Reduced-dose Craniospinal Irradiation Research Articles

MDB-92. EFFECT OF REDUCED-DOSE CRANIOSPINAL IRRADIATION AND REDUCED-DOSE ADJUVANT CHEMOTHERAPY ON CHILDREN AND ADOLESCENTS WITH WNT MEDULLOBLASTOMA WITHOUT RESIDUAL OR METASTATIC DISEASE: RESULTS FROM THE SJMB12 CLINICAL TRIAL

Abstract BACKGROUND In response to studies showing medulloblastoma (MB) survival is not only contingent on clinical factors (e.g. metastases, residual disease) but also on molecular factors (e.g. molecular group, gene aberrations), we launched the SJMB12 (NCT01878617) trial to stratify treatment using both clinical and molecular risk factors. Specifically, we sought to evaluate if patients with WNT-group MB, without metastatic (M0) or residual disease (R0), treated with reduced-dose craniospinal irradiation (CSI) and reduced-dose cyclophosphamide-based chemotherapy could maintain a high survival with fewer treatment-related side effects. METHODS Tumors were molecularly stratified via immunohistochemistry and fluorescence in-situ hybridization. Patients with WNT tumors were grouped into 3 strata: W1 (M0, R0, classic histology, monosomy of chromosome 6); W2 (M0, R0, without monosomy 6 or classic histology); W3 [metastatic (M+), residual disease (R+), or MYC/MYCN amplification]. Treatment of W1 consisted of 15-Gy CSI/51-Gy primary site (0.5cm CTV margin) followed by 4 cycles of chemotherapy resulting in cumulative doses of 8 mg/m2 vincristine, 300 mg/m2 cisplatin, 12 gm/m2 cyclophosphamide. Serial audiology, neurocognitive, and endocrine evaluations were conducted over a six-year follow-up period. RESULTS From 2013-2022, 72 patients enrolled onto the W1 stratum: median age was 10.3 years (4.9-22.0); 62.5% female; median time of follow-up was 4.5 years (1.1-10.1). 5-year progression-free survival (PFS) and overall survival were 90.4 ± 5.1% and 98.6 ± 2.1%, respectively. Five patients had PFS events: 4 relapses and 1 accidental death. Relapsed disease was local in 2, distant in 1, and mixed in 1. Time to relapse was > 2 years from enrollment for 3 patients. Severe ototoxicity (SIOP grade ≥ 3) at the end of therapy occurred in 14.4 ± 4.5%. Neurocognitive, endocrine, and detailed molecular data are forthcoming. CONCLUSIONS Patients with low-risk WNT-MB maintained a high PFS (>90%) when treated with reduced-dose CSI and reduced-dose cyclophosphamide-based chemotherapy. Preliminary data suggests fewer treatment-related side effects.

Molecular characterization of long-term survivors of metastatic medulloblastoma treated with reduced-dose craniospinal irradiation.

Current standard treatment for metastatic medulloblastoma consists of 36 Gray (Gy) of craniospinal irradiation (CSI) supplemented with local irradiation and adjuvant chemotherapy after surgery. Although contemporary protocols have been designed to limit a radiation dose using risk-adapted CSI dosing to reduce neurocognitive morbidity, high-dose CSI remains the standard of care. Recently, the molecular classification of medulloblastoma has been emerging but its clinical significance has not been established particularly in patients with metastatic medulloblastoma treated with lower dose of CSI. We molecularly analyzed three cases of metastatic medulloblastoma treated with 24.0 Gy of CSI by DNA methylation analysis using the Illumina EPIC array. All three patients had spinal metastases at the time of diagnosis. Postoperative treatment included multiple courses of chemotherapy, 24 Gy of CSI with focal boost to primary and metastatic sites, and high-dose chemotherapy. There was no disease progression observed during the 9.0, 7.7, and 5.7 years post-diagnosis follow-up. The molecular diagnosis was Group 3/4 in all three cases. Cases 1 and 2 belonged to Subtypes 7 and 4, both of which were reported to be good prognostic subtypes among the group. Case 3 belonged to Subtype 5 with MYC amplification. The present cases suggest that the novel subtype classification in Group 3/4 medulloblastoma may be useful for risk stratification of patients with metastatic medulloblastoma who received lower dose of CSI than standard treatment.

MEDB-26. Outcomes of children with standard-risk and high-risk medulloblastoma treated with pre-irradiation chemotherapy and risk-adapted craniospinal irradiation: a report on patients from the Polish Pediatric Neuro-oncology Group

BACKGROUND: The last two decades have witnessed several efforts to minimize the adverse sequelae of craniospinal irradiation (CSI), a standard of care treatment modality in medulloblastoma. This has been accomplished by adding chemotherapy to the treatment backbone. The use of pre-irradiation chemotherapy has also been previously reported. In one of the largest studies to date, we analyze treatment outcomes in children with standard and high-risk medulloblastoma treated with pre-irradiation chemotherapy followed by reduced-dose radiotherapy in SR and maintenance chemotherapy. METHODS: Data from the Polish Pediatric Neuro-oncology Group (PPNG) was analyzed in patients greater than 3 years of age with newly-diagnosed medulloblastoma. RESULTS : Among 138 patients, median age at diagnosis was 7.9 years and median follow-up was 5.5 years. Comprehensive molecular subgrouping was not available for all patients at the time of data collection. Of 60 standard-risk patients, there was pre-irradiation disease recurrence in one patient. One patient expired prior to radiation due to metastatic disease. Of 78 high-risk patients, one had pre-irradiation recurrence. Overall survival (OS) for high-risk patients at 3 and 5 years (± standard error) was 89.2 ± 4.0% and 81.3 ± 5.8%, respectively. OS for standard-risk patients at 3 and 5 years was 92.5 ± 3.8% and 88.2 ± 5.1%, respectively. Among high-risk patients, event-free survival (EFS) at 3 and 5 years was 82.5 ± 5.3% and 81.0 ± 5.6%. Among standard-risk patients, 3-year EFS was 89.2 ± 4.6% and 5-year EFS was 86.8 ± 5.3%. CONCLUSION : This study demonstrates promising survival outcomes in pediatric medulloblastoma patients treated with pre-irradiation chemotherapy followed by reduced-dose CSI and adjuvant chemotherapy. Such an approach may be helpful if delays in starting radiotherapy are expected, which is usually the case in many institutions around the globe.

Sequential improvement in paediatric medulloblastoma outcomes in a low-and-middle-income country setting over three decades

Background: Medulloblastoma (MB) is the commonest malignant brain tumour of childhood. Accurate clinical data on paediatric MB in the low-and-middle-income countries (LMIC) setting are lacking. Sequential improvements in outcomes seen in high-income countries are yet to be reflected in LMICs.Aim: The aim of this study was quantification of paediatric MB outcomes in the LMIC setting over three decades of advances in multidisciplinary intervention.Setting: Cape Town, South Africa.Methods: This was a retrospective study of 136 children with MB diagnosed between 1985 and 2015. The modified Chang criteria were used for risk stratification. The primary objective of this study was overall survival (OS), quantified by analysis of epidemiological, clinical and pathological data.Results: OS improved significantly during the most recent decade (2005–2015) when compared with the preceding two decades (1985–1995 and 1995–2005). Despite reduced-dose craniospinal irradiation (CSI) for standard risk cases, OS was significantly greater than during the preceding two decades. High-risk disease was identified in 71.4% of cases and was associated with significantly inferior OS compared with standard-risk cases. Improved OS was positively correlated with the therapeutic era, three-dimensional (3D) conformal radiotherapy technique, older age at diagnosis, classic and desmoplastic histology, extent of resection and absence of leptomeningeal spread on imaging.Conclusion: Advances in multidisciplinary management of MB in our combined service are associated with improved survival. Access to improved imaging modalities, advances in surgical techniques, increased number of patients receiving risk-adapted combination chemotherapy or radiotherapy, as well as CSI using a linear accelerator with 3D planning, are considered as contributing factors.

MBCL-28. LONG-TERM FOLLOW-UP RESULTS OF REDUCED DOSE CRANIOSPINAL RADIOTHERAPY AND TANDEM HIGH-DOSE CHEMOTHERAPY IN PATIENTS WITH HIGH-RISK MEDULLOBLASTOMA

BACKGROUNDIn this study, we report the follow-up results of reduced-dose of craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) in patients with high-risk medulloblastoma (MB).METHODSNewly diagnosed high-risk MB patients (metastatic disease, postoperative residual tumor > 1.5 cm2 or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre-RT chemotherapy, RT including reduced-dose CSRT (23.4 or 30.6 Gy), 4 cycles of post-RT chemotherapy and tandem HDCT were given. NanoString and DNA sequencing were done with archival tissues.RESULTSForty patients were enrolled, and molecular subgrouping was possible in 21 patients (2 WNT, 3 SHH, 8 Group 3 and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (10-year cumulative incidence 10.4 ± 0.3%). However, six patients died from treatment-related mortality (TRM) (4 acute TRMs and 2 late TRMs) resulting in 18.5 ± 0.5% of 10-year cumulative incidence. Taken together, the 10-year event-free survival and overall survival were 71.1 ± 8.0% and 68.9 ± 8.5%, respectively. Late effects were evaluated in 25 patients and high-tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.CONCLUSIONSStrategy using tandem HDCT following reduced-dose CSRT showed promising results in terms of low relapse/progression rate, however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can have benefit from HDCT will be needed in the future study.

QOL-44. ASSESSMENT OF NEUROCOGNITIVE FUNCTION AND MRI PARAMETERS IN LONG-TERM SURVIVORS WITH POSTERIOR FOSSA TUMORS: A COMPARISON BETWEEN MEDULLOBLASTOMAS TREATED BY REDUCED-DOSE CRANIOSPINAL IRRADIATION AND OTHER TUMORS

BACKGROUNDChildren with medulloblastoma cannot avoid chemoradiotherapy including craniospinal radiation, although prognosis of medulloblastoma has improved and previous studies have reported a significant risk of intellectual disturbance by these treatments. We retrospectively analysed neurocognitive functions, clinical MRI parameters of patients with posterior fossa tumors, especially medulloblastomas.MATERIALS AND METHODSTwenty-two patients (12 medulloblastomas, 5 ependymomas, 5 astrocytomas) treated in our institution were enrolled in this study. Mean age was 7.8 years and 6.5 years, percentage of hydrocephalus at onset was 66.7% and 60%, respectively in medulloblastoma group and in other tumor group (ependymoma and astrocytoma). Postoperative chemoradiotherapy including reduced-dose craniospinal irradiation (18Gy) was done for medulloblastoma group and local radiation or operation only was done for other group. Version 3 or 4 of Wechsler Intelligent Scale for Children (WISC) was used by neurocognitive function analysis. Ventricular size, white matter volume and other parameters were also was estimated based on MRI. Follow-up duration was 6–17 years (mean: 10.5 years).RESULTSEvaluations of neurocognitive functions based on WISC pointed out lower performance IQ than verbal IQ in long term survivor of both group, especially working memory (P=0.05). Both hydrocephalus and cranial nerve complications was influenced lower scores of WISC, but age at onset did not influence WISC scores. Comparison between both group showed there was no significant difference about cognitive function and white matter volume.

MPC-08 Molecular risk stratification using genome-wide DNA methylation data of standard-risk medulloblastomas treated with 18-Gy craniospinal irradiation

A novel risk stratification of medulloblastoma has been proposed based on retrospective data from patients undergoing standard treatment. However, it remains unclear whether the classification is applicable to patients receiving reduced-dose craniospinal irradiation (CSI). We performed molecular diagnosis and copy number analysis using methylation array on patients with standard-risk medulloblastoma treated with 18 Gy CSI at our institution. Nine tumor samples were available for analysis from seven patients who had a median age of 7.4 years at disease onset and a median observation period of 73 months. Three patients had recurrence, and another patient developed radiation-induced glioblastoma. From the three recurrent cases, one was molecularly diagnosed as SHH subtype with MYCN amplification; another case was a Group 4 tumor without favorable prognostic chromosomal aberrations, and the remaining patient experienced a very late relapse despite low-risk stratification. Of the recurrence-free cases, one was classified as WNT subtype, and another was a Group 4 tumor with chromosome 7 gain, and loss of chromosomes 8 and 11, both of which were associated with good prognosis. Methylation analysis also unveiled the fact that the recurrent tumor diagnosed as relapsing medulloblastoma by conventional diagnostic tools was in fact a radiation-induced glioblastoma. Our data suggested that the new risk stratification may be useful for cases treated with CSI reduced to 18 Gy. However, due to the presence of the late-relapsed case stratified to low risk, further investigations with a larger cohort should be required to confirm the data.

Promising survival rate but high incidence of treatment-related mortality after reduced-dose craniospinal radiotherapy and tandem high-dose chemotherapy in patients with high-risk medulloblastoma.

BackgroundIn this study, we report the follow‐up results of reduced dose of craniospinal radiotherapy (CSRT) followed by tandem high‐dose chemotherapy (HDCT) in patients with high‐risk medulloblastoma (MB).MethodsNewly diagnosed high‐risk MB patients (metastatic disease, postoperative residual tumor >1.5 cm2, or large cell/anaplastic histology) over 3 years of age were enrolled in this study. Two cycles of pre‐RT chemotherapy, radiotherapy (RT) including reduced‐dose CSRT (23.4 or 30.6 Gy), four cycles of post‐RT chemotherapy, and tandem HDCT were administered. NanoString and DNA sequencing were performed using archival tissues.ResultsIn all, 40 patients were enrolled, and molecular subgrouping was possible in 21 patients (2 wingless, 3 sonic hedgehog, 8 Group 3, and 8 group 4). All patients including two patients who experienced progression during the induction chemotherapy underwent HDCT. Relapse/progression occurred only in four patients (5‐year cumulative incidence [CI] 10.4 ± 0.3%). However, six patients died from treatment‐related mortality (TRM) (four acute TRMs and two late TRMs) resulting in 18.5 ± 0.5% of 5‐year CI. Taken together, the 5‐year event‐free survival and overall survival were 71.1 ± 8.0% and 73.2 ± 7.9%, respectively. Late effects were evaluated in 25 patients and high‐tone hearing loss, endocrine dysfunction, dyslipidemia, and growth retardation were common.ConclusionsThe strategy using tandem HDCT following reduced‐dose CSRT showed promising results in terms of low relapse/progression rate; however, the high TRM rate indicates that modification of HDCT regimen and careful selection of patients who can benefit from HDCT will be needed in the future study.

P14.77 Reduced dose craniospinal irradiation (CSI) is feasible for standard risk adult medulloblastoma (MBL) patients similarly to pediatric population

Abstract BACKGROUND MBL is the most common malignant pediatric brain tumor but represents 1% of adult brain tumors. Recent molecular classification suggests that MBL is not the same disease in children and adults. For standard risk pediatric medulloblastomas current therapy includes CSI at reduced doses (23.4Gy) associated with chemotherapy. Most adult patients with similar risk factors still receive CSI at 36 Gy±chemotherapy (CT): in the adult series treated according to the HIT protocol (CSI 35.2 Gy + boost to 55.2 Gy to posterior fossa followed in most patients by maintenance CT with lomustine, vincristine and cisplatin) a 73% 5-year PFS was reported {Friedrich, Eur J Cancer 2013}, so far the best published data. Hence retrospective experience of 23.4 Gy together with CT for adult patients in some institutions is worthwhile reporting. MATERIAL AND METHODS We gathered M0 patients, aged over 18 years with medulloblastomas and no/minimal post-surgical residues/no biological negative factor, between 1996–2018 in Centre Léon Bérard of-Lyon and Fondazione IRCCS Istituto Nazionale dei Tumori-Milan. RESULTS Forty-four patients were included, median age 26 (18–48) years,20 females. Median follow-up 90 months(10–227). Thirty-six and 8 received 23.4Gy and 30Gy CSI, respectively, + posterior fossa/tumor bed boost and CT in all: pre-RT (carbo/VPx2 courses or 8 drugs-in-one day x 2 courses (13 patients)) and/or post-RT (carbo/VPx2 courses in 11 and 8 drugs-in-one day x 2 courses in 10; CDDP/VCR/CCNU x 8courses in other 22). The 5/10 year PFS and OS were respectively 80.9±6.5%/76.8±7.4% and 88.4±5.5%/73.1±8.5%. Median progression time was 44 months. Relapses (8) were local (4), local+CSF or spine or bone in one instance each and bone only in one. Among variable considered, higher CSI dose than 23.4 Gy, pre-RT CT did not influence PFS, while females had a trend to better PFES and OS (P=0.07). CONCLUSION These combined series present results comparable to - or even better than- those obtained after high CSI doses highlighting the need for treatment redefinition in adults.

Is there an increased risk of spinal relapse in standard-risk medulloblastoma/primitive neuroectodermal tumor patients who receive only a reduced dose of craniospinal radiotherapy?

Medulloblastoma (MBL) is the most common pediatric brain malignancy. Postoperative radiotherapy to the entire craniospinal axis is the standard-of-care but has linked to long-term morbidity. In this study, we analyzed the implication of reduced dose craniospinal radiotherapy (RT) for survival and pattern of relapse in MBL patients. The clinical characteristics of 32 consecutively diagnosed medulloblastoma/primitive neuroectodermal tumor patients were analyzed. After surgical resection, a dose of 23.4Gy of spinal RT with a posterior fossa boost of 30.6Gy was prescribed to standard-risk patients, whereas high-risk patients received 36Gy spinal RT with additional boosts to the posterior fossa up to 54Gy. Then, both groups received the same chemotherapy protocol. Five-year OS for standard and high-risk patients was 94 and 50%, respectively. When analyzing prognostic factors, postoperative tumor size is the most important one which affects the OS. Ten patients relapsed during follow-up, and there was no isolated spinal relapse in either group. The risk of isolated spinal relapse does not increase with reduced-dose craniospinal RT, since there is no isolated relapse in either the standard or high-risk groups of patients.

Intellectual Outcome in Molecular Subgroups of Medulloblastoma.

Purpose To evaluate intellectual functioning and the implications of limiting radiation exposure in the four biologically distinct subgroups of medulloblastoma: wingless (WNT), sonic hedgehog (SHH), Group 3, and Group 4. Patients and Methods A total of 121 patients with medulloblastoma (n = 51, Group 4; n = 25, Group 3; n = 28, SHH; and n = 17, WNT), who were treated between 1991 and 2013 at the Hospital for Sick Children (Toronto, Ontario, Canada), Children's National Health System (Washington, DC), or the Lucile Packard Children's Hospital (Palo Alto, CA), had intellectual assessments. First, we compared intellectual trajectories between subgroups. Next, we evaluated the effect of treatment with reduced-dose craniospinal irradiation (CSI) plus a tumor bed boost versus treatments that deliver higher CSI doses and/or larger boost volumes to the brain (all other treatments) within subgroups. Linear mixed modeling was used to determine the stability or change in intelligence scores over time. Results Intellectual outcomes declined comparably in each subgroup except for processing speed; SHH declined less than Group 3 ( P = .04). SHH had the lowest incidence of cerebellar mutism and motor deficits. Treatment with reduced-dose CSI plus a tumor bed boost was associated with preserved intellectual functioning in WNT and Group 4 patients considered together (ie, subgroups containing patients who are candidates for therapy de-escalation), and not in Group 3 or SHH. Across all subgroups, patients in the all other treatments group declined over time (all P < .05). Conclusion SHH patients appear to have the most distinct functional (ie, motor deficits and mutism) outcomes and a unique processing speed trajectory. Only WNT and Group 4 patients seem to benefit from limiting radiation exposure. Our findings highlight the value of conducting subgroup-specific analyses, and can be used to inform novel biologically based treatment protocols for patients with medulloblastoma.

Vulnerability of white matter to insult during childhood: evidence from patients treated for medulloblastoma.

OBJECTIVE Craniospinal irradiation damages the white matter in children treated for medulloblastoma, but the treatment-intensity effects are unclear. In a cross-sectional retrospective study, the effects of treatment with the least intensive radiation protocol versus protocols that delivered more radiation to the brain, in addition to the effects of continuous radiation dose, on white matter architecture were evaluated. METHODS Diffusion tensor imaging was used to assess fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity. First, regional white matter analyses and tract-based spatial statistics were conducted in 34 medulloblastoma patients and 38 healthy controls. Patients were stratified according to those treated with 1) the least intensive radiation protocol, specifically reduced-dose craniospinal irradiation plus a boost to the tumor bed only (n = 17), or 2) any other dose and boost combination that delivered more radiation to the brain, which was also termed the "all-other-treatments" group (n = 17), and comprised patients treated with standard-dose craniospinal irradiation plus a posterior fossa boost, standard-dose craniospinal irradiation plus a tumor bed boost, or reduced-dose craniospinal irradiation plus a posterior fossa boost. Second, voxel-wise dose-distribution analyses were conducted on a separate cohort of medulloblastoma patients (n = 15). RESULTS The all-other-treatments group, but not the reduced-dose craniospinal irradiation plus tumor bed group, had lower fractional anisotropy and higher radial diffusivity than controls in all brain regions (all p < 0.05). The reduced-dose craniospinal irradiation plus tumor bed boost group had higher fractional anisotropy (p = 0.05) and lower radial diffusivity (p = 0.04) in the temporal region, and higher fractional anisotropy in the frontal region (p = 0.04), than the all-other-treatments group. Linear mixed-effects modeling revealed that the dose and age at diagnosis together 1) better predicted fractional anisotropy in the temporal region than models with either alone (p < 0.005), but 2) did not better predict fractional anisotropy in comparison with dose alone in the occipital region (p > 0.05). CONCLUSIONS Together, the results show that white matter damage has a clear association with increasing radiation dose, and that treatment with reduced-dose craniospinal irradiation plus tumor bed boost appears to preserve white matter in some brain regions.

SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease

We conducted a nonrandomized international study for intracranial germinoma that compared chemotherapy followed by local radiotherapy with reduced-dose craniospinal irradiation (CSI) alone, to determine whether the combined treatment regimen produced equivalent outcome and avoided irradiation beyond the primary tumor site(s). Patients with localized germinoma received either CSI or 2 courses of carboplatin and etoposide alternating with etoposide and ifosfamide, followed by local radiotherapy. Metastatic patients received CSI with focal boosts to primary tumor and metastatic sites, with the option to be preceded with chemotherapy. Patients with localized germinoma (n = 190) received either CSI alone (n = 125) or combined therapy (n = 65), demonstrating no differences in 5-year event-free or overall survival, but a difference in progression-free survival (0.97 ± 0.02 vs 0.88 ± 0.04; P = .04). Seven of 65 patients receiving combined treatment experienced relapse (6 with ventricular recurrence outside the primary radiotherapy field), and only 4 of 125 patients treated with CSI alone experienced relapse (all at the primary tumor site). Metastatic patients (n = 45) had 0.98 ± 0.023 event-free and overall survival. Localized germinoma can be treated with reduced dose CSI alone or with chemotherapy and reduced-field radiotherapy. The pattern of relapse suggests inclusion of ventricles in the radiation field. Reduced-dose craniospinal radiation alone is effective in metastatic disease.

Reduced-dose craniospinal radiotherapy followed by tandem high-dose chemotherapy and autologous stem cell transplantation in patients with high-risk medulloblastoma

We assessed the feasibility and effectiveness of reduced-dose craniospinal (CS) radiotherapy (RT) followed by tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/autoSCT) in reducing late adverse effects without jeopardizing survival among children with high-risk medulloblastoma (MB). From October 2005 through September 2010, twenty consecutive children aged >3 years with high-risk MB (presence of metastasis and/or postoperative residual tumor >1.5 cm(2)) were assigned to receive 2 cycles of pre-RT chemotherapy, CSRT (23.4 or 30.6 Gy) combined with local RT to the primary site (total 54.0 Gy), and 4 cycles of post-RT chemotherapy followed by tandem HDCT/autoSCT. Carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens were used for the first and second HDCT, respectively. Of 20 patients with high-risk MB, 17 had metastatic disease and 3 had a postoperative residual tumor >1.5 cm(2) without metastasis. The tumor relapsed/progressed in 4 patients, and 2 patients died of toxicities during the second HDCT/autoSCT. Therefore, 14 patients remained event-free at a median follow-up of 46 months (range, 23-82) from diagnosis. The probability of 5-year event-free survival was 70.0% ± 10.3% for all patients and 70.6% ± 11.1% for patients with metastases. Late adverse effects evaluated at a median of 36 months (range, 12-68) after tandem HDCT/autoSCT were acceptable. In children with high-risk MB, CSRT dose might be reduced when accompanied by tandem HDCT/autoSCT without jeopardizing survival. However, longer follow-up is needed to evaluate whether the benefits of reduced-dose CSRT outweigh the long-term risks of tandem HDCT/autoSCT.

Radiation therapy quality in CCG/POG intergroup 9961: implications for craniospinal irradiation and the posterior fossa boost in future medulloblastoma trials

Purpose: Associations of radiation therapy (RT) deviations and outcomes in medulloblastoma have not been defined well, particularly in the era of reduced-dose craniospinal irradiation and chemotherapy. The aim of this study is to evaluate the quality of RT on Children’s Cancer Group/Pediatric Oncology Group 9961 and analyze associations of RT deviations with outcome. Materials and Methods: Major volume deviations were assessed based on the distance from specified anatomical region to field edge. We investigated associations of RT deviations with progression-free survival (PFS), overall survival (OS), and explored associations with demographics and clinical variables. Results: Of the 308 patients who were evaluable for volume deviations, 101 patients (33%) did not have any. Of the remaining 207 patients, 50% had only minor deviations, 29% had only major deviations, and 21% had both minor and major deviations. Of the patients with major deviations, 73% had a single major deviation. The most common major deviation was in the cribriform plate region, followed by the posterior fossa (PF); PF deviations resulted from treating less than whole PF. There were no significant differences in PFS or OS between patients with deviations and those without. There was no evidence of associations of deviations with patient age. Conclusions: Approximately one-third of patients had major volume deviations. There was no evidence of a significant association between these and outcome. This lack of correlation likely reflects the current high quality of RT delivered in Children’s Oncology Group institutions, our strict definition of volume deviations, and the relatively few instances of multiple major deviations in individual patients. In is noteworthy that the types of PF volume deviations observed in this study were not adversely associated with outcome. As we move forward, quality assurance will continue to play an important role to ensure that deviations on study do not influence study outcome.

Long-Term Follow-Up of Dose-Adapted and Reduced-Field Radiotherapy With or Without Chemotherapy for Central Nervous System Germinoma

To update our institutional experience with neoadjuvant chemotherapy and minimized radiotherapy vs. radiation monotherapy for intracranial germinoma. We retrospectively reviewed records of 59 patients with diagnosis of primary intracranial germinoma between 1977 and 2007. Treatment was irradiation alone or neoadjuvant platinum-based chemotherapy and local irradiation (initial tumor plus margin) for patients with localized complete response and reduced-dose craniospinal irradiation for others. For the chemoradiotherapy group (n = 28), median follow-up was 7 years. No patient died. The freedom from progression (FFP) rate was 88% at 5 years and 80% at 10 years. In 4 patients, disease recurred 1.1 to 6.8 years after diagnosis. All were young male patients who received 30.6 Gy to local fields after complete response to chemotherapy. The FFP rate was 88% for local irradiation vs. 100% for more extensive fields (p = .06). For the radiotherapy-alone group (n = 31), median follow-up was 15 years. Overall and disease-free survival rates were 93% and 93% at 5 years and 90% and 87% at 15 years. In 5 patients, disease recurred 1.1 to 4.9 years after diagnosis. Most patients in this group were young men 18 to 23 years of age with suprasellar primary disease treated with about 50 Gy to local fields. The FFP rate was 44% for local irradiation vs. 100% for more extensive fields (p < .01). The addition of neoadjuvant chemotherapy to local-field radiotherapy reduced central nervous system cancer recurrence when high-risk patients were excluded by thorough pretreatment staging. There was trend toward improved central nervous system tumor control when larger fields (whole brain, whole ventricle, or craniospinal axis) were used.

Reduced-dose craniospinal radiotherapy followed by high-dose chemotherapy and autologous stem cell rescue for children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuroectodermal tumor

BackgroundIn this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).MethodsBetween March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.ResultsA total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.ConclusionAlthough the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.

High-dose chemotherapy with reduced-dose craniospinal radiotherapy in children with newly diagnosed high-risk brain tumor

TO THE EDITOR: A recent report of Reduced-dose craniospinal radiotherapy followed by high-dose chemotherapy and autologous stem cell rescue for children with newly diagnosed high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor (sPNET) by Kim et al. has shown encouraging results concerning event-free survival [1]. Reduced dose radiation therapy for children with cancer is important because of its effects on intelligence quotient and endocrinologic complications. In this study, Kim et al. report an event-free survival of 77% for children with high-risk medulloblastoma or sPNET, which is comparable to other studies, despite having lowered CSI dose to standard risk patient level of 23.4 Gy. The major limitations of this study are, however, short duration of follow-up and limited number of patients enrolled (13 overall), necessitating further follow-up of the study cohort. Treatment of patients with high-risk medulloblastoma or sPNET has yet to reach a consensus, but few doubt the importance of adjuvant radiotherapy and chemotherapy after surgical resection. Radiation therapy ranging from 35-39 Gy combined with either chemotherapy or high dose chemotherapy and autologous stem cell transplantation has led to progression-free survival of 35-70% [2-4]. However, the specific regimen comprising chemotherapy varies considerably. High dose chemotherapy and autologous stem cell rescue (HDCT and ASCR) are administered in an attempt to maximize chemotherapeutic effect. Gajjar et al. reported a 70% event-free survival for 48 patients with high-risk medulloblastoma after 4 cycles of cyclophosphamide-based HDCT and ASCR, emphasizing the efficacy of HDCT for patients with chemotherapy-responsive brain tumors [4]. However, the amount of cyclophosphamide utilized in this study may have resulted in patient infertility, and a similar concern should be voiced for potential long-term complications in the Korean recipients of tandem transplantation. Several other pertinent points should be made; the 2 patients who relapsed before proceeding to HDCT indicate the possible advantages of modifying the current protocol in order to shorten the interval between radiotherapy and HDCT, or giving due consideration to novel modalities such as hyperfractionated radiation therapy or IMRT. Also, the 2 patients who are surviving event-free despite having undergone only 1 cycle of HDCT and ASCR raise the question of the necessity of a second cycle. Medulloblastoma itself is a diagnosis that encompasses numerous disease entities, and recent research has shed some light on the relationship between tumor biology and pathology, and overall patient prognosis [5]. With developments in risk adapted treatment and targeted therapy according to diagnostic subgroup, more specific pathologic classification and biologic characterization may become imperative for future patients receiving similar therapy.

A longitudinal study of processing speed among children treated for medulloblastoma (MB), supratentorial primitive neuroectodermal tumor (SPNET), or atypical teratoid rhabdoid tumor (ATRT)

10028 Background: Indicating a strong relationship to intelligence, processing speed parallels with the rate of knowledge acquisition. To further our understanding of the etiology of deficits in intellectual ability that continues to plague this group of children, the current study prospectively examined longitudinal changes in an underlying cognitive ability, processing speed. Methods: The study included 174 patients (median age at diagnosis = 9.0) enrolled on a multi-site protocol (SJMB03) for MB, SPNET or ATRT. Patients were treated with post-surgical risk-adapted craniospinal irradiation (CSI) followed by 4 cycles of high-dose chemotherapy (cyclophosphamide, cisplatin, vincristine) with stem cell support. High risk (HR, n = 55) patients received 36 - 39.6 Gy CSI and 3D conformal boost to the primary site to 55.8 –59.4 Gy. Average-risk (AR, n=119) patients received 23.4 Gy CSI, 3D conformal boost to the primary site to 55.8 Gy. Those who had posterior fossa syndrome were excluded (n = 26) resulting in 148 patients who completed 459 neuropsychological evaluations using the Woodcock Johnson Tests of Cognitive Abilities-III over a period of 0.03 –4.94 years postdiagnosis. Results: Multivariate modeling revealed a statistically significant decline in processing speed for those &lt; 7 years of age at time of diagnosis (-3.83 points per year, p = 0.003). Those who were &gt; 7 years at diagnosis did not experience a significant change (.86, NS). HR patients experienced greater declines (-.82) than those who were AR (-0.29), but neither slope was statistically significant. Interaction models revealed declines for those in the &lt;7/AR group (-4.17, p = 0.003), and &lt;7/HR group (-3.38, NS). Those &gt;7/AR and &gt;7/HR did not experience significant change (1.06 and 0.32, respectively). Conclusions: Young age at diagnosis is a prominent risk factor for processing speed impairment among survivors of pediatric embryonal tumors. Processing speed may also be among the first deficits to appear following treatment. This study represents the largest comparison of processing speed ability among patients treated for pediatric embryonal tumors with conventional or reduced dose CSI and adjuvant chemotherapy. No significant financial relationships to disclose.

Feasibility and outcome of patients with medulloblastoma treated with pre-irradiation chemotherapy and reduced dose craniospinal radiotherapy (csrh) using mycc as a molecular marker for prognosis

10040 Background: Children with medulloblastoma are more susceptible to the deleterious effects of craniospinal irradiation (CSRT) and have a higher relapse rate when treated with low-dose CSRT alone. Cytogenetic abnormalities that have been described in childhood medulloblastoma include loss of 17p, amplification of MYCC, amplification of MYCN and isochromosome 17q. This study was undertaken to determine the feasibility and efficacy of treating children with medulloblastoma with pre-irradiation chemotherapy and reduced-dose craniospinal radiotherapy and investigated the frequency and prognostic significance of MYCC amplification. Methods: 65 patients received 3 cycles of alternating chemotherapy (vincristine, etoposide and carboplatin and vincristine, etoposide and cyclophosphamide). All patients received radiotherapy to the craniospinal axis (25 Gy followed by a boost to posterior fossa with 30 Gy). After completion of CSRT, the patients received additional 3 cycles of alternating chemotherapy. Fluorescence in situ hybridization (FISH) was used to detect amplification of the MYCC oncogene. Results: Among the 65 patients, the median survival time was 21.0 months (3–52.0 months) from the date of diagnosis. The overall response rate was 89%. The estimated four-year progression-free survival was 78 percent and the four-year overall survival was 84 percent. The most predominant toxicity with post-irradiation chemotherapy was myelosuppression. Grade III neutropenia occurred in ≥60% of patients in each cycle. MYCC amplification was founded in 4 positive cases (6%). Estimate of the survival distributions for patients with and without MYCC amplification, reveals sufficient evidence to conclude that survival among MYCC-amplified patients is poorer than among non-amplified patients (P < .0001). Conclusions: This study has demonstrated the feasibility and benefits of administering pre-irradiation chemotherapy with reduced dose craniospinal irradiation in patients with medulloblastoma and confirmed the frequency of MYCC amplification in a large cohort of patients and further suggest that MYCC amplification may be a marker of poor prognosis. No significant financial relationships to disclose.