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Children with medulloblastoma, atypical teratoid rhabdoid tumor (ATRT), and ependymoma are treated with a multidisciplinary approach including surgery, radiotherapy, and chemotherapy. Lower doses of craniospinal irradiation and tumor bed boost together with chemotherapy are the current standard of care for average-risk medulloblastoma in the Children's Oncology Group (COG). The International Society of Pediatric Oncology (SIOP) is examining the role of hyperfractionated craniospinal irradiation and chemotherapy in high-risk patients. The recent stratification of medulloblastoma into specific molecular risk groups has prompted both COG and SIOP to reexamine the role of these modalities in these different risk groups to maximize cure rates and minimize long-term complications. Proton therapy has shown lower rates of neurocognitive and endocrine complications compared with photons. Ependymomas are treated with maximal surgical resection and adjuvant radiation therapy. The role of chemotherapy in ependymoma is currently being studied in both COG and SIOP. Likewise, for ATRT the role of different high-dose chemotherapy regimens together with local radiation therapy in infants, or craniospinal radiation in older children, is the current focus of research., (© 2020 Wiley Periodicals LLC.)

Primary hypothyroidism commonly occurs after radiotherapy (RT), and coincides with increased circulating thyroid-stimulating hormone (TSH) levels.We tested therefore the protective effect of suppressing TSH with L-thyroxine during RT for medulloblastoma/PNET and Hodgkin lymphoma (HL) in a prospective cohort study. From1998 to 2001, a total of 37 euthyroid children with medulloblastoma/PNET plus 14 with HL, scheduled for craniospinal irradiation and mediastinum/neck radiotherapy, respectively, underwent thyroid ultrasound and free triiodothyronine (FT3), free thyroxine (FT4), and TSH evaluation at the beginning and end of craniospinal iiradiation. From 14 days before and up to the end of radiotherapy, patients were administered L-thyroxine checking every 3 days TSH to ensure a value < 0.3 μIU/mL. During follow-up, blood tests and ultrasound were repeated; primary hypothyroidism was considered an increased TSH level greater than normal range. Twenty-two/37 patients with medulloblastoma/PNET and all the 14 patients with HL were alive after a median 231 months from radiotherapy with 7/22 and 8/14 having correctly reached TSH levels < 0.3 μIU/mL and well matched for other variables. Twenty years on, hypothyroidism-free survival rates differed significantly, being 60% ± 15% and 15.6% ± 8.2% in TSH-suppressed vs. not-TSH suppressed patients, respectively (P = 0.001). These findings suggest that hypothyroidism could be durably prevented in two populations at risk of late RT sequelae, but it should be confirmed in a larger cohort.

Introduction: Medulloblastoma is the most common malignant brain tumor in children, but accounts for only 1% of brain cancers in adults. For standard-risk pediatric medulloblastoma, current therapy includes craniospinal irradiation (CSI) at reduced doses (23.4 Gy) associated with chemotherapy. Whereas most same-stage adult patients are still given CSI at 36 Gy, with or without chemotherapy, we report here on our use of reduced-dose CSI associated with chemotherapy for older patients., Methods: We gathered non-metastatic patients over 18 years old (median age 28 years, range 18-48) with minimal or no residual disease after surgery, no negative histological subtypes, treated between 1996-2018 at the Centre Léon Bérard (Lyon) and the INT (Milano). A series of 54 children with similar tumors treated in Milano was used for comparison., Results: Forty-four adults were considered (median follow-up 101 months): 36 had 23.4 Gy of CSI, and 8 had 30.6 Gy, plus a boost to the posterior fossa/tumor bed; 43 had chemotherapy as all 54 children, who had a median 83-month follow-up. The PFS and OS were 82.2 ± 6.1% and 89 ± 5.2% at 5 years, and 78.5 ± 6.9% and 75.2 ± 7.8% at ten, not significantly different from those of the children. CSI doses higher than 23.4 Gy did not influence PFS. Female adult patients tended to have a better outcome than males., Conclusion: The results obtained in our combined series are comparable with, or even better than those obtained after high CSI doses, underscoring the need to reconsider this treatment in adults.

Wilms tumor (or nephroblastoma), rhabdomyosarcoma, and medulloblastoma, common embryonal tumors in children, can occasionally occur in adults, for whom survival is significantly inferior than pediatric patients. Available data on adults with Wilms tumor consist of case or case series reports. Among other factors, the unfamiliarity of adult oncologists and pathologists with nephroblastoma and consequent delays in initiating the appropriate risk-adapted chemotherapy may negatively influence outcomes. The survival decrement in adults with rhabdomyosarcoma has been attributed to the lack of centralized care, the inconsistent use of standard protocol-driven multimodal therapy, and lower chemotherapy tolerance in adult patients. In children with medulloblastoma, evidence from randomized clinical trials has led to risk-tailored therapies tuned on histology, extent of initial disease, and biological features. Such refinements are still missing for adults due to the lack of similar trials and studies that might provide the same or a different understanding regarding patients' individual prognosis, treatment morbidity, and quality of life. Recent experiences have suggested that applying or adjusting pediatric protocols to adult patients with these tumors is feasible and can improve survival. Here, we provide an evaluation of the current evidence for the management of Wilms tumor, rhabdomyosarcoma, and medulloblastoma arising in adults. This review aims to promote the referral of adolescents and adults with pediatric tumors to pediatric centers for inclusion into pediatric protocols, or into protocols and studies specifically designed for that age group with the cooperation between pediatric and adult oncologists.

Medulloblastoma and central nervous system (CNS) germ cell tumors are very rare in adults, while they account for 25% and 5% of brain tumors in children, respectively (Pastore et al. Eur J Cancer 42:2064-208, 2006). Pediatric experiences, mostly from randomized and controlled clinical trials, have led to different tailored treatments, based on various risk factors, including histology, and extent of disease. For medulloblastoma, biological features have recently emerged that enable therapies to be scaled down in some cases, or pursued more aggressively in the event of chromosomal and/or genetic alterations (Massimino et al. Crit Rev Oncol Hematol 105:35-51, 2016). Such refinements are still impossible for adult patients due to the lack of similar clinical trials that might provide the same or a different understanding regarding patients' prognosis, long-term survival, quality of life, and acute and late toxicities. This review aims to contribute to the debate on the treatment of adults with these two diseases and promote the creation of broad-based, national and international trials to advance our knowledge in this area and to share the skills between pediatric and adult oncologists as adolescent and young adults (AYA) brain tumor national boards are currently requiring.

Purpose: Pediatric radiotherapy (RT) is a highly specialized field, requiring great experience to delineate correctly tumor targets and organs at risk. To reduce treatment failures related to planning inaccuracies and to obtain robust clinical results despite the limited numbers of enrolled pediatric patients, the SIOP PNET5MB clinical trial on medulloblastoma requires a real-time, pre-radiation review of the RT treatment (craniospinal irradiation and boost plan) under the direct responsibility of the national coordinator center. Here we describe the centralized radiotherapy quality assurance (QA) program developed in Italy for this purpose., Methods: Using the software package VODCA (MSS, Hagendorn, Switzerland, www.vodca.ch ), we developed a cloud platform able to handle computed tomography (CT) images and RT objects and to support the complete workflow required by the review process in the context of the SIOP PNET5 trial., Results: All Italian centers participating in the PNET5 trial adopted the proposed QA system. 24 patients were successfully enrolled and reviewed. For 15 patients (62.5%), one or more plan revisions were requested for the craniospinal irradiation plan and for 11 patients (45.8%) plan revisions were requested for the boost. RT was delivered after the plan was centrally approved for all enrolled patients. So far, in Italy, no patients have been excluded from PNET5 due to dosimetric incompliance to the protocol or for exceeding the RT starting time limit., Conclusion: The cloud platform successfully supported the trial workflow, producing official review documents. This efficient QA was crucial to guarantee optimized treatments and protocol compliance for all pediatric patients enrolled in the SIOP protocol.

Purpose: An intensive therapeutic strategy for metastatic medulloblastoma was launched in 1998 in our Institution. The aim of this study was to examine the long-term quality of life (QoL) in survivor patients at least 3 years after the end of the treatment., Methods: Patients were asked to complete self-administered QoL questionnaires. An index of physical impairment (IPI) was scored (range 0-100; the lower the score the better) based on clinical objective observations. Patients were divided into two groups (lower IPI group, and higher IPI group) and descriptively compared accordingly., Results: The study was completed by 25/33 eligible patients. Despite patients with a higher IPI reported worse perceived health condition, they had better emotional and psychological scores than those with a lower IPI in all QoL questionnaires., Conclusion: In our sample, patients with more severe objective and perceived physical impairments reported a better psychosocial QoL, possibly because the greater attention paid to them by society and family contributes to a better adjustment in long-term survivors. On this base, it should be recommended that all survivors receive a strong support as the most impaired patients.

Medulloblastoma accounts for 15-20% of childhood nervous system tumours. The risk of dying was reduced by 30% in the last twenty years. Patients are divided in risk strata according to post-surgical disease, dissemination, histology and some molecular features such as WNT subgroup and MYC status. Sixty to 70% of patients older than 3 years are assigned to the average-risk group. High-risk patients include those with disseminated and/or residual disease, large cell and/or anaplastic histotypes, MYC genes amplification. Current and currently planned clinical trials will: (1) evaluate the feasibility of reducing both the dose of craniospinal irradiation and the volume of the posterior fossa radiotherapy (RT) for those patients at low biologic risk, commonly identified as those having a medulloblastoma of the WNT subgroup; (2) determine whether intensification of chemotherapy (CT) or irradiation can improve outcome in patients with high-risk disease; (3) find target therapies allowing tailored therapies especially for relapsing patients and those with higher biological risk., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Managing patients who suffer from both cancer and end-stage renal disease is challenging because there is a paucity of data, especially for children. There are no published reports of adjuvant chemotherapy for medulloblastoma being used in children on dialysis. In this article we describe the case of an Italian 5-year-old boy on hemodialysis for chronic renal failure who presented with a desmoplastic medulloblastoma with extensive nodularity and nuclear β-catenin expression. The patient was treated with craniospinal irradiation after complete surgical resection, followed by six cycles of cyclophosphamide and vincristine. Vincristine was administered at the usual dosage for children with normal kidney function, cyclophosphamide was delivered after dialysis and over the course of the following day, starting with 50% of the commonly used dosage. This is the first case report of chemotherapy given during hemodialysis in a child with medulloblastoma. This treatment proved easy to administer despite the child's kidney disease and it maintained disease remission with no additional toxicity.

Purpose: We retrospectively report strategies used for medulloblastoma patients progressing after craniospinal irradiation where we aimed for: symptom control, a satisfactory quality of life, accrual in phase 1-2 trials, when available, and the first two conditions could no longer be satisfied by already experienced second-line strategies., Methods: Surgery was used in cases of doubtful relapse or when only one site was affected. Radiotherapy was given whenever possible, especially to relieve symptoms. The main chemotherapy regimens were oral temozolomide/etoposide, intravenous (iv.) cisplatin/etoposide, iv. gemcitabine/oxaliplatin, an oral sonic hedgehog pathway inhibitor and oral melphalan., Results: Between 1998 and 2011, we treated 18 patients relapsed after median 20 months. Nine had relapsed locally, four had dissemination, three single metastases, and two had one synchronous local and metastatic recurrence. Responses to chemotherapy were seen in 32% of cases. The median hospital stay for treatments/complications was 19 days. The 1- and 3-year progression-free survival (PFS) rates were 28 ± 10% and 0%, respectively, for OS, they were 44 ± 12% and 22 ± 10% but no patient was cured. The median PFS after a first relapse was 7 months (range 1-29); the median OS was 7 months (range 4-44). No patients died due to treatment toxicity. Late recurrence (more than 1-2 years after diagnosis) and involvement of single sites were favorable prognostic factors., Conclusions: Without succeeding in patients cure, we ensured them further treatment with short hospital stay thus affording low personal and social costs. The chances of cure may emerge from tailored therapies according to genetic stratification.

Background: Medulloblastoma histological classification has gained in importance and newer treatment protocols will include histology stratification. We centrally reviewed medulloblastoma cases from past 10 years reassessing their histology to ascertain its prognostic significance., Methods: Samples from 125 consecutive patients (99 males; 10 under age 3 years) were reviewed according to the two WHO classifications of 2000/2007., Results: Eighty-two patients did not have metastases, the primary tumor was completely resected in 101. The median follow-up was 96 months. Treatment was: our institutional protocol, that is, hyperfractionated accelerated radiotherapy (HART), for 39 non-metastatic cases up to 2003; according to the European PNET IV protocol in 31 cases; a HART-based strategy in 39 metastatic cases; tailored to the age below 3 years and based on high-dose chemotherapy in 10; and tailored to the patients conditions in 7. The 5-year PFS/OS rates were 76% and 81%, respectively. Histology was classic in 93 cases, nodular/desmoplastic in 20, anaplastic/large-cell in 9, and with extensive nodularity (MBEN) in 3. Stratification by residual disease after resection, metastases, age, or protocols was not prognostic. Histology suggested 5-year PFS rates of 82% for the desmoplastic and MBEN variants, 78% for classic medulloblastoma, 44% for the anaplastic/large-cell variants (P = 0.01). Multivariable analysis demonstrated statistically significant difference in PFS by histology (P = 0.02), due to the poor prognosis of anaplastic/large-cell medulloblastoma., Conclusions: Tailoring treatments to known risk factors cancelled all prognostic differences, except for anaplasia (not considered as such within previous trials) which proved the most powerful prognostic factor, warranting appropriate treatment intensification., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose: To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy., Patients and Methods: In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine., Results: After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up., Conclusion: In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.

To reduce the sequelae of craniospinal irradiation (CSI) in children under 10 (≥3) years old and to improve the prognosis for high-risk medulloblastoma in adolescents, we adjusted postoperative chemotherapy and CSI doses to patients' stage and age. From 1986 to 1995, 73 patients entered the study. Children under 10 and adolescents with metastases, residual disease (RD) or stage >T3 received postoperative IV vincristine and high-dose (HD) ± intrathecal (IT) methotrexate, while standard-risk adolescents were given IV vincristine and IT methotrexate. Chemotherapy was followed by CSI (19.8 Gy for children <10; 36 Gy for adolescents), with a 54-Gy posterior fossa boost. Maintenance chemotherapy with lomustine and vincristine was administered for a year afterwards. A total of 39 children were under 10 of whom 20 had metastases. Response to chemotherapy was recorded in 70%, but 5-year EFS and OS were only 48 and 56%, respectively. Results were significantly worse for metastatic cases, patients under 10, those with RD, and those staged without MRI (unavailable early in the study). Efforts to preserve survivors' quality of life did not pay off, and most patients over 30 still depended on their parents' income and had severe cognitive/endocrine disabilities. In conclusion, despite a very high response rate with this preradiation HD methotrexate schedule, the outcome for high-risk medulloblastoma patients did not improve (especially when lower CSI doses were used) and patients still developed severe morbidities.

Among all the childhood central nervous system tumours, medulloblastoma and other neuroectodermal tumours account for 16-25% of cases. The causative factors of medulloblastoma/PNET have not been well established. It is more frequent in boys than in girl and in children than in adults. There was a significant improvement of survival for children diagnosed in 2000-2002 compared to those diagnosed in 1995-1999. The risk of dying was reduced by 30%. Patients are generally divided into risk-stratified schemes on the basis of age, the extent of residual disease, and dissemination. Sixty to 70% of patients older than 3 years are assigned to the average-risk group. High-risk patients include those in the disseminated category, and in North American trials those that have less than a gross or near-total resection, which is arbitrarily defined as 1.5 cm(2) of post-operative residual disease. Current and currently planned clinical trials will:define molecular and biological markers that improve outcome prediction in patients with medulloblastoma and which can be incorporated for front-line stratification of newly defined risk subgroups., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation., Methods and Materials: In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa (+/- carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible., Results: Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapy in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months., Conclusions: Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.

Purpose: With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after intensive sequential chemotherapy., Patients and Methods: Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue., Results: Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far., Conclusion: HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.

We retrospectively studied 26 consecutive adults treated for medulloblastoma using paediatric protocols. Between 1987 and 2003, patients 18 years old were given adjuvant chemotherapy consisting of one of two 'paediatric' regimens (depending on the time of presentation) and craniospinal local-boost radiotherapy: regimen A (n = 12), vincristine (VCR), intrathecal and/or intravenous methotrexate and conventional radiotherapy; or regimen B (n = 11) sequencing intensive doses of multiple agents followed by hyperfractionated accelerated radiotherapy (HART). A VCR-lomustine-based maintenance followed both regimens. Three additional patients received a tailored treatment due to their impaired neurological status after surgery. The median age at diagnosis was 26 years (range 18-41 years). With a median follow-up of 46 months, 5-year disease-free and overall survival rates were 65+/-11% and 73+/-10%, respectively, for the series as a whole. All patients who received regimen B (5 of whom had metastatic Chang M2-M3 disease) are alive with no evidence of disease at 39 months. Although the number of patients is limited, our data suggest that the sandwich sequential, moderately intensive chemotherapy in combination with HART is an effective treatment for medulloblastoma in adults, and this approach seems to overcome previously-recognised risk factors.

Background: Cognitive impairment occurs after malignant brain tumor treatment in children, following brain radiotherapy and systemic and intrathecal chemotherapy., Objectives: 1) To compare two groups of children who underwent surgery for cerebellar medulloblastoma with their cousins and siblings, assessing intelligence, executive function, attention, visual perception, and short-term memory. Both groups were treated with the same combined radiotherapy-chemotherapy, but differed in that only one group received intrathecal methotrexate (MTX+). 2) To relate these measures to MRI findings (leukomalacia)., Results: The two groups performed worse than their control subjects in all tests. The MTX+ group younger than 10 years performed significantly worse in all tests, particularly executive ones. The group older than 10 years performed significantly worse only in short-term memory. Younger patients without MTX performed significantly worse than controls only in some neuropsychological measures; there were no differences between older patients and control subjects. Only in the MTX+ group was there a direct correlation between extent of leukomalacia and performance in some tests., Conclusions: The administration of intrathecal methotrexate to children with medulloblastoma worsens the cognitive deficits induced by chemotherapy and radiotherapy. The use of intrathecal methotrexate in the treatment of medulloblastoma and other malignancies should be reassessed.

To reduce the sequelae from CNS irradiation (RT), 16 children younger than 3 years with medulloblastoma-PNET (13 cases) and ependymoma (3 cases) were treated between 1987-1993 according to different postsurgical chemotherapy (CT) programs. None of these patients presented with metastases. Eleven patients were rendered disease-free by surgery, while 5 had residual tumor. Adjuvant therapy depended on patients' age, postsurgical status and parents' consent to radiotherapy (RT). Nine of the 16 infants remained alive in continuous complete remission from the first neoplasm (median follow-up 7 years). Three of them had been treated with CT alone and 6 with combined CT + RT (posterior fossa 4, whole CNS 2). Seven patients relapsed a median of 13 months after diagnosis, and all 7 of them died of their disease. Despite the omission of RT in 6 of the 16 patients and administration of only focal RT in 8 of the 16, the outcome of this series was satisfactory. Local failure (in 5/7 patients) was the major problem, despite the high dose of RT used in 2 of these 5. In 4 of 6 evaluable children school performance was satisfactory. One child in whom the entire CNS was irradiated developed glioblastoma multiforme 120 months after the first diagnosis of medulloblastoma.