Multimodality therapy for CNS mixed malignant germ cell tumors (MMGCT): results of a phase II multi-institutional study.

In order to improve outcomes for CNS mixed malignant germ cell tumors (MMGCT) we sought to increase complete responses (CR) to initial therapy, through intensifying neoadjuvant chemotherapy (CHT1) with added ifosfamide, encouraging second-look surgery, and administering dose-intensive, stem cell-supported chemotherapy (CHT2) to patients with residual tumor, all prior to radiation therapy (RT). Diagnosis was confirmed by biopsy or elevated germ cell tumor markers. After tumor staging was completed, patients received four cycles of chemotherapy (cisplatin, etoposide and ifosfamide, "CHT1"). In patients with <CR, second-look surgery was encouraged. Patients with residual tumor received two cycles of high dose, sub-ablative chemotherapy with carboplatin and cyclophosphamide ("CHT2") with peripheral stem cell support. All patients then received RT: for localized tumors with CR before RT, 36 gray (Gy) whole ventricular radiation therapy (WVRT) plus 50.4 Gy boost to primary; for disseminated tumors or < CR before RT, craniospinal irradiation (CSI) plus boosts to primary site(s) and bulky metastases. 26 patients (19 M0, 7 M+) were enrolled. The diagnosis was established by histology (20) or elevated markers (6). Objective responses to CHT1 were complete in 12/22 patients with evaluable disease and partial in 10; 8 additional tumors were rendered CR prior to RT (5 surgical CRs: 3 initial, 2 second-look; 3 CRs to CHT2). Thus, 20/26 patients (77%) were free of disease (CR) prior to RT. Six-year relapse-free survival was 63 ± 10%; overall survival was 68 ± 9%. Of 16 M0 patients who received only WVRT, four relapsed in the spine, outside the radiation field. The relatively high frequency (25%) of relapse outside the initial RT volume highlights the limitations of initial staging criteria and the curative potential of conventional and high dose chemotherapy. CSI remains the standard of care for CNS MMGCT, even for patients with localized disease.