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Childhood Extracranial Germ Cell Tumors Treatment (PDQ®)

Health Professional Version
Last Modified: 06/06/2014

Treatment of Malignant Gonadal GCTs in Children

Childhood Malignant Testicular GCTs
        Malignant testicular GCTs in prepubertal males
        Malignant testicular GCTs in postpubertal males
        Current Clinical Trials
Childhood Malignant Ovarian GCTs
        Dysgerminomas of the ovary
        Malignant nongerminomatous ovarian GCTs
        Current Clinical Trials



Childhood Malignant Testicular GCTs

Malignant testicular GCTs in prepubertal males

Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial surgical approach to evaluate a testicular mass in a young boy is important because a transscrotal biopsy can risk inguinal node metastasis.[3,4] Radical inguinal orchiectomy with initial high ligation of the spermatic cord is the procedure of choice.[5]

Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging. Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) associated with lymph node dissection.[6,7]

The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. All malignant testicular GCTs should be resected. Primary resection of other areas of disease may be appropriate when feasible, without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is resection of the testis for diagnosis followed by subsequent excision in selected patients who have residual masses after undergoing chemotherapy.

Standard treatment options for malignant GCTs in prepubertal males

Standard treatment options for malignant GCTs in prepubertal males (younger than 15 years) include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II through IV).

The treatment options for malignant GCTs in prepubertal males differ by stage of disease.

Stage I

Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[8,3]

Evidence (surgery and observation for stage I disease):

  1. A Children’s Cancer Group (CCG)/Pediatric Oncology Group (POG) clinical trial evaluated surgery followed by observation for boys aged 10 years or younger with stage I testicular tumors.[3,4]
    • This treatment strategy resulted in a 6-year event-free survival (EFS) of 82%.

    • Boys who developed recurrent disease received salvage therapy with four cycles of standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.

Stages II through IV

Surgery and chemotherapy with four cycles of standard PEB is a common treatment regimen. Patients treated with this regimen have an overall survival (OS) outcome greater than 90%, suggesting that a reduction in therapy could be considered.[9,10]

Surgery and treatment with four to six cycles of carboplatin, etoposide, and bleomycin (JEB) is an alternative treatment regimen.[8]

Evidence (surgery and chemotherapy for stages II–IV disease):

  1. A CCG/POG clinical trial evaluated boys younger than 10 years with stage II tumors who were treated with four cycles of PEB after diagnosis.[9]
    • The 6-year EFS and OS rates were 100%.

  2. In the same CCG/POG clinical trial, boys and adolescents (age not limited to 10 years or younger) with stage III and stage IV testicular tumors were treated with surgical resection followed by four cycles of standard-dose or high-dose (HD)–PEB therapy.[10]
    • The 6-year survival outcome for males younger than 15 years with stage III and stage IV tumors was 100%.

    • The 6-year EFS for males younger than 15 years was 100% for stage III tumors and 94% for stage IV tumors.

    • The use of HD-PEB therapy did not improve the outcome for these boys but did cause increased incidence of otologic toxic effects.

  3. Excellent outcomes for boys with testicular GCTs using surgery and observation for stage I tumors and JEB and other cisplatin-containing chemotherapy regimens for stage II, stage III, and stage IV tumors have also been reported by European investigators.[6,8]

Malignant testicular GCTs in postpubertal males

The treatment options described above for young boys may not be strictly applicable to adolescent males (aged 15 years and older). In particular, the use of retroperitoneal lymph node dissection may play a crucial role in the evaluation of early-stage testicular GCT [11] and for residual disease after chemotherapy for the treatment of metastatic GCT.[12,13]

In this age group, the presence of a sarcomatous component in the primary testis GCT does not alter the prognosis; however, if a sarcomatous component is found in a metastatic lesion, survival is likely to be compromised.[14]

Standard treatment options for malignant testicular GCTs in postpubertal males

Refer to the PDQ summary on Testicular Cancer Treatment for more information about the treatment of malignant testicular GCTs in postpubertal males.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant testicular 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.

Childhood Malignant Ovarian GCTs

Most ovarian neoplasms in children and adolescents are of germ cell origin.[1] Ovarian GCTs are very rare in young girls, but the incidence begins to increase in children aged approximately 8 or 9 years and continues to rise throughout adulthood.[1]

Childhood malignant ovarian GCTs can be divided into germinomatous (dysgerminomas) and nongerminomatous malignant GCTs (i.e., yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas).

(Refer to the Mature Teratomas [Nonsacrococcygeal Sites] section of this summary for more information about childhood mature and immature teratomas arising in the ovary and the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information on the treatment of ovarian GCT in postpubertal females.)

Dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary

Standard treatment options for dysgerminomas of the ovary include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stages II through IV).

The treatment options for dysgerminomas of the ovary differ by stage of disease.

Stage I

For stage I ovarian dysgerminomas of the ovary, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[8,15-18]

Chemotherapy may be given if tumor markers do not normalize or if tumors recur.

Stages II through IV

While advanced-stage ovarian dysgerminomas, like testicular seminomas, are highly curable with surgery and radiation therapy, the effects on growth, fertility, and risk of treatment-induced second malignancy in these young patients [19,20] make chemotherapy a more attractive adjunct to surgery.[21,22] Complete tumor resection is the goal for advanced dysgerminomas; platinum-based chemotherapy can be given preoperatively to facilitate resection or postoperatively (after debulking surgery) to avoid mutilating surgical procedures.[18] This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with dysgerminomas.[21,23]

Malignant nongerminomatous ovarian GCTs

A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialists and the pediatric oncologist must be involved in clinical decisions. The reproductive surgical approach for pediatric GCTs is often guided by the hope that function can be preserved.

Standard treatment options for malignant nongerminomatous ovarian GCTs

Standard treatment options for malignant nongerminomatous ovarian GCTs include the following:

  1. Surgery and observation (stage I).
  2. Surgery and chemotherapy (stage I and stages II through IV).
  3. Biopsy followed by chemotherapy and surgery (initially unresectable tumors).

The treatment of ovarian malignant GCTs that are not dysgerminomas or immature teratomas generally involves surgical resection and adjuvant chemotherapy.[24,25]

The role for surgery at diagnosis is age- and site-dependent and must be individualized. The use of laparoscopy in children with ovarian GCTs has not been well studied.

Pediatric surgical guidelines to determine stage I disease have been published.[26] Adult surgical guidelines to determine stage are more extensive. (Refer to the Stage Information for Ovarian Germ Cell Tumors section of the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information about staging of ovarian GCTs in postpubertal females.) Strict surgical staging guidelines need to be followed to determine true stage I disease. Historically, in both pediatric and adult studies, comprehensive staging guidelines have not been followed. If strict surgical staging guidelines are not followed, surgery followed by chemotherapy, rather than surgery followed by observation, is the standard treatment.[8,27] If conservative surgery is the choice, a high rate of cure can be obtained with adjuvant chemotherapy, and adherence to strict surgical guidelines is not necessary.[28]

Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children.[8-10,15] BEP is a common regimen in young women with ovarian GCTs.[29,30] BEP differs from PEB with the addition of weekly bleomycin. This approach results in a high rate of cure and the preservation of menstrual function and fertility in most patients with nondysgerminomas.[25,27] (Refer to Table 4 for more information about the dosing schedules for BEP, PEB, and JEB.)

Stage I

When strict surgical staging guidelines are followed, surgery followed by observation may be an appropriate treatment choice.

Evidence (surgery and observation for stage I disease):

  1. In a Children's Oncology Group (COG) trial, 25 girls with stage I ovarian malignant GCTs were treated with surgery and observation.[26]
    • The 4-year EFS was 52%.

    • Relapse was detected in 12 patients by tumor marker elevation (mean time, 2 months). Eleven patients later underwent salvage therapy with three cycles of PEB. The 4-year OS was 96%.

Similar results have been reported in other international pediatric trials, but the number of patients has been small.[8]

When strict surgical staging guidelines are not followed, surgery followed by chemotherapy is an appropriate treatment choice. Chemotherapy consists of four cycles of PEB.[9,10]

Evidence (surgery and chemotherapy for stage I disease):

  1. A pediatric intergroup trial studied patients with ovarian GCTs (stages I–IV). [9,28]
    • For stage I ovarian cancer, the EFS and OS rates were both 95.1%.

  2. In a previous U.S. intergroup trial where there was incomplete adherence to surgical staging guidelines, all reported stage I patients were given adjuvant chemotherapy and survived.[8,27] Patients had excellent survival with four cycles of PEB and conservative surgery.

Stages II through IV

Surgery and chemotherapy with four to six cycles of standard PEB in younger girls [9,10] and BEP in postpubertal girls are considered standard treatments.[29,30] Patients with normalization of tumor markers are imaged after four cycles of PEB, and any residual tumor is removed. If the tumor is completely resected but the specimen contains viable tumor, two additional cycles of PEB can be given.[10] Any persistent viable tumor that remains indicates that the treatment has failed.

Alternatively, surgery and chemotherapy with four to six cycles of JEB (patients were all younger than 15 years) is also a treatment option.[8]

Initially unresectable tumor

Primary resection of ovarian GCT is usually attempted. In rare instances where primary resection of the ovary is not possible without undue risk of damage to adjacent structures, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in patients who have residual masses after undergoing chemotherapy.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood malignant ovarian 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
  1. Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649. Also available online. Last accessed October 24, 2014. 

  2. Walsh TJ, Grady RW, Porter MP, et al.: Incidence of testicular germ cell cancers in U.S. children: SEER program experience 1973 to 2000. Urology 68 (2): 402-5; discussion 405, 2006.  [PUBMED Abstract]

  3. 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]

  4. Canning DA: Excellent outcome in patients with stage I germ cell tumors of the testes: a study of the Children's Cancer Group/Pediatric Oncology Group [Editorial Comment on Schlatter]. J Urol 174 (1): 310, 2005. 

  5. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.  [PUBMED Abstract]

  6. Haas RJ, Schmidt P, Göbel U, et al.: Treatment of malignant testicular tumors in childhood: results of the German National Study 1982-1992. Med Pediatr Oncol 23 (5): 400-5, 1994.  [PUBMED Abstract]

  7. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.  [PUBMED Abstract]

  8. 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]

  9. 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]

  10. 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]

  11. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006.  [PUBMED Abstract]

  12. Carver BS, Shayegan B, Serio A, et al.: Long-term clinical outcome after postchemotherapy retroperitoneal lymph node dissection in men with residual teratoma. J Clin Oncol 25 (9): 1033-7, 2007.  [PUBMED Abstract]

  13. Carver BS, Shayegan B, Eggener S, et al.: Incidence of metastatic nonseminomatous germ cell tumor outside the boundaries of a modified postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol 25 (28): 4365-9, 2007.  [PUBMED Abstract]

  14. Guo CC, Punar M, Contreras AL, et al.: Testicular germ cell tumors with sarcomatous components: an analysis of 33 cases. Am J Surg Pathol 33 (8): 1173-8, 2009.  [PUBMED Abstract]

  15. 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]

  16. Dark GG, Bower M, Newlands ES, et al.: Surveillance policy for stage I ovarian germ cell tumors. J Clin Oncol 15 (2): 620-4, 1997.  [PUBMED Abstract]

  17. 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]

  18. Gershenson DM: Chemotherapy of ovarian germ cell tumors and sex cord stromal tumors. Semin Surg Oncol 10 (4): 290-8, 1994 Jul-Aug.  [PUBMED Abstract]

  19. Teinturier C, Gelez J, Flamant F, et al.: Pure dysgerminoma of the ovary in childhood: treatment results and sequelae. Med Pediatr Oncol 23 (1): 1-7, 1994.  [PUBMED Abstract]

  20. Mitchell MF, Gershenson DM, Soeters RP, et al.: The long-term effects of radiation therapy on patients with ovarian dysgerminoma. Cancer 67 (4): 1084-90, 1991.  [PUBMED Abstract]

  21. Brewer M, Gershenson DM, Herzog CE, et al.: Outcome and reproductive function after chemotherapy for ovarian dysgerminoma. J Clin Oncol 17 (9): 2670-75, 1999.  [PUBMED Abstract]

  22. Williams SD, Blessing JA, Hatch KD, et al.: Chemotherapy of advanced dysgerminoma: trials of the Gynecologic Oncology Group. J Clin Oncol 9 (11): 1950-5, 1991.  [PUBMED Abstract]

  23. Gershenson DM: Menstrual and reproductive function after treatment with combination chemotherapy for malignant ovarian germ cell tumors. J Clin Oncol 6 (2): 270-5, 1988.  [PUBMED Abstract]

  24. 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]

  25. Mitchell PL, Al-Nasiri N, A'Hern R, et al.: Treatment of nondysgerminomatous ovarian germ cell tumors: an analysis of 69 cases. Cancer 85 (10): 2232-44, 1999.  [PUBMED Abstract]

  26. Billmire DF, Cullen JW, Rescorla FJ, et al.: Surveillance after initial surgery for pediatric and adolescent girls with stage I ovarian germ cell tumors: report from the Children's Oncology Group. J Clin Oncol 32 (5): 465-70, 2014.  [PUBMED Abstract]

  27. Palenzuela G, Martin E, Meunier A, et al.: Comprehensive staging allows for excellent outcome in patients with localized malignant germ cell tumor of the ovary. Ann Surg 248 (5): 836-41, 2008.  [PUBMED Abstract]

  28. Billmire D, Vinocur C, Rescorla F, et al.: Outcome and staging evaluation in malignant germ cell tumors of the ovary in children and adolescents: an intergroup study. J Pediatr Surg 39 (3): 424-9; discussion 424-9, 2004.  [PUBMED Abstract]

  29. Williams SD: Ovarian germ cell tumors: an update. Semin Oncol 25 (3): 407-13, 1998.  [PUBMED Abstract]

  30. Williams S, Blessing JA, Liao SY, et al.: Adjuvant therapy of ovarian germ cell tumors with cisplatin, etoposide, and bleomycin: a trial of the Gynecologic Oncology Group. J Clin Oncol 12 (4): 701-6, 1994.  [PUBMED Abstract]