The Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG) studies discussed in the Treatment Option Overview ¹ section of this summary, as well as other contemporary European studies,[1,2] suggest that a more refined risk-adapted therapy, based on stage and primary site, is possible for children with malignant extracranial germ cell tumors (Table 4 ²). The Children’s Oncology Group (COG) trial, AGCT0132 ³, is currently studying the effect of decreased chemotherapy for low and intermediate risk patients (see below.). The new classification schema proposed by the COG stratifies patients into three risk groups, as follows:

• Low-Risk: Patients with stage I immature teratomas and gonadal malignant germ cell tumors. Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[1,3-5] Strict guidelines for the evaluation and follow-up of these observation patients are mandated in the current COG study to ensure that disease recurrence or regrowth are detected early. Similar trials are ongoing in other international pediatric oncology groups.



• Intermediate-Risk: Patients with stages II, III, and IV gonadal tumors (excluding patients aged 15 years or older with stage IV testicular tumors and all stage IV ovarian tumors), and patients with stages I and II extragonadal tumors. These patients have an overall survival outcome greater than 90% with four to six courses of standard cisplatin, etoposide, and bleomycin (PEB), suggesting that a reduction in therapy could be considered.[6,7] The COG is investigating a modified standard PEB treatment (three PEB courses given over 3 days) for intermediate-risk patients, with the goal of decreasing the duration and cumulative doses of chemotherapy (25% dose reduction) and lessening the cost of treatment. Studies in adult males with good-risk germ cell cancer demonstrated equivalent outcome for patients treated with three or four cycles of PEB chemotherapy that was administered in 3 days versus 5 days.[8] Because of the decreased bleomycin dosing in pediatric PEB and the potential difference in clinical response of pediatric germ cell tumors to this decreased chemotherapy approach, the modified standard PEB treatment approach should be utilized in pediatric patients only in the context of the COG-controlled clinical trial. The outcome for these intermediate-risk patients is also excellent using four to six cycles of carboplatin, etoposide, and bleomycin (JEB).[1] A United Kingdom's Childhood Cancer Group (UKCCG) trial is also studying the reduction of total JEB cycles.



• High-Risk: Patients with advanced (stages III and IV) extragonadal tumors. For these patients, survival with the standard platinum-based regimens (PEB or JEB) is approximately 80%. The POG/CCG intergroup protocol showed that patients receiving high-dose PEB (HD-PEB) had better event-free survival (EFS) than patients receiving standard PEB,[7] though the incidence and severity of long-term toxicities in the HD-PEB group was significantly higher. A subsequent COG study explored the use of amifostine to diminish the platinum-related toxicity of HD-PEB. The preliminary results of this study, however, do not show any benefit from the addition of amifostine, and approximately 70% of the patients continue to develop severe hearing loss.[9] New strategies are needed for these patients. A completed COG study investigated the addition of cyclophosphamide to standard PEB. The results of this study are pending.

References

1. 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]
   
   
2. Baranzelli MC, Kramar A, Bouffet E, et al.: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17 (4): 1212, 1999.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.  [PUBMED Abstract]
   
   
5. 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]
   
   
6. 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]
   
   
7. 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]
   
   
8. 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]
   
   
9. Marina N, Malogolowkin M, London WB, et al.: Amifostine does not protect against the ototoxicity associated with high-dose cisplatin, etoposide and bleomycin (HD-PEB) in pediatric germ cell tumors (PGCT): A PGCT Intergroup Study. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-3208, 798, 2003.