Neoadjuvant Chemotherapy Followed by Response-Based Radiation Therapy

Chemotherapy has been explored to reduce radiation therapy doses and associated neurodevelopmental morbidity. Several studies have confirmed the feasibility of this approach for maintaining excellent survival rates.[1-4][Level of evidence B4]; [5-8][Level of evidence C1]

Chemotherapy agents such as cyclophosphamide, ifosfamide, etoposide, cisplatin, and carboplatin are highly active in CNS germinomas. Managing patients receiving chemotherapy agents that require hyperhydration (e.g., cyclophosphamide, ifosfamide, and cisplatin) can be quite challenging because of the possibility of diabetes insipidus in patients with primary tumors of the suprasellar region.[9]

An international group of investigators explored a chemotherapy-only approach primarily for younger children. A complete response was achieved in 84% of patients with germinomas who were treated with chemotherapy alone. However, 50% of these patients suffered tumor relapse or progression. Many recurrences were local, local plus ventricular, and ventricular alone and/or with leptomeningeal dissemination throughout the CNS, which required additional therapy, including radiation.[10]

Subsequent studies have continued to support the need for radiation therapy after chemotherapy and the likely requirement for whole-ventricular irradiation (24 Gy) with local tumor site–boost radiation therapy (total dose, 40 Gy).[11][Level of evidence B4]; [12][Level of evidence C1] Excellent results have also been reported for patients with metastatic germinomas who received craniospinal irradiation of 24 Gy with local tumor site–boost radiation therapy (total dose, 40 Gy).[1][Level of evidence B4]; [13]

Optimal management of bifocal lesions is less clear, but most investigators consider this presentation a form of metachronous primary disease to be staged as M0. A meta-analysis of 60 patients demonstrated excellent progression-free survival after craniospinal irradiation alone. Chemotherapy plus localized radiation therapy, including whole-ventricular irradiation, also resulted in excellent disease control.[14][Level of evidence C2] For germinomas that arise outside of the pineal or suprasellar region, the effectiveness of therapy, as used for pineal and/or suprasellar lesions, is not well delineated. However, one retrospective review of 47 patients with basal ganglion and thalamic tumors reported progression-free survival (PFS) and overall survival (OS) rates that were similar to those reported in patients with tumors arising in more common areas of the brain.[15]

Results have been reported for the ACNS1123 (NCT01602666) phase II trial (stratum 2) that investigated response-based radiation therapy for localized germinomas. Patients were aged 3 to 21 years. Patients who had a complete response to carboplatin and etoposide chemotherapy received 18 Gy of whole-ventricle irradiation and a 12-Gy boost to the tumor bed. Patients who had a partial response to chemotherapy proceeded to receive 24 Gy of whole-ventricle irradiation and a 12-Gy boost to the tumor bed. Longitudinal cognitive functioning was evaluated prospectively. There were 137 eligible patients. Among 90 evaluable patients, 74 were treated with 18 Gy of radiation, and 16 were treated with 24 Gy of whole-ventricle irradiation.[16]

Other studies have supported this treatment approach, reporting excellent outcomes in children with CNS germinomas.[17,18]