melphalan and Pinealoma

We evaluated the usefulness of a treatment regimen that included high-dose chemotherapy (HDC) with autologous stem-cell rescue (ASCR) in patients with newly diagnosed pineoblastoma (PBL).. Twelve patients with PBL were initially treated with surgery and induction chemotherapy. All but two patients underwent radiotherapy. Subsequently, all patients received HDC using cyclophosphamide (CTX) + melphalan (MEL) or busulfan (Bu) + MEL regimens and ASCR.. A total of six children and six adults with median ages of 4.2 (range, 0.3 to 19.8 years) and 23 years (range, 23 to 43.7 years), respectively, were treated according to this strategy. Four patients had metastatic disease confined to the neuraxis. Five of 12 patients (42%) had a complete tumor resection at diagnosis. Ten patients received radiotherapy at median doses of 36.0 and 59.4 Gy to the neuraxis and pineal region, respectively. Eleven patients received HDC with CTX + MEL, and one patient received BU + MEL followed by ASCR. Nine patients are alive with no evidence of disease recurrence at a median of 62 months from diagnosis (range, 28 to 125 months), including three patients with metastatic disease and two infants who did not receive any radiotherapy. Three patients have died of progressive disease at 19, 32, and 37 months from diagnosis, respectively. The actuarial 4-year progression-free and overall survivals are 69% (95% confidence interval [CI], 39% to 99%) and 71% (95% CI, 43% to 99%), respectively.. The use of HDC in addition to radiotherapy seems to be an effective treatment for patients with newly diagnosed pineoblastoma.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Disease-Free Survival; Female; Humans; Infant; Male; Melphalan; Middle Aged; North Carolina; Pineal Gland; Pinealoma; Stem Cell Transplantation; Survival Rate; Transplantation, Autologous

Irinotecan (CPT-11), a water-soluble topoisomerase I inhibitor, is metabolized by carboxylesterase enzymes to form an active metabolite, SN-38. Recent studies have shown that irinotecan also undergoes oxidative metabolism by the P450 isozyme CYP3A4, leading to the formation of a minor inactive metabolite, 7-ethyl-10-[4-N-[(5-aminopentanoic acid)-1-piperidino]-carbonyloxy-camptothecin (APC). The elucidation of this metabolic pathway suggests the potential for drug interactions when irinotecan is administered with other inducers or substrates of CYP3A4. In this report, the authors summarize the pharmacokinetic profile of irinotecan and its major metabolites with and without concomitant phenytoin administration in an individual patient. These studies revealed that concomitant phenytoin administration resulted in a marked decrease in the systemic exposure to irinotecan and SN-38 and an increase in the exposure to APC. The area under the curve of irinotecan and SN-38 decreased by 63% and 60%, respectively; the area under the curve of APC increased by approximately 16%. Further detailed pharmacokinetic studies of irinotecan in patients receiving concomitant therapy with enzyme-inducing anticonvulsants are required so that rational dosing recommendations can be provided for this patient population.

Topics: Adolescent; Anticonvulsants; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Brain Neoplasms; Camptothecin; Carboplatin; Cisplatin; Combined Modality Therapy; Cranial Irradiation; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Dexamethasone; Disease Progression; Drug Interactions; Enzyme Induction; Etoposide; Hematopoietic Stem Cell Transplantation; Humans; Irinotecan; Male; Melphalan; Mixed Function Oxygenases; Neoplasm Recurrence, Local; Ondansetron; Phenobarbital; Phenytoin; Pineal Gland; Pinealoma; Prodrugs; Salvage Therapy; Seizures

We treated 49 patients with recurrent or poor-prognosis CNS malignancies with high-dose chemotherapy regimens followed by autologous marrow rescue with or without peripheral-blood stem-cell augmentation to determine the toxicity of and event-free survival after these regimens.. Nineteen patients had medulloblastomas, 12 had glial tumors, seven had pineoblastomas, five had ependymomas, three had primitive neuroectodermal tumors, two had germ cell tumors, and one had fibrosarcoma. Thirty-seven received chemotherapy with cyclophosphamide 1.5 g/m2 daily x 4 and melphalan 25 to 60 mg/m2 daily x 3. Nine received busulfan 37.5 mg/m2 every 6 hours x 16 and melphalan 180 mg/m2 (n = 7) or 140 mg/m2 (n = 2). Three received carboplatin 700 mg/m2/d on days -7, -5, and -3 and etoposide 500 mg/m2/d on days -6, -4, and -2. All patients received standard supportive care.. Eighteen of 49 patients survive event-free 22+ to 55+ months (median, 33+) after transplantation, including nine of 16 treated before recurrence and nine of 33 treated after recurrence. There was one transplant-related death from pulmonary aspergillosis. Of five patients assessable for disease response, one had a partial remission (2 months), one has had stable disease (55+ months), and three showed progression 2, 5, and 8 months after transplantation.. The toxicity of these regimens was tolerable. Certain patients with high-risk CNS malignancies may benefit from such a treatment approach. Subsequent trials should attempt to determine which patients are most likely to benefit from high-dose chemotherapy with autologous stem-cell rescue.

Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Brain Neoplasms; Busulfan; Child; Child, Preschool; Combined Modality Therapy; Cyclophosphamide; Ependymoma; Female; Fibrosarcoma; Glioblastoma; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Medulloblastoma; Melphalan; Neoplasm Recurrence, Local; Pinealoma; Transplantation, Autologous; Treatment Outcome

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.

Topics: Adolescent; Adult; Brain Neoplasms; Cerebellar Neoplasms; Child, Preschool; Drug Evaluation; Female; Humans; Infant; Medulloblastoma; Melphalan; Neoplasm Recurrence, Local; Pinealoma; Prognosis