The 5 year survival for patients with malignant intracranial non-germinoma germ cell tumors (NGGCT) which include endodermal sinus tumors, embryonal carcinomas, choriocarcinomas and immature teratomas is less than 25% following a small resection and radiotherapy. In an effort to improve the survival of these patients, an approach using an attempt at radical resection where feasible followed by multi-modality 'sandwich' therapy (chemotherapy-radiation-chemotherapy) was used to treat 18 newly diagnosed patients between 1986 and 1994 in a multi-institution study. Fourteen patients had histologically proven NGGCT and four were presumed NGGCT because of markedly elevated concentrations of serum and/or CSF alpha fetoprotoin (AFP) and/or beta human chorionic gonadatrophin (b-HCG). The primary tumor was confined to the pineal region in 12 patients, the suprasellar region in five, and a cerebral hemisphere in one. None of the patients had central nervous system metastases at diagnosis by MRI imaging of the spine and CSF cytology. Radical surgical resection was performed initially in 11 patients (gross total -6, subtotal -5): four had a biopsy and three had no surgery. All patients then received 3 or 4 cycles of neoadjuvant chemotherapy with cisplatin (100 mg/m2/cycle) and VP-16 (500 mg/m2/cycle). Of the 12 patients with evaluable disease there were 9 responses to the neoadjuvant chemotherapy (5 CR, 4 PR); 2 patients had stable disease and I progressed during chemotherapy. Six patients with no evaluable disease after a gross total resection had a continuous complete response. Seventeen patients received radiation therapy (involved field -11, involved field + craniospinal -4, involved field + whole brain -2). Twelve patients received 4 cycles post-radiation chemotherapy with vinblastine (6.5 mg/m2/cycle). bleomycin (15 U/m2/cycle), VP-16 (300 mg/m2/cycle, carboplatin (450 mg/m2/cycle). A total of four patients have died (3-progressive/recurrent disease, 1-metabolic). Four year actuarial event-free and total survival rates are 67% and 74%. This multi-modality adjuvant therapy approach appears to dramatically improve the outcome of malignant intracranial NGGCT.