any sign of recurrence or disease progression (preventive RT). In four children, RT was delayed and administered only as salvage therapy after recurrence or progression (salvage RT). Median time interval between surgery and start of irradiation was 6.5 months (range, 3 to 23 months).
Survival
Follow-up for all patients ranged from 4 to 128 months. In survivors, median time of follow-up was 98.0 months (range, 51 to 128 months). For all patients, the 3-year estimated OS rate and 3-year PFS rate were 17.2% and 14.9%, respectively (Fig 4). In 17 children with central histologic review, PFS rates were estimated separately without any difference detected (3-year OS and PFS of 17.7% and 13.5%, respectively). Twenty-four children died of recurrent disease. There were no other causes for death.
Patterns of Failure
At last follow-up, five children were alive and free of disease (17.2%). Twenty-four patients had died after progression (82.8%). Thirteen children (44.8%) failed at the tumor site only. Three children developed isolated dissemination within the CNS (all intracranial; two children also had positive CSF findings); eight children (27.6%) developed combined local and distant failures (in five, intracranial; in one, intracranial and spinal; in one, kidney, in one, site not specified). Median time to progression was 8 months (range, 2 to 128 months), and median time to death was 14.0 months (range, 4 to 128 months).
Late Effects
At last follow-up, information about late toxicity was available for two survivors. One child had impaired hearing and needed a hearing aid. Additionally, growth retardation was also observed (below 3 days percentile). In that patient, no irradiation had been applied at all. Another boy had hearing impairment, pituitary insufficiency, and was described to have memory difficulties. He had received craniospinal RT.
Prognostic Factors
The treatment-related and clinical variables with correlations to estimated PFS are listed in Table 2. Neither age, sex, initial dissemination of disease, nor complete resection were found to have an impact on outcome. The PFS rate of children treated with RT was 24.1% at 3 years. In contrast, children without RT achieved a PFS of only 6.7%. Only one child out of 15 not receiving RT survived. This advantage for irradiated children was also observed in OS rates (Table 3; Fig 5). In children receiving RT, time to progression was longer as compared with those not receiving RT (median, 15.5 months and 6.5 months, respectively). Among the six children receiving reduced dose to the CNS, one child survived. Administering RT for prevention or salvage did not show significant correlation with OS (Table 3; Fig 6). Four children received RT after progression. All of them died. For the group with preventive RT, time interval between surgery and RT was 5 to 9 months (median, 7.0 months) in the seven children who failed compared with 3 to 14 months (median, 4.0 months) in those three without recurrence. In these two subgroups (preventative RT with or without failure), potential risk factors such as pos. metastatic (M)-stage, incomplete resection, and younger age did not differ significantly (M+ in two of seven v zero of three; R+ in six of seven v one of three; age, < 2 years in two of seven v one of three). Comparison of treatment groups with respect to survival is shown in Table 4.
Discussion
RT plays an important role in the treatment of stPNET.7,8,18,19 Results have been disappointing even after combined treatment, regardless of children’s age, with survival rates below 50%.7,9,20 However, in young children, RT is associated with severe late adverse effects.10,21,22 Recently, attempts have been made to delay or omit irradiation, but data are still poor. To reduce treatment sequelae without compromising survival, the optimal sequence of RT needs to be defined.
Our regimen resulted in 3-year OS and PFS rates of 17.2% and 14.9%, respectively, for all patients. These results are comparable with those previously published.11,13,23 Since the number of stPNET in all previously published series was small, there is little information about prognostic factors. Also, in our study, only univariate analysis could be performed because of low patient numbers. However, according to our findings, neither sex nor age was found to influence outcome.
There is little information about impact of initial M-stage. In the patient cohort of the Baby French Society of Pediatric Oncology (SFOP), four children had metastases at time of diagnosis, but no influence of initial stage on survival was reported.23 In our cohort, seven children were staged M+ before treatment, but no difference in treatment outcome was detected in comparison with the localized tumors. However, the suboptimal staging procedures performed in these early multi-institutional brain tumor trials weaken our findings regarding potential risk factors.
The impact of the extent of resection on survival is still unclear. In the SFOP-series, event-free survival was 50% in those children with complete resection as compared with 8% for those with incomplete resection.23 Also, the Baby Pediatric Oncology Group (POG) I, including 17 infants with stPNET, revealed a 3-year survival of 100% after gross total resection as compared with 11% after incomplete resection.24 In contrast, the Children’s Cancer Group (CCG) trial reported an advantage for complete resection when not adjusting for M-stage.13 Our analysis also shows a positive trend towards complete resection, but this is not statistically significant. However, complete resection is hard to achieve in these children. Only one-third of all infants with stPNET could be resected completely in our series, which is similar to the experiences of other groups.
In our analysis, the only factor predictive for survival was the administration of RT (P = .02). Lashford et al25 reported that there was no evidence from the United Kingdom Children’s Cancer Study Group study using intensive multiagent chemotherapy, that RT could be forgone. In 16 children with PNET (10 infratentorial and six supratentorial), only one survived without RT. In contrast, it was shown in the Australia and New Zealand Childhood Cancer Study Group study that six of 14 children, after surgery and vincristine, etoposide, and escalating cyclophosphamide (VETOPEC) chemotherapy, were alive and in continuous remission without any RT.11 In our analysis, only one child out of 15 survived without RT. Therefore, we strongly support the need for definite RT in infants with stPNET in the primary treatment.
With our strategy, only five of 29 children remained free of progression, with four of five survivors having received preventive RT. None of the four children receiving RT after progression could have salvage treatment. Median time to progression was only 8 months. In 19 children, progression occurred during chemotherapy. Even if statistical strength is low because of the small number of children, we feel it is hazardous to delay RT. Although high efficacy of the intensive postoperative chemotherapy regimen HIT-SKK92 was demonstrated for children with medulloblastoma,16 it was far less effective in this cohort of young children with stPNET. In the POG, as well as in the CCG trial, median time to progression was only 6 months.13,14 In the POG trial, Duffner et al14 concluded that intensive chemotherapy could postpone RT only for a favorable group (complete resection, good responder) but suggested to limit the delay for 1 year maximum. However, only a small subset of patients comprised stPNET. Detailed data for these 16 children were not given, but it was reported that they had the least favorable prognosis of all children after delay of delivering the RT. On the basis of these findings, we propose to limit the delay of RT to a maximum of 6 months.
With regard to target volume, we cannot draw many conclusions from our series because all irradiated children received craniospinal therapy. However, chemotherapy alone was not sufficient to prevent spinal dissemination. In the subgroup of children given chemotherapy only, spinal relapse was observed in eight of 15 children. The Baby SFOP was the only study in which salvage RT, consisting of a local field irradiation and high-dose chemotherapy, achieved disease control in two of 25 children.23 However, from our analysis of children > 3 years of age with stPNET, we learned that irradiation of the whole CNS is indispensable to achieve cure.7 Three-year PFS of 43.7% was achieved when CSI was given as compared with 14.3% after local treatment. CSI is also recommended by Paulino et al.26 They report on 25 patients with stPNET between the ages of 12 months to 32 years. Following CSI, 5- and 10-year survival was 47.1% as compared with 12.5% and 0% for whole brain and focal treatment, respectively. Therefore, we still suggest to treat the whole CNS for all stPNET.
Optimal irradiation dose for stPNET in young children cannot be derived clearly from this study nor from others. In the analysis of the older pediatric group in the German HIT-trials, craniospinal doses of 35 Gy and local doses of 54 Gy seemed necessary.7 Local doses of at least 54 Gy resulted in a 3-year PFS rate of 44.7% as compared with 10% after administering lower doses. For CSI, doses above 35 Gy also had significant positive impact on PFS, with a 3-year PFS rate of 49.3% as compared with 0%. This was in accordance with other investigators.9,27,28 Finally, there is no evidence that reduction of craniospinal dose to 24 Gy is sufficient for young children.
The importance of RT is strongly supported by the patterns of failure observed. The CCG study 921 reviewed the pattern of failure in 44 patients with stPNET after craniospinal irradiation, including 12 children between 1.5 and 3.0 years of age.29 In M0-staged children, local relapse rate was 42%; whereas, 11% relapsed at the spinal site. For the 14 children younger than 18 months treated in the CCG-921 for stPNET, results were worse. Local and spinal relapse rates were 57% and 21%, respectively, with the majority not receiving RT.30 The Baby SFOP study administering none or focal RT revealed local failures in 100% of all relapses, which was associated with dissemination in 33%.23 Our findings were similar, with local relapses in 88% of all failures; one-third of them in combination with metastases. Isolated metastases without local failure were observed in only three children.
We conclude that RT plays a major role in treatment of children with stPNET. It may be possible in the future to distinguish low risk subgroups in which dose or volume of RT may be restricted. To date, we have no indication that RT can be abandoned. Therefore, RT has to be integrated in the primary treatment regimen after postoperative chemotherapy. Unfortunately, especially in young children, RT is associated with severe late effects. There still is some hope that high-dose chemotherapy or new agents will be more effective. To achieve higher rates of complete resections without significant morbidity, surgery should be performed in experienced centers only and, neurosurgical guidelines should be established. Exhaustive documentation on all treatment modalities and late effects has to be carried out in every trial focusing on children.
In the ongoing HIT2000 trial, the craniospinal volume is restricted to 24 Gy for children under 4 years of age, considering potential late effects with a local dose of 54 Gy. To delay RT, an intensive chemotherapy is given postoperatively. However, every child will definitely receive RT as an important part of primary treatment.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Author Contributions
Conception and design: Rolf-Dieter Kortmann, Joachim Kühl
Administrative support: Beate Timmermann, Rolf-Dieter Kortmann, Joachim Kühl, Michael Bamberg
Provision of study materials or patients: Beate Timmermann, Joachim Kühl, Torsten Pietsch
Collection and assembly of data: Beate Timmermann, Joachim Kühl, Stefan Rutkowski, Frank Deinlein
Data analysis and interpretation: Beate Timmermann, Stefan Rutkowski, Christof Meisner, Monika Warmuth-Metz
Manuscript writing: Beate Timmermann, Rolf-Dieter Kortmann
Final approval of manuscript: Beate Timmermann, Rolf-Dieter Kortmann, Stefan Rutkowski, Christof Meisner, Torsten Pietsch, Frank Deinlein, Christian Urban, Monika Warmuth-Metz, Michael Bamberg
| Characteristics | No. of Patients (N = 29) | % | |
|---|---|---|---|
| Age, months | |||
| Median | 23.0 | ||
| Range | 3.0-37.0 | ||
| Sex | |||
| Male | 13 | 44.8 | |
| Female | 16 | 55.2 | |
| Site | |||
| Pineal | 2 | 6.9 | |
| Nonpineal | 27 | 93.1 | |
| Metastases | |||
| M0/Mx | 22 | 75.9 | |
| M1 | 4 | 13.8 | |
| M2/3 | 3 | 10.3 | |
| Resection | |||
| Complete | 6 | 20.7 | |
| Incomplete | 23 | 79.3 | |
| Chemotherapy | |||
| HIT-SKK 87 | 13 | 44.8 | |
| HIT-SKK 92 | 16 | 55.2 | |
| Radiotherapy | |||
| CSI + boost | 13 | 44.8 | |
| Local field | 1 | 3.5 | |
| None | 15 | 51.7 | |
| Radiotherapy | |||
| Preventive | 10 | 51.7 | |
| Salvage | 4 | 34.5 | |
| None | 15 | 13.8 | |
Abbreviations: stPNET, supratentorial primitive neuroectodermal tumor; CSI, neuraxis.
| Parameter | No. of Patients (N = 29) | 3-Year PFS Rate (%) | 95% CI | P |
|---|---|---|---|---|
| Age, months | .46 | |||
| < 18 | 13 | 7.7 | 0 to 22.2 | |
| > 18 | 16 | 21.4 | 0.3 to 42.5 | |
| Sex | .47 | |||
| Male | 13 | 15.4 | 0 to 35.0 | |
| Female | 16 | 14.6 | 0 to 33.0 | |
| Metastases* | .44 | |||
| M0 | 18 | 13.7 | 0 to 40.2 | |
| M1/2/3 | 7 | 14.3 | 0 to 31.1 | |
| Resection | .54 | |||
| Complete | 6 | 33.3 | 0 to 71.1 | |
| Incomplete | 23 | 9.5 | 0 to 21.9 | |
| Schedule | .48 | |||
| HIT-SKK 87 | 13 | 18.0 | 0 to 40.2 | |
| HIT-SKK 92 | 16 | 12.5 | 0 to 28.7 | |
| Histology | .98 | |||
| Reviewed | 17 | 13.5 | 0 to 30.5 | |
| Not reviewed | 12 | 16.7 | 0 to 37.7 | |
| Radiotherapy | .04† | |||
| Given | 14 | 24.1 | 0.6 to 47.6 | |
| Not given | 15 | 6.7 | 0 to 19.3 |
Abbreviations: PFS, progression-free survival; stPNET, supratentorial primitive neuroectodermal tumor.
*
Children without CSF examination were excluded from this analysis.
†
Significant.
| Parameter | No. of Patients (N = 29) | 3-Year OS Rate (%) | 95% CI | P |
|---|---|---|---|---|
| Radiotherapy | .02* | |||
| Given | 14 | 28.6 | 4.9 to 52.2 | |
| Not given | 15 | 6.7 | 0 to 19.3 | |
| Radiotherapy | .13 | |||
| Preventive | 10 | 40.0 | 9.6 to 70.4 | |
| Salvaging | 4 | 0 | 0 to 0? | |
| Resection | .50 | |||
| Complete | 6 | 33.3 | 0 to 71.1 | |
| Incomplete | 23 | 13.0 | 0 to 26.8 | |
| Schedule | .38 | |||
| HIT-SKK 87 | 13 | 23.1 | 0.2 to 46.0 | |
| HIT-SKK 92 | 16 | 12.5 | 0 to 28.7 |
Abbreviation: OS, overall survival.
*
Significant.
| Time to Death (months) | Pattern of Failure | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| TX Group | No. of Patients | Overall Survival (%) | Median | Range | Local | Distant | Combined | None | ||||
| Chemotherapy, no RT | 15 | 6.7 | 9 | 3-71 | 6 | 2 | 6 | 1 | ||||
| Chemotherapy, preventive RT | 10 | 40 | 24 | 8-128 | 4 | 1 | 1 | 4 | ||||
| Chemotherapy, salvage RT | 4 | 0 | 13 | 10-35 | 3 | 0 | 1 | 0 | ||||
Abbreviations: TX, treatment; RT, radiotherapy.
Acknowledgments
We thank our colleagues from the HIT working group for their support and contributions over many years.
Presented at the 12th European Conference on Clinical Oncology, Copenhagen, Denmark, September 21-25, 2003.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Published in print: April 01, 2006
Published online: September 21, 2016
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Role of Radiotherapy in Supratentorial Primitive Neuroectodermal Tumor in Young Children: Results of the German HIT-SKK87 and HIT-SKK92 Trials. JCO 24, 1554-1560(2006).
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