Treatment of Childhood Malignant Extragonadal GCTs
Extragonadal germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than adults. Children with extragonadal malignant GCTs, particularly those with advanced stage, have the highest risk of treatment failure for any GCT presentation.[2,3] In a study of prognostic factors in pediatric extragonadal malignant GCTs, age older than 12 years was the most important prognostic factor. In a multivariate analysis, children aged 12 years or older with thoracic tumors had six times the risk of death compared with children younger than 12 years with primary nonthoracic tumors. Outcome has improved remarkably, however, since the advent of platinum-based chemotherapy and the use of a multidisciplinary treatment approach.[2,5] Complete resection prior to chemotherapy may be possible in some patients without major morbidity, but for patients with locally advanced sacrococcygeal tumors, mediastinal tumors, or large pelvic tumors, tumor biopsy followed by preoperative chemotherapy can facilitate subsequent complete tumor resection and improve ultimate patient outcome.[5-8]
Sacrococcygeal GCTs are very common extragonadal tumors that occur in very young children, predominately young females. They are usually diagnosed at birth, when large external lesions predominate (usually benign or immature teratomas), or later in the first years of life, when presacral lesions with higher malignancy rates predominate. Malignant sacrococcygeal tumors are usually very advanced at diagnosis; two-thirds of patients have locoregional disease and metastases are present in 50% of the patients.[7,10,11] Because of advanced presentation, the management of sacrococcygeal tumors requires a multimodal approach with chemotherapy followed by delayed tumor resection. Platinum-based therapies, with either cisplatin or carboplatin, are the cornerstone of treatment. The cisplatin, etoposide, and bleomycin (PEB) regimen or the carboplatin, etoposide, and bleomycin (JEB) regimen produces event-free survival (EFS) rates of 75% to 85%; overall survival (OS) rates of 80% to 90% can be achieved.[7,8] Surgery is usually facilitated by preoperative chemotherapy, and completeness of surgical resection is a very important prognostic factor. Patients with resected tumors with negative microscopic margins have EFS rates greater than 90%; patients with microscopic margins have EFS rates of 75% to 85%; and patients with macroscopic residual disease after surgery have EFS rates less than 40%. In any patient with a sacrococcygeal GCT, resection of the coccyx is mandatory.[7,8]
Mediastinal GCTs account for 15% to 20% of malignant nongonadal, extracranial GCTs in children. The histology of mediastinal GCT is dependent on age, with teratomas predominating among infants and with yolk sac tumor histology predominating among children aged 1 to 4 years. Children with mediastinal teratomas are treated with tumor resection, which is curative in almost all patients. Children with malignant, nonmetastatic mediastinal GCTs who receive cisplatin-based chemotherapy have 5-year EFS and OS rates of 90%, but an EFS closer to 70% occurs with metastatic mediastinal tumors.[5,6] Most mediastinal GCTs in adolescents and young adults occur in males and 50% have cytogenetic changes consistent with Klinefelter syndrome. The age of presentation is younger in patients with Klinefelter syndrome.[12,13] As with sacrococcygeal tumors, primary chemotherapy is usually necessary to facilitate surgical resection of mediastinal GCTs, and the completeness of resection is a very important prognostic indicator.[6,14] Survival rates for the older adolescent and young adult population with mediastinal tumors are generally less than 60%.[4,15-17]; Level of evidence: 3iiA Patients with a malignant mediastinal primary tumor and extracranial metastases are at the highest risk of developing brain metastases and are followed closely for signs and symptoms of central nervous system involvement.[Level of evidence: 3iiB] (Refer to the PDQ summary on Extragonadal Germ Cell Tumors Treatment for more information.)
Malignant GCTs located in the retroperitoneum or abdomen usually present in children before age 5 years; most tumors are of advanced stage and locally unresectable at diagnosis. A limited biopsy followed by platinum-based chemotherapy to shrink tumor bulk can lead to complete tumor resection in most patients. Despite advanced-stage disease in most patients, the 6-year EFS using PEB was 83% in the Pediatric Oncology Group/Children's Cancer Group intergroup study.
Though rare, benign and malignant GCTs can occur in the head and neck region, especially in infants. Often the airway is threatened. Surgery for nonmalignant tumors plus chemotherapy for malignant tumors can be curative.[Level of evidence: 3iiiDii]Standard Treatment Options
Surgery: The role for surgery at diagnosis for extragonadal tumors is age- and site-dependent and must be individualized. Depending on the clinical setting, the appropriate surgical approach may range from no surgery (e.g., mediastinal primary tumor in a patient with a compromised airway and elevated tumor markers), to biopsy, to primary resection. In some cases, an appropriate strategy is biopsy at diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.
Stages I and II
- Surgery and treatment with four to six cycles of standard PEB. These patients have an OS outcome greater than 90% with this regimen, suggesting that a reduction in therapy could be considered.[2,22]
- Surgery and treatment with six cycles of JEB.
Stages III and IV
- Surgery and treatment with four to six cycles of standard PEB. These patients have an OS outcome approaching 80% with this regimen.
- Surgery and treatment with six cycles of JEB yield similar OS.
The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.
- A completed COG trial investigated the addition of cyclophosphamide to standard-dose PEB. The results of this study are pending.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood extragonadal 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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- 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]
- 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]
- Marina N, London WB, Frazier AL, et al.: Prognostic factors in children with extragonadal malignant germ cell tumors: a pediatric intergroup study. J Clin Oncol 24 (16): 2544-8, 2006. [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]
- Schneider DT, Calaminus G, Reinhard H, et al.: Primary mediastinal germ cell tumors in children and adolescents: results of the German cooperative protocols MAKEI 83/86, 89, and 96. J Clin Oncol 18 (4): 832-9, 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 F, Billmire D, Stolar C, et al.: The effect of cisplatin dose and surgical resection in children with malignant germ cell tumors at the sacrococcygeal region: a pediatric intergroup trial (POG 9049/CCG 8882). J Pediatr Surg 36 (1): 12-7, 2001. [PUBMED Abstract]
- Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974. [PUBMED Abstract]
- Rescorla FJ, Sawin RS, Coran AG, et al.: Long-term outcome for infants and children with sacrococcygeal teratoma: a report from the Childrens Cancer Group. J Pediatr Surg 33 (2): 171-6, 1998. [PUBMED Abstract]
- Calaminus G, Schneider DT, Bökkerink JP, et al.: Prognostic value of tumor size, metastases, extension into bone, and increased tumor marker in children with malignant sacrococcygeal germ cell tumors: a prospective evaluation of 71 patients treated in the German cooperative protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89. J Clin Oncol 21 (5): 781-6, 2003. [PUBMED Abstract]
- Nichols CR, Heerema NA, Palmer C, et al.: Klinefelter's syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 5 (8): 1290-4, 1987. [PUBMED Abstract]
- Schneider DT, Schuster AE, Fritsch MK, et al.: Genetic analysis of mediastinal nonseminomatous germ cell tumors in children and adolescents. Genes Chromosomes Cancer 34 (1): 115-25, 2002. [PUBMED Abstract]
- Billmire D, Vinocur C, Rescorla F, et al.: Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg 36 (1): 18-24, 2001. [PUBMED Abstract]
- Vuky J, Bains M, Bacik J, et al.: Role of postchemotherapy adjunctive surgery in the management of patients with nonseminoma arising from the mediastinum. J Clin Oncol 19 (3): 682-8, 2001. [PUBMED Abstract]
- Ganjoo KN, Rieger KM, Kesler KA, et al.: Results of modern therapy for patients with mediastinal nonseminomatous germ cell tumors. Cancer 88 (5): 1051-6, 2000. [PUBMED Abstract]
- Bokemeyer C, Nichols CR, Droz JP, et al.: Extragonadal germ cell tumors of the mediastinum and retroperitoneum: results from an international analysis. J Clin Oncol 20 (7): 1864-73, 2002. [PUBMED Abstract]
- Kang CH, Kim YT, Jheon SH, et al.: Surgical treatment of malignant mediastinal nonseminomatous germ cell tumor. Ann Thorac Surg 85 (2): 379-84, 2008. [PUBMED Abstract]
- Göbel U, von Kries R, Teske C, et al.: Brain metastases during follow-up of children and adolescents with extracranial malignant germ cell tumors: risk adapted management decision tree analysis based on data of the MAHO/MAKEI-registry. Pediatr Blood Cancer 60 (2): 217-23, 2013. [PUBMED Abstract]
- Billmire D, Vinocur C, Rescorla F, et al.: Malignant retroperitoneal and abdominal germ cell tumors: an intergroup study. J Pediatr Surg 38 (3): 315-8; discussion 315-8, 2003. [PUBMED Abstract]
- Bernbeck B, Schneider DT, Bernbeck B, et al.: Germ cell tumors of the head and neck: report from the MAKEI Study Group. Pediatr Blood Cancer 52 (2): 223-6, 2009. [PUBMED Abstract]
- 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]