ACNS2021 A Phase 2 Trial of Chemotherapy Followed by Response-Based Whole Ventricular & Spinal Canal Irradiation (WVSCI) for Patients with Localized Non-Germinomatous Central Nervous System Germ Cell Tumor

Non-germinomatous germ cell tumors (NGGCT) demonstrate a more aggressive histology, with increased risk of failure both locoregionally and in the spine compared with pure germinoma.1 They are less treatment sensitive and the 5-year survival with radiation alone is poor, ranging from 20% to 45%. The addition of chemotherapy to radiation therapy (RT) has resulted in markedly improved disease outcomes, and combined modality treatment is the standard of care. The Children’s Oncology Group (COG) ACNS0122 trial assessed the use of 6 cycles of Induction chemotherapy with CARBOplatin/etoposide alternating with ifosfamide/etoposide prior to 36 Gray (Gy) craniospinal irradiation (CSI) and 54 Gy to the primary tumor bed, with or without second-look surgery.2 Seventy-nine patients (76%) had localized tumors. Analyses revealed a 3-year event-free survival (EFS) and overall survival (OS) of 92% and 94.1%, respectively, for patients with localized disease who achieved a complete response (CR) or partial response (PR), with the majority of failures being local. The subsequent COG study, ACNS1123 Stratum 1, was developed for patients with localized NGGCT who responded well to Induction chemotherapy and were most appropriate for consideration of reduced-intensity RT.3 Patients on ACNS1123 received the same Induction chemotherapy regimen utilized on COG ACNS0122 and, if they achieved a CR or PR on imaging with normalization of tumor markers, they were eligible for reduced RT, defined as 30.6 Gy whole ventricular irradiation (WVI) and 54 Gy to the tumor bed. Overall, 66 of 107 patients with non-metastatic NGGCT (61.7%) achieved a CR/PR and proceeded to reduced RT, resulting in a 3-year progression free survival (PFS) and OS of 87.8% and 92.4%, respectively.3 While these early outcomes were promising, this study was closed, as it met early stopping rules when 10 patients were found to have relapsed. Though only 8 were found to be eligible for reduced-dose radiation, after careful review, the pattern of relapse was concerning as all relapses involved a spinal component. ACNS2021 is built on the backbone of the Induction chemotherapy used in ACNS0122 and ACNS1123, the excellent outcomes of ACNS0122, and the pattern of relapse seen in ACNS1123 (predominantly spine). As compared to ACNS1123, this study will add back spinal radiation in an attempt to reduce relapses in the spine. While the addition of spinal radiation may increase morbidity, modern radiation techniques are capable of minimizing radiation exposure to tissues anterior to the spinal canal. The greatest morbidity from CSI for most patients is whole brain radiation therapy (WBRT). This study will use WVI (as used in ACNS1123) rather than WBRT (as used in ACNS0122) with the intent of minimizing neurocognitive and other late effects of WBRT. Whole ventricle spinal canal irradiation (WVSCI) is a novel radiation volume. The reduced dose of 30.6 Gy for microscopic disease used in ACNS1123 will also be used in ACNS2021, as no relapses were seen in the ventricles on ACNS1123. ACNS2021 will differ from previous COG studies in that the trial will keep patients without a radiographic CR/PR and/or elevated markers on study and intensify treatment to improve treatment response and outcome of this high-risk group by 1) requiring second-look surgery for patients with < radiographic CR/PR and normalization of markers following Induction chemotherapy and 2) using High-Dose Chemotherapy with Peripheral Stem Cell Rescue (HDCSCR) for patients with persistent disease and/or elevated markers following Induction chemotherapy. HDCSCR has curative potential for both systemic and intracranial relapsed germ cell tumors and this study will further describe response in refractory disease.