Medulloblastoma Primitive Neuroectodermal Tumors Research Articles

Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial

The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. Median age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile.

Low-grade Bone Lesions in Survivors of Childhood Medulloblastoma/Primitive Neuroectodermal Tumor

Medulloblastoma/primitive neuroectodermal tumor (MB/PNET) is the most common malignant tumor of the central nervous system (CNS) in children. MB/PNET survivors are at an increased risk for developing second malignancies. Little has been reported on development of low-grade lesions of the calvarium in the radiation field in MB/PNET survivors. The purpose of this study was to assess the frequency of the low-grade bone lesion development in the radiotherapy field in pediatric MB/PNET survivors and describe the imaging characteristics of these lesions. Institutional review board approval was obtained for this retrospective review which was compliant with Health Insurance Portability and Accountability Act. Forty-one MB/PNET patients (29 male) who survived for at least 2 years after initiation of radiation therapy were included. The medical records were reviewed. The most recent available brain magnetic resonance imaging studies were evaluated. Three patients (7.3%) developed low-grade calvarial lesions and underwent resection and/or biopsy of the lesions. There were one Langerhans cell histiocytosis, one benign spindle cell lesion with myxoid change, and one fibrous dysplasia. Development of low-grade bone lesions of calvarium is not very rare in pediatric PNET/MB survivors. Bones in the radiation therapy field need to be carefully examined for assessment of secondary lesions.

Immunohistochemical analysis of hSNF5/INI1 in pediatric CNS neoplasms.

Atypical teratoid/rhabdoid tumor (AT/RT) may be misdiagnosed as primitive neuroectodermal tumor/medulloblastoma (PNET) and occasionally as other tumors. Molecular genetic analysis of AT/RT demonstrates deletion and mutation of the hSNF5/INI1 gene in most cases, with decreased or absent expression at the RNA or protein level. Immunohistochemistry with an antibody to INI1 was performed to determine whether this would be a sensitive and specific means of assessing INI1 loss in pediatric brain tumors. Fifty-three tumors consisting of 20 AT/RTs, 10 PNETs, and 23 other central nervous system tumors were examined. No nuclear staining was found in all 20 AT/RTs. Most other central nervous system tumors demonstrated nuclear staining. Eight cases in which classification as AT/RT or PNET was difficult were also examined. Seven cases had no chromosome 22 deletion or INI1 mutation; INI1 antibody showed nuclear staining in these cases. One case was a recurrent tumor with features consistent with an AT/RT. INI1 immunostaining was negative in this case, and a mutation in INI1 was subsequently identified. Immunohistochemical staining with an INI1 antibody correlates with molecular findings in AT/RT and may be useful in confirming the histologic diagnosis. INI1 immunostaining may have particular utility in the analysis of tumors with indeterminate histologic features or atypical immunophenotypic profiles.

Autocrine secreted insulin-like growth factor-I stimulates MAP kinase-dependent mitogenic effects in human primitive neuroectodermal tumor/medulloblastoma.

Primitive neuroectodermal tumors/medulloblastoma (PNET/MB) have similarities to neuroectodermal progenitor cells of the developing CNS. Since insulin-like growth factor I (IGF-I) exerts pleiotrophic effects on cells in the developing CNS, we evaluated the production, mitogenic effects and signaling pathways of IGF-I in PNET/MB cells and found that IGF-I is an autocrine growth factor in human PNET/MB cell lines tested. Stimulation of DAOY cells by IGF-I led to phosphorylation of its cognate receptor (IGF-IR) and resulted in cell proliferation. These effects of IGF-I were suppressed by IGF-IR blocking antibodies and by PD 98059, MAP kinase pathway inhibitor. The results demonstrate the existence of an autocrine IGF-I/IGF-IR loop and indicate that IGF-I promotes proliferation via MAP kinase pathway.

Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma

Between 1975 and 1989, 108 children with newly diagnosed medulloblastoma/primitive neuroectodermal tumor (MB/PNET) of the posterior fossa were treated at the authors' institution. The patients were managed uniformly, and treatment included aggressive surgical resections, postoperative staging evaluations for extent of disease, and craniospinal radiation therapy with a local boost. Beginning in 1983, children with MB/PNET were prospectively assigned to risk groups; those with "standard-risk" MB/PNET were treated with radiation therapy alone, while those in the "poor-risk" group received similar radiation therapy plus adjuvant chemotherapy with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), vincristine, and cisplatin. The 5-year actuarial disease-free survival rate for all patients treated between 1975 and 1982 was 68%, and 73% when patients who died within 2 weeks after operation were excluded. This survival rate was statistically better for patients treated after 1982 (82%) compared to those treated between 1975 and 1982 (49%) (p less than 0.004). There was no difference in disease-free survival rates over time for children with standard-risk factors; however, there was a significant difference in the 5-year survival rate for poor-risk patients treated prior to 1982 (35%) compared to those treated later (87%) (p less than 0.001). For the group as a whole, a younger age at diagnosis correlated with a poorer survival rate; however, this relationship between age and outcome was significant only for children treated before 1983 (p less than 0.001). These results demonstrated an encouraging survival rate for children with MB/PNET, especially those treated with aggressive surgical resection followed by both radiation therapy and chemotherapy. The results strongly suggest that chemotherapy has a role for some, and possibly all, children with MB/PNET.

Chemotherapy for medulloblastoma/primitive neuroectodermal tumors of the posterior fossa

Chemotherapy has only marginal efficacy in adult malignant brain tumors. In contrast, drug therapy is considerably more effective in medulloblastoma/primitive neuroectodermal tumors (MB/PNET) of the posterior fossa, the most common childhood primary central nervous system tumor. At the time of disease recurrence, a variety of different single agents and drug combinations result in tumor shrinkage and increased survival. The addition of chemotherapy to standard radiotherapy improves the rate and length of disease-free survival for those children with MB/PNET who have the most extensive tumors at diagnosis. It remains to be determined which drug or drug combinations are the most effective in MB/PNET, and which patients are most likely to benefit from chemotherapy. Chemotherapy may be useful to reduce or, in selected cases, obviate the need for radiotherapy and reduce treatment-related sequelae.

Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine

Primitive neuroectodermal tumors/medulloblastoma (PNET/MB) are the most common posterior fossa tumors in childhood. Despite surgery and radiation therapy, 40% to 50% of children with PNET/MB will have recurrent disease. Various chemotherapeutic agents are transiently effective in recurrent PNET/MB, but long-lasting responses are rarely attainable. To increase the rate and duration of response in children with recurrent PNET/MB, the authors treated seven patients (ages 2-18 years; median, 10 years) with lomustine (CCNU) (100 mg/m2), cisplatin (CPDD) (90 mg/m2) and vincristine (VCR) (1.5 mg/m2; maximum, 2 mg) in a 6-week cycle for a maximum of eight cycles. Six of six evaluable patients responded to chemotherapy. Four patients had a complete response; three with complete disappearance of tumor by imaging studies; and one with eradication of extraneural disease for a median of 24 months from relapse (13-29 months). Overall disease-free survival was 18.5 months. All six patients have subsequently died of recurrent tumor. Major toxicities consisted of reversible bone marrow suppression (six of six), high frequency hearing loss (six of six) and decreased renal function (three of six). All patients required dosage modification for toxicity. A regimen of CCNU, VCR, and CPDD is effective therapy in children with relapsed PNET/MB and can produce relatively long-term disease control with good quality of life. Further investigation into the efficacy of this combination as adjuvant chemotherapy in newly diagnosed high-risk PNET/MB is now being performed.

Chemotherapy For Medulloblastoma

The efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma/primitive neuroectodermal tumors (MB/PNET) has been studied at the Children’s Hospital of Philadelphia, University of Pennsylvania, PA.

Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: a preliminary report.

Recent studies have demonstrated that preoperative and postoperative factors can broadly stratify patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET) into risk groups. For children with factors that suggest poor outcome after treatment with surgery and radiotherapy, the addition of chemotherapy can improve survival. Since 1983, 26 children with poor-risk posterior fossa MB/PNET have been treated at our institution with craniospinal radiation therapy and adjuvant chemotherapy. Chemotherapy consisted of vincristine during radiotherapy and eight 6-week cycles of vincristine, cis-platinum, and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Twenty-five of 26 patients (96%) who have been entered on this protocol remain alive and free of disease at a median of 24 months from diagnosis (range 6 to 50 months). Twenty patients have completed all therapy and are at a median of 32 months from initial diagnosis with no evidence of disease. These patients were compared to a group of children with similar prognostic features treated at our institution between 1975 and 1983. Actuarial disease-free survival was statistically significantly better for protocol patients than for historical control subjects (p less than 0.002). This difference was most marked in patients who had received radiation therapy alone (p less than 0.0003). Actuarial 2-year disease-free survival was 96% for patients on protocol as compared to 59% for historical control patients who had been treated with radiotherapy alone. The chemotherapy given in this protocol was well tolerated. The results of this study, although preliminary, suggest that adjuvant chemotherapy is at least transiently effective in improving the rate of disease-free survival for children with poor-risk MB/PNET.

Late recurrence of primitive neuroectodermal tumor/medulloblastoma.

The period of risk for recurrence of primitive neuroectodermal tumor/medulloblastoma (PNET/MB) is not clearly defined. With current treatment since more than 50% of children with PNET/MB can be expected to survive for at least 5 years after diagnosis, determining the evidence of "late" recurrence is of increasing concern. Collins has stated that patients with embryonal tumors who survive, disease free, for a period of time equal to the age at diagnosis plus 9 months can be declared cured. This, so-called Collins' law has been applied to patients with PNET/MB. To determine the incidence of "late" recurrence, factors which impact on recurrence and applicability of Collins' law, the authors studied all patients diagnosed with PNET/MB at the Children's Hospital of Philadelphia, Hospital of the University of Pennsylvania, Philadelphia, and Geisinger Medical Center, Danville, Pennsylvania, between 1970 and 1984. For the 44 patients in this study, the disease-free survival at 5, 10, and 12 years was 54%, 41% and 30%, respectively. For children surviving 5 years, the actuarial survival at 10 years was 75% and at 12 years, 51%. Age, sex, dose of radiotherapy, chemotherapy, or extent of surgery were not predictive of late relapse. Recurrence in three of seven patients (43%) occurred outside the "period of risk" as predicted by Collins. It appears that the "period of risk" for recurrent central nervous system tumors after PNET/MB is as yet undefined and probably indefinite.

Hemorrhagic brain tumors in pediatric patients.

In an unselected pediatric series of 113 newly tissue verified intracranial tumors, intracranial hemorrhage was the initial presentation in 10% of the cases. Review of all cases of subarachnoid hemorrhage admitted to Children's Hospital of Philadelphia during the period of 1976--1979 revealed that intracranial tumors were present in 15%. The largest hemorrhagic pathological group was medulloblastoma-primitive neuroectodermal tumors. No particular age predominance was noted. The high incidence of intracranial tumor hemorrhage in this series of pediatric patients suggests that this may be a more common presentation than previously reported.