Current Clinical Trials

Prior to effective chemotherapy, children with extracranial malignant germ cell tumors had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[1-3] though boys with localized testicular tumors did well with surgical resection.[4,5] Cisplatin-based chemotherapy has dramatically improved the outcome for these children, with 5-year survival rates increasing to 75% and more than 90%.[6-9] The standard chemotherapy regimen for both adults and children with malignant nonseminomatous germ cell tumors includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults.[6,7,10-12] The combination of carboplatin, etoposide, and bleomycin (JEB) has undergone clinical investigation in the United Kingdom in children younger than 16 years and is reported to have a similar event-free survival (EFS) by site and stage as PEB;[8,13] however, these were not randomized trials. The use of JEB appears to be associated with less ototoxicity and nephrotoxicity than PEB.[8] Adult studies have substituted standard-dose carboplatin for cisplatin in combination with etoposide alone and in combination with etoposide and low-dose bleomycin,[14] but the carboplatin regimens demonstrated inferior EFS and overall survival compared with cisplatin-containing therapy among patients with malignant germ cell tumors. No randomized comparison of PEB versus JEB has been conducted in children.  [Note: See Table 2 for pediatric PEB and JEB chemotherapy dosing schedules.]

 [Note: Adult doses of PEB and JEB chemotherapy are different than pediatric doses.]

The outcome for most children and adolescents with extracranial germ cell tumors is now favorable when appropriate treatment is provided.[15] Prognosis and appropriate treatment depend on factors such as histology (e.g., seminomatous vs. nonseminomatous), age (young children vs. adolescents), stage of disease, and primary site.[16,17] 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, renal dysfunction), it is important that children with extracranial malignant germ cell tumors be cared for at pediatric cancer centers with experience treating these rare tumors. Based on clinical factors, appropriate treatment may involve: surgical resection followed by careful monitoring for disease recurrence; diagnostic tumor biopsy and preoperative platinum-based chemotherapy followed by definitive tumor resection; or initial surgical resection followed by a platinum-based chemotherapy.[18] The current approach to the management of extracranial germ cell tumors has been informed by the results of two recent intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[6,7,19] These studies explored the use of PEB for the treatment of localized gonadal germ cell tumors [6] 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 germ cell tumors.[7]

For patients with completely resected immature teratomas at any location (even those with malignant elements) or patients with completely resected (stage I) gonadal tumors, additional therapy may not be necessary; however, close follow-up is important.[19] 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. For patients with stage II gonadal tumors, treatment with PEB results in survival rates greater than 94%. The survival rates for patients with advanced gonadal tumors (stages III and IV) were also greater than 90% using standard PEB, and higher doses of platinum (HD-PEB) did not add any significant benefit. The subgroup of patients older than 15 years with metastatic testicular tumors, however, had a worse outcome (survival <85%). For patients with extragonadal tumors, loco-regional disease (stage I and stage II) was associated with very good outcome with standard PEB (survival of 93%), whereas patients with stages III and IV had survival rates of approximately 80%. For patients with advanced extragonadal tumors, the intensification of cisplatin in the HD-PEB regimen provided some improvement in EFS; however, the use of HD-PEB was associated with a significantly higher incidence and severity of ototoxicity and nephrotoxicity. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.[20]

The discussion of treatment options below focuses on the extracranial germ cell tumors of children. (Refer to the PDQ summaries on Ovarian Germ Cell Tumor Treatment and Testicular Cancer Treatment for more information.) Specific details of treatment by primary site and clinical condition are given below. Table 3 provides an overview of standard treatment options.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with childhood extracranial germ cell tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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9. 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]
   
   
10. 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]
    
    
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