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Treatment Background for Childhood Extracranial GCTs

Prior to effective chemotherapy, children with extracranial malignant germ cell tumors (GCTs) had 3-year survival rates of 15% to 20% with surgery and radiation therapy,[1,2,3] though young boys with localized testicular tumors did well with surgical resection.[4,5] The outcome for most children and adolescents with extracranial GCT is now favorable when appropriate treatment is provided. 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.[6,7,8,9] 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), it is important that children with extracranial malignant GCTs 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 platinum-based chemotherapy.[10] 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 follow-up is important.[11,12] 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.

Cisplatin-based chemotherapy has dramatically improved the outcome for children with extracranial GCTs, with 5-year survival rates of more than 90%.[6,7,8,9] The standard chemotherapy regimen for both adults and children with malignant nonseminomatous GCTs includes cisplatin, etoposide, and bleomycin (PEB), though children receive fewer doses of bleomycin than adults.[6,7,13,14] 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.[8,15] 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,[16] 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. See Table 4 for pediatric PEB and JEB chemotherapy dosing schedules.

The approach to the management of extracranial GCTs has been informed by the results of two intergroup studies conducted by the Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG).[6,7,11] These studies explored the use of PEB for the treatment of localized gonadal GCT [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 GCTs.[7]

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 ototoxicity and nephrotoxicity. In a subsequent study, amifostine was not effective in preventing hearing loss in patients who received HD-PEB.[17]

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