Treatment Option Overview for Childhood Extracranial GCTs
Childhood extracranial germ cell tumors (GCTs) are very heterogenous. The benefits and limitations of therapy are related to differences in histology. For example, pediatric GCTs, such as mature and immature teratomas, may not respond to chemotherapy.
- Histology (e.g., seminomatous vs. nonseminomatous).
- Age (young children vs. adolescents).
- Stage of disease.
- Primary site of disease.
To maximize the likelihood of long-term survival while minimizing the likelihood of treatment-related long-term sequelae (e.g., secondary leukemias, infertility, hearing loss, and renal dysfunction), children with extracranial malignant GCTs need to be cared for at pediatric cancer centers with experience treating these rare tumors.
On the basis of clinical factors, appropriate treatment for extracranial GCTs may involve one of the following:
- Surgical resection followed by careful monitoring for disease recurrence.
- Initial surgical resection followed by platinum-based chemotherapy.
- Diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection.
For patients with completely resected immature teratomas at any location (even those with malignant elements) and patients with localized, completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close monitoring is important.[6,7] The watch-and-wait approach requires scheduled serial physical examination, tumor marker determination, and primary tumor imaging to ensure that a recurrent tumor is detected without delay.
Surgery is an essential component of treatment. Specific treatments will be discussed for each tumor type.
Germinomas (testicular and mediastinal seminomas in males and ovarian dysgerminomas in females) are sensitive to radiation, but radiation therapy is rarely recommended. With the advent of effective chemotherapy, it became possible for patients to avoid the toxic effects of radiation.
Before effective chemotherapy became available, children with extracranial malignant GCTs had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[8-10] although young boys with localized testicular tumors did well with surgical resection.[11,12] Cisplatin-based chemotherapy has significantly improved the outcome for most children and adolescents with extracranial GCTs; 5-year survival rates are now more than 90%.
The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin. Adult patients receive weekly bleomycin throughout treatment (bleomycin, etoposide, and cisplatin [BEP]). Pediatric patients do not receive bleomycin during the weeks between cycles (cisplatin, etoposide, and bleomycin [PEB]). (Refer to Table 5 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.)[1,2,13-15] The combination of carboplatin, etoposide, and bleomycin (JEB) underwent clinical investigation in the United Kingdom in children younger than 16 years and was reported to have an event-free survival (EFS) by site and stage similar to that of PEB.[3,16] The use of JEB appears to be associated with fewer otologic toxic effects and renal toxic effects than does the use of PEB. PEB and JEB have not been compared in a randomized pediatric GCT trial.
Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin, but the carboplatin regimens demonstrated inferior EFS and overall survival (OS) compared with cisplatin-containing therapy among patients with malignant GCTs. No randomized comparison of PEB versus JEB has been conducted in children.
Refer to Table 5 for adult BEP and pediatric PEB and JEB chemotherapy dosing schedules.
|BEP = bleomycin, etoposide, and cisplatin; GFR = glomerular filtration rate; JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.|
|aAdult doses of PEB and JEB chemotherapy are different from pediatric doses.|
|bThe adult BEP regimen is provided here for comparison only; BEP is not used in the treatment of children.|
|Adult BEP (every 21 days)b [15,18]||30 units/m2, days 1, 8, 15||100mg/m2, days 1–5||20 mg/m2, days 1–5|
|Pediatric PEB (every 21 days) [1,2]||15 units/m², day 1||100 mg/m², days 1–5||20 mg/m², days 1–5|
|Pediatric JEB (every 21–28 days) ||15 units/m², day 3||120 mg/m², days 1–3||600 mg/m² or GFR-based dosing, day 2|
The approach to the management of extracranial GCTs has been derived from the results of several intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[1,2,6] These studies explored the use of PEB for the treatment of localized gonadal GCT  and the benefit of increasing the dose of cisplatin (high-dose [HD]-PEB: 200 mg/m2 vs. PEB: 100 mg/m2 of cisplatin) in a randomized manner in patients with extragonadal and advanced gonadal GCTs. The intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS but no difference in OS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of otologic toxic effects and renal toxic effects. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.
Table 6 provides an overview of standard treatment options for children with extracranial GCTs. Specific details of treatment by primary site and clinical condition are described in subsequent sections.
|Histology||Standard Treatment Options|
|JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.|
|Mature teratoma (nonsacrococcygeal)||Surgery and observation|
|Immature teratoma (nonsacrococcygeal)||Surgery and observation (stage I)|
|Surgery and chemotherapy (stages II–IV) (refer to the Childhood Malignant Ovarian GCTs section of this summary for specific information about the treatment of ovarian immature teratoma)|
|Mature and immature teratomas (sacrococcygeal)||Surgery and observation|
|Malignant gonadal GCTs in children:|
|Childhood malignant testicular GCTs:|
|Malignant testicular GCTs in prepubertal males||Surgery and observation (stage I)|
|Surgery and chemotherapy (PEB) (stages II–IV)|
|Malignant testicular GCTs in postpubertal males||Refer to the PDQ summary on Testicular Cancer Treatment for more information.|
|Childhood malignant ovarian GCTs:|
|Dysgerminomas of the ovary||Surgery and observation (stage I)|
|Surgery and chemotherapy (PEB) (stages II–IV)|
|Malignant nongerminomatous ovarian GCTs (yolk sac and mixed GCTs)||Surgery and observation (stage I) (refer to the Childhood Malignant Ovarian GCTs section of this summary for specific information about the treatment of ovarian immature teratoma)|
|Surgery and chemotherapy (PEB) (stage I and stages II–IV)|
|Biopsy followed by chemotherapy (PEB) and surgery (initially unresectable tumors)|
|Malignant extragonadal extracranial GCTs in children||Surgery and chemotherapy (PEB)|
|Biopsy followed by chemotherapy (PEB) and possibly surgery|
|Recurrent malignant GCTs in children||Refer to the Treatment of Recurrent Malignant GCTs in Children section of this summary for more information.|
GCT With Non-GCT Elements
The treatment of GCTs with other non-GCT elements is complex and few data exist to direct treatment. In adolescents, central primitive neuroectodermal tumors and sarcomas have been found in teratomas.[20,21] The Italian Pediatric Germ Cell Tumor group identified 14 patients with malignant somatic tumors, such as neuroblastoma and rhabdomyosarcoma, imbedded in teratomas (<2% of extracranial GCTs). The optimal treatment strategy for GCT with non-GCT elements has not been determined, and separate treatments for both malignant GCT and non-GCT elements may be required.
- Rogers PC, Olson TA, Cullen JW, et al.: Treatment of children and adolescents with stage II testicular and stages I and II ovarian malignant germ cell tumors: A Pediatric Intergroup Study--Pediatric Oncology Group 9048 and Children's Cancer Group 8891. J Clin Oncol 22 (17): 3563-9, 2004. [PUBMED Abstract]
- Cushing B, Giller R, Cullen JW, et al.: Randomized comparison of combination chemotherapy with etoposide, bleomycin, and either high-dose or standard-dose cisplatin in children and adolescents with high-risk malignant germ cell tumors: a pediatric intergroup study--Pediatric Oncology Group 9049 and Children's Cancer Group 8882. J Clin Oncol 22 (13): 2691-700, 2004. [PUBMED Abstract]
- Mann JR, Raafat F, Robinson K, et al.: The United Kingdom Children's Cancer Study Group's second germ cell tumor study: carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors, with acceptable toxicity. J Clin Oncol 18 (22): 3809-18, 2000. [PUBMED Abstract]
- Göbel U, Schneider DT, Calaminus G, et al.: Multimodal treatment of malignant sacrococcygeal germ cell tumors: a prospective analysis of 66 patients of the German cooperative protocols MAKEI 83/86 and 89. J Clin Oncol 19 (7): 1943-50, 2001. [PUBMED Abstract]
- Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999. [PUBMED Abstract]
- Marina NM, Cushing B, Giller R, et al.: Complete surgical excision is effective treatment for children with immature teratomas with or without malignant elements: A Pediatric Oncology Group/Children's Cancer Group Intergroup Study. J Clin Oncol 17 (7): 2137-43, 1999. [PUBMED Abstract]
- Schlatter M, Rescorla F, Giller R, et al.: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group. J Pediatr Surg 38 (3): 319-24; discussion 319-24, 2003. [PUBMED Abstract]
- Kurman RJ, Norris HJ: Endodermal sinus tumor of the ovary: a clinical and pathologic analysis of 71 cases. Cancer 38 (6): 2404-19, 1976. [PUBMED Abstract]
- Chretien PB, Milam JD, Foote FW, et al.: Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region. Clinical and pathologic aspects of 21 cases. Cancer 26 (3): 522-35, 1970. [PUBMED Abstract]
- Billmire DF, Grosfeld JL: Teratomas in childhood: analysis of 142 cases. J Pediatr Surg 21 (6): 548-51, 1986. [PUBMED Abstract]
- Hawkins EP, Finegold MJ, Hawkins HK, et al.: Nongerminomatous malignant germ cell tumors in children. A review of 89 cases from the Pediatric Oncology Group, 1971-1984. Cancer 58 (12): 2579-84, 1986. [PUBMED Abstract]
- Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992. [PUBMED Abstract]
- de Wit R, Roberts JT, Wilkinson PM, et al.: Equivalence of three or four cycles of bleomycin, etoposide, and cisplatin chemotherapy and of a 3- or 5-day schedule in good-prognosis germ cell cancer: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council. J Clin Oncol 19 (6): 1629-40, 2001. [PUBMED Abstract]
- Gershenson DM, Morris M, Cangir A, et al.: Treatment of malignant germ cell tumors of the ovary with bleomycin, etoposide, and cisplatin. J Clin Oncol 8 (4): 715-20, 1990. [PUBMED Abstract]
- Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987. [PUBMED Abstract]
- Stern JW, Bunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol 39 (3): 163-7, 2002. [PUBMED Abstract]
- Horwich A, Sleijfer DT, Fosså SD, et al.: Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 15 (5): 1844-52, 1997. [PUBMED Abstract]
- Einhorn LH, Williams SD, Loehrer PJ, et al.: Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol. J Clin Oncol 7 (3): 387-91, 1989. [PUBMED Abstract]
- Marina N, Chang KW, Malogolowkin M, et al.: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children's Oncology Group study. Cancer 104 (4): 841-7, 2005. [PUBMED Abstract]
- Ehrlich Y, Beck SD, Ulbright TM, et al.: Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor. Ann Oncol 21 (9): 1846-50, 2010. [PUBMED Abstract]
- Rice KR, Magers MJ, Beck SD, et al.: Management of germ cell tumors with somatic type malignancy: pathological features, prognostic factors and survival outcomes. J Urol 192 (5): 1403-9, 2014. [PUBMED Abstract]
- Terenziani M, D'Angelo P, Bisogno G, et al.: Teratoma with a malignant somatic component in pediatric patients: the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) experience. Pediatr Blood Cancer 54 (4): 532-7, 2010. [PUBMED Abstract]