Treatment of Newly Diagnosed Nongerminomatous Germ Cell Tumors
The prognosis for children with nongerminomatous germ cell tumors (NGGCTs) remains inferior in comparison to germinomas. While difficult to state definitively due to the small number of patients, it appears that patients with NGGCTs and higher elevations in tumor markers, particularly alpha-fetoprotein (AFP), have a worse prognosis.[1,2] With the current treatment regimens, the 10-year overall survival (OS) for NGGCTs is between 70% and 80%.[3,4] NGGCTs are radiosensitive; however, survival following standard craniospinal irradiation alone has been poor, ranging from 20% to 45% at 5 years. The majority of NGGCTs relapse within 18 months. OS rates can be stratified by histologic subtypes. Patients with pure choriocarcinoma, yolk sac tumor, or embryonal carcinoma appear to have the worst outcomes compared with patients with pure germinoma or teratoma mixed with other NGGCT elements. The addition of chemotherapy has been shown to improve OS rates. Effective agents include carboplatin, etoposide, bleomycin, ifosfamide, and vinblastine.[3,4] As with patients with germinoma, the administration of chemotherapy requiring hyperhydration can be complex when the patient has a comorbidity of diabetes insipidus.
The optimal treatment regimen for NGGCTs remains unclear. The addition of chemotherapy to radiation therapy has increased survival, but the specific chemotherapy regimen and length of therapy and the optimal radiation field, timing, and dose remain under investigation.[3,6,7] Some investigators have proposed radiation therapy fields that are smaller than craniospinal irradiation (e.g., focal or focal whole ventricular) for nondisseminated NGGCT patients. Results of these trials appear promising, although controversy exists over the pattern of relapse for patients treated with chemotherapy and focal radiation.[3,4,8,9]
Commonly, patients treated with chemotherapy may have normalization of tumor markers with a less than complete radiographic response. A second-look surgery can help determine if the residual mass contains teratoma or fibrosis versus residual NGGCT. Occasionally, the mass continues to expand in size even though tumor markers may have normalized; this may be due to the growing teratoma syndrome and not a failure to treat the NGGCT component.[10,11] In such circumstances, surgery is usually required for debulking and histologic confirmation.
High-dose chemotherapy with autologous stem cell rescue has shown promise as consolidation therapy for some high-risk germ cell tumors.Treatment Options Under Clinical Evaluation
The following is an example of a national and/or institutional clinical trial that is currently being conducted or is under analysis. Information about ongoing clinical trials is available from the NCI Web site.
- COG-ACNS1123 (Chemotherapy Followed by Radiation Therapy in Treating Younger Patients With Newly Diagnosed Localized Central Nervous System [CNS] GCTs): COG-ACNS1123 is a Children’s Oncology Group cooperative multi-institutional trial. This phase II trial of response-based radiation therapy for patients with localized CNS GCTs will compare the event-free survival and OS rates of a short course of chemotherapy followed by response-based whole-ventricular radiation with a boost to the primary site. For patients who obtain a complete response, the whole-ventricular radiation dose will be 25% lower than the standard whole-ventricular dose; the standard whole-ventricular dose will be used for patients who have less than a complete response after chemotherapy with or without second-look surgery.
- Kim A, Ji L, Balmaceda C, et al.: The prognostic value of tumor markers in newly diagnosed patients with primary central nervous system germ cell tumors. Pediatr Blood Cancer 51 (6): 768-73, 2008. [PUBMED Abstract]
- Lee D, Suh YL: Histologically confirmed intracranial germ cell tumors; an analysis of 62 patients in a single institute. Virchows Arch 457 (3): 347-57, 2010. [PUBMED Abstract]
- Robertson PL, DaRosso RC, Allen JC: Improved prognosis of intracranial non-germinoma germ cell tumors with multimodality therapy. J Neurooncol 32 (1): 71-80, 1997. [PUBMED Abstract]
- Baranzelli M, Patte C, Bouffet E, et al.: Carboplatin-based chemotherapy (CT) and focal irradiation (RT) in primary germ cell tumors (GCT): A French Society of Pediatric Oncology (SFOP) experience (meeting abstract). [Abstract] Proceedings of the American Society of Clinical Oncology 18: A-538, 140A, 1999.
- Afzal S, Wherrett D, Bartels U, et al.: Challenges in management of patients with intracranial germ cell tumor and diabetes insipidus treated with cisplatin and/or ifosfamide based chemotherapy. J Neurooncol 97 (3): 393-9, 2010. [PUBMED Abstract]
- Matsutani M; Japanese Pediatric Brain Tumor Study Group: Combined chemotherapy and radiation therapy for CNS germ cell tumors--the Japanese experience. J Neurooncol 54 (3): 311-6, 2001. [PUBMED Abstract]
- Calaminus G, Bamberg M, Jürgens H, et al.: Impact of surgery, chemotherapy and irradiation on long term outcome of intracranial malignant non-germinomatous germ cell tumors: results of the German Cooperative Trial MAKEI 89. Klin Padiatr 216 (3): 141-9, 2004 May-Jun. [PUBMED Abstract]
- Aoyama H, Shirato H, Ikeda J, et al.: Induction chemotherapy followed by low-dose involved-field radiotherapy for intracranial germ cell tumors. J Clin Oncol 20 (3): 857-65, 2002. [PUBMED Abstract]
- Kim JW, Kim WC, Cho JH, et al.: A multimodal approach including craniospinal irradiation improves the treatment outcome of high-risk intracranial nongerminomatous germ cell tumors. Int J Radiat Oncol Biol Phys 84 (3): 625-31, 2012. [PUBMED Abstract]
- Yagi K, Kageji T, Nagahiro S, et al.: Growing teratoma syndrome in a patient with a non-germinomatous germ cell tumor in the neurohypophysis--case report. Neurol Med Chir (Tokyo) 44 (1): 33-7, 2004. [PUBMED Abstract]
- Kim CY, Choi JW, Lee JY, et al.: Intracranial growing teratoma syndrome: clinical characteristics and treatment strategy. J Neurooncol 101 (1): 109-15, 2011. [PUBMED Abstract]
- Motzer RJ, Mazumdar M, Bajorin DF, et al.: High-dose carboplatin, etoposide, and cyclophosphamide with autologous bone marrow transplantation in first-line therapy for patients with poor-risk germ cell tumors. J Clin Oncol 15 (7): 2546-52, 1997. [PUBMED Abstract]