My Sanford Chart allows you secure online access to your personal health information and your child's health information. It's available anywhere you have internet access. There is no cost to you and registering is quick and simple.

Sign Up for My Sanford Chart

Childhood Extracranial Germ Cell Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

Childhood Extracranial Germ Cell Tumors Treatment

General Information About Childhood Extracranial Germ Cell Tumors (GCTs)

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[1] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation therapists, pediatric oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. Specific information about supportive care for children and adolescents with cancer can be found in the PDQ Supportive and Palliative Care summaries.

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[2] At these pediatric cancer centers, clinical trials are available for most of the types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. The majority of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2002, childhood cancer mortality decreased by more than 50%. For gonadal extracranial germ cell tumor (GCT), the 5-year survival rate has increased over the same time from 89% to 98% for children younger than 15 years and from 70% to 95% for adolescents aged 15 to 19 years. For extragonadal GCT, the 5-year survival rate from 1979 to 2002 increased from 42% to 83% for children younger than 15 years.[1] Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Childhood GCTs are rare in children younger than 15 years, accounting for approximately 3% of cancer cases in this age group.[3,4,5] In the fetal/neonatal age group, the majority of extracranial GCTs that occur are benign teratomas occurring at midline locations including sacrococcygeal, retroperitoneal, mediastinal, and cervical regions. Despite the small percentage of malignant teratomas that occur in this age group, perinatal tumors have a high morbidity rate due to hydrops fetalis and premature delivery.[6,7] Extracranial GCTs (particularly testicular GCTs) are much more common among adolescents aged 15 to 19 years, representing approximately 14% of cancer diagnoses in this age group. The distribution of extracranial GCTs by 5-year age group and by gender is shown in Table 1 below.

Table 1. Extracranial Germ Cell Tumors by Age Group and Gendera

0–4 years 5–9 years 10–14 years 15–19 years
a Rates are per million children from 1986 to 1995 for the nine SEER regions plus Los Angeles.
Males 7 0.3 1.4 31
Females 5.8 2.4 7.8 25.3

GCTs develop from primordial germ cells, which migrate during embryogenesis from the yolk sac through the mesentery to the gonads.[8,9] Childhood extracranial GCTs can be divided into gonadal and extragonadal types. Most childhood extragonadal GCTs arise in midline sites (i.e., sacrococcygeal, mediastinal, and retroperitoneal); the midline location may represent aberrant embryonic migration of the primordial germ cells.

The histologic and genetic properties of these tumors are heterogeneous and vary by primary tumor site and the gender and age of the patient.[10,11] Histologically identical GCTs that arise in younger children have different biological characteristics from those that arise in adolescents and young adults.[12]

References:

1. Smith MA, Seibel NL, Altekruse SF, et al.: Outcomes for children and adolescents with cancer: challenges for the twenty-first century. J Clin Oncol 28 (15): 2625-34, 2010.
2. Guidelines for the pediatric cancer center and role of such centers in diagnosis and treatment. American Academy of Pediatrics Section Statement Section on Hematology/Oncology. Pediatrics 99 (1): 139-41, 1997.
3. Miller RW, Young JL Jr, Novakovic B: Childhood cancer. Cancer 75 (1 Suppl): 395-405, 1995.
4. 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 March 28, 2013.
5. Poynter JN, Amatruda JF, Ross JA: Trends in incidence and survival of pediatric and adolescent patients with germ cell tumors in the United States, 1975 to 2006. Cancer 116 (20): 4882-91, 2010.
6. Isaacs H Jr: Perinatal (fetal and neonatal) germ cell tumors. J Pediatr Surg 39 (7): 1003-13, 2004.
7. Heerema-McKenney A, Harrison MR, Bratton B, et al.: Congenital teratoma: a clinicopathologic study of 22 fetal and neonatal tumors. Am J Surg Pathol 29 (1): 29-38, 2005.
8. Dehner LP: Gonadal and extragonadal germ cell neoplasia of childhood. Hum Pathol 14 (6): 493-511, 1983.
9. McIntyre A, Gilbert D, Goddard N, et al.: Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes Chromosomes Cancer 47 (7): 547-57, 2008.
10. Hawkins EP: Germ cell tumors. Am J Clin Pathol 109 (4 Suppl 1): S82-8, 1998.
11. Schneider DT, Calaminus G, Koch S, et al.: Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols. Pediatr Blood Cancer 42 (2): 169-75, 2004.
12. Horton Z, Schlatter M, Schultz S: Pediatric germ cell tumors. Surg Oncol 16 (3): 205-13, 2007.

Histologic Classification of Childhood Extracranial GCTs

Childhood extracranial germ cell tumors (GCTs) comprise a variety of histologic diagnoses and can be broadly classified into mature or immature teratomas and malignant GCTs.

Mature Teratomas

Mature teratomas usually occur in the ovary or at extragonadal locations and are the most common histological subtype of childhood GCT.[1,2,3] These teratomas usually contain well-differentiated tissues from the ectodermal, mesodermal, and endodermal germ cell layers, and any tissue type may be found within the tumor. Mature teratomas are benign, though some mature and immature teratomas may secrete enzymes or hormones, including insulin, growth hormone, androgens, prolactin, and vasopressin.[4,5,6]

Immature Teratomas

Immature teratomas contain tissues from all three germ cell layers, but immature tissues, primarily neuroepithelial, are also present. Immature teratomas are graded from 0 to 3 based on the amount of immature neural tissue found in the tumor specimen.[7] Tumors of higher grade are more likely to have foci of yolk sac tumor.[8] Immature teratomas occur primarily in young children at extragonadal sites and in the ovaries of girls near the age of puberty, but there is no correlation between tumor grade and patient age.[8,9]

Malignant GCTs

GCTs contain frankly malignant tissues of germ cell origin, and rarely, tissues of somatic origin. Isolated malignant elements may constitute a small fraction of a predominantly mature or immature teratoma.[9,10] Malignant germ cell elements of children, adolescents, and young adults can broadly be classified by location (see Tables 2 and 3).

Table 2. Histology of Malignant Germ Cell Tumors in Young Childrena

Malignant Germ Cell Elements Location
E = extragonadal; O = ovarian; T = testicular.
a Modified from Perlman et al.[11]
Yolk sac tumor E, O, T
Dysgerminoma (rare in young children) O

Table 3. Histology of Malignant Germ Cell Tumors in Adolescents and Young Adultsa

Malignant Germ Cell Elements Location
E = extragonadal; O = ovarian; T = testicular.
a Modified from Perlman et al.[11]
Seminoma T
Dysgerminoma O
Germinoma E
Yolk sac tumor E, O, T
Choriocarcinoma E, O, T
Embryonal carcinoma T
Mixed germ cell tumors E, O

Yolk sac tumors produce alpha-fetoprotein (AFP), while germinomas (seminomas and dysgerminomas), and especially choriocarcinomas, produce beta-human chorionic gonadotropin, resulting in elevated serum levels of these substances. Most children with malignant GCTs will have a component of yolk sac tumor and have elevations of AFP,[12,13] which is serially monitored during treatment to help assess response to therapy.[9,10,12]

Adolescents and young adults present with more germinomas (testicular and mediastinal seminomas in males and ovarian dysgerminomas in females). These tumors are usually treated with chemotherapy. They are also sensitive to radiation therapy, but radiation is rarely recommended. Radiation therapy and surgery for the patient with brain metastases may provide palliation and occasionally, long-term survival.[14][Level of evidence: 3iiiA]

References:

1. Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.
2. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.
3. Harms D, Zahn S, Göbel U, et al.: Pathology and molecular biology of teratomas in childhood and adolescence. Klin Padiatr 218 (6): 296-302, 2006 Nov-Dec.
4. Tomlinson MW, Alaverdian AA, Alaverdian V: Testosterone-producing benign cystic teratoma with virilism. A case report. J Reprod Med 41 (12): 924-6, 1996.
5. Lam SK, Cheung LP: Inappropriate ADH secretion due to immature ovarian teratoma. Aust N Z J Obstet Gynaecol 36 (1): 104-5, 1996.
6. Kallis P, Treasure T, Holmes SJ, et al.: Exocrine pancreatic function in mediastinal teratomata: an aid to preoperative diagnosis? Ann Thorac Surg 54 (4): 741-3, 1992.
7. Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976.
8. Heifetz SA, Cushing B, Giller R, et al.: Immature teratomas in children: pathologic considerations: a report from the combined Pediatric Oncology Group/Children's Cancer Group. Am J Surg Pathol 22 (9): 1115-24, 1998.
9. 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.
10. Göbel U, Calaminus G, Schneider DT, et al.: The malignant potential of teratomas in infancy and childhood: the MAKEI experiences in non-testicular teratoma and implications for a new protocol. Klin Padiatr 218 (6): 309-14, 2006 Nov-Dec.
11. Perlman EJ, Hawkins EP: Pediatric germ cell tumors: protocol update for pathologists. Pediatr Dev Pathol 1 (4): 328-35, 1998 Jul-Aug.
12. 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.
13. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.
14. Göbel U, Schneider DT, Teske C, et al.: Brain metastases in children and adolescents with extracranial germ cell tumor - data of the MAHO/MAKEI-registry. Klin Padiatr 222 (3): 140-4, 2010.

Pediatric GCT Biology

The following paragraphs describe the biologically distinct subtypes of GCTs found in children and adolescents. It should be emphasized that very few pediatric GCT specimens have been analyzed to date. Biologic distinctions between GCTs in children versus adults may not be absolute.[1,2,3]

Testicular GCTs

  • Children: These GCTs typically present during early childhood. The tumors are commonly composed of pure yolk sac tumor (also known as endodermal sinus tumor), are generally diploid or tetraploid, and usually lack the isochromosome of the short arm of chromosome 12 that characterizes testicular cancer in young adults.[1,4,5,6,7] Deletions of chromosomes 1p, 4q, and 6q and gains of chromosomes 1q, 3, and 20q are reported as recurring chromosomal abnormalities for this group of tumors.[6,7,8]
  • Adolescents and young adults: These tumors typically possess an isochromosome of the short arm of chromosome 12 [9,10,11,12] and are aneuploid.[4,12] Although adolescent testicular germ cell patients may be best treated at pediatric oncology centers, the treatment regimens for adolescents older than 14 years follow regimens used in adults. (Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

Ovarian GCTs

Ovarian GCTs occur primarily in adolescent and young adult females. While the majority of ovarian GCTs are benign mature teratomas, a heterogeneous group of malignant GCTs occur in females, including immature teratomas, dysgerminomas, yolk sac tumors, and mixed GCTs. Patients with pediatric ovarian GCTs have an excellent prognosis. One series of 66 patients followed over 44 years reported recurrence and mortality rates of 4.5% and 3%, respectively.[13] The malignant ovarian GCT commonly shows increased copies of the short arm of chromosome 12.[14] (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.)

Extragonadal Extracranial GCTs

  • Children: These tumors typically present at birth or during early childhood. The majority of these tumors are benign teratomas occurring in the sacrococcygeal region, and hence SEER data do not include them.[15,16] Malignant yolk sac tumor histology occurs in a minority of these tumors, however, with cytogenetic abnormalities similar to those observed for tumors occurring in the testes of young males.[5,6,7,8]
  • Older children, adolescents, and young adults: The mediastinum is the most common primary site for extragonadal GCTs in older children and adolescents.[17] Mediastinal GCTs in children younger than 8 years share the same genetic gains and losses as sacrococcygeal and testicular tumors in young children.[18,19,20] The gain in chromosome 12p has been reported in mediastinal tumors in children aged 8 years and older.[20,21]

There is very little data about the potential genetic or environmental factors associated with childhood extracranial GCTs. Patients with Klinefelter syndrome [22,23,24] are at increased risk for mediastinal GCTs, while patients with Swyer syndrome [25,26] are at increased risk for gonadoblastomas and germinomas.

References:

1. Palmer RD, Foster NA, Vowler SL, et al.: Malignant germ cell tumours of childhood: new associations of genomic imbalance. Br J Cancer 96 (4): 667-76, 2007.
2. Palmer RD, Barbosa-Morais NL, Gooding EL, et al.: Pediatric malignant germ cell tumors show characteristic transcriptome profiles. Cancer Res 68 (11): 4239-47, 2008.
3. Poynter JN, Hooten AJ, Frazier AL, et al.: Associations between variants in KITLG, SPRY4, BAK1, and DMRT1 and pediatric germ cell tumors. Genes Chromosomes Cancer 51 (3): 266-71, 2012.
4. Oosterhuis JW, Castedo SM, de Jong B, et al.: Ploidy of primary germ cell tumors of the testis. Pathogenetic and clinical relevance. Lab Invest 60 (1): 14-21, 1989.
5. Silver SA, Wiley JM, Perlman EJ: DNA ploidy analysis of pediatric germ cell tumors. Mod Pathol 7 (9): 951-6, 1994.
6. Perlman EJ, Cushing B, Hawkins E, et al.: Cytogenetic analysis of childhood endodermal sinus tumors: a Pediatric Oncology Group study. Pediatr Pathol 14 (4): 695-708, 1994 Jul-Aug.
7. Schneider DT, Schuster AE, Fritsch MK, et al.: Genetic analysis of childhood germ cell tumors with comparative genomic hybridization. Klin Padiatr 213 (4): 204-11, 2001 Jul-Aug.
8. Perlman EJ, Valentine MB, Griffin CA, et al.: Deletion of 1p36 in childhood endodermal sinus tumors by two-color fluorescence in situ hybridization: a pediatric oncology group study. Genes Chromosomes Cancer 16 (1): 15-20, 1996.
9. Rodriguez E, Houldsworth J, Reuter VE, et al.: Molecular cytogenetic analysis of i(12p)-negative human male germ cell tumors. Genes Chromosomes Cancer 8 (4): 230-6, 1993.
10. Bosl GJ, Ilson DH, Rodriguez E, et al.: Clinical relevance of the i(12p) marker chromosome in germ cell tumors. J Natl Cancer Inst 86 (5): 349-55, 1994.
11. Mostert MC, Verkerk AJ, van de Pol M, et al.: Identification of the critical region of 12p over-representation in testicular germ cell tumors of adolescents and adults. Oncogene 16 (20): 2617-27, 1998.
12. van Echten J, Oosterhuis JW, Looijenga LH, et al.: No recurrent structural abnormalities apart from i(12p) in primary germ cell tumors of the adult testis. Genes Chromosomes Cancer 14 (2): 133-44, 1995.
13. De Backer A, Madern GC, Oosterhuis JW, et al.: Ovarian germ cell tumors in children: a clinical study of 66 patients. Pediatr Blood Cancer 46 (4): 459-64, 2006.
14. Riopel MA, Spellerberg A, Griffin CA, et al.: Genetic analysis of ovarian germ cell tumors by comparative genomic hybridization. Cancer Res 58 (14): 3105-10, 1998.
15. Malogolowkin MH, Mahour GH, Krailo M, et al.: Germ cell tumors in infancy and childhood: a 45-year experience. Pediatr Pathol 10 (1-2): 231-41, 1990.
16. Marsden HB, Birch JM, Swindell R: Germ cell tumours of childhood: a review of 137 cases. J Clin Pathol 34 (8): 879-83, 1981.
17. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.
18. Dal Cin P, Drochmans A, Moerman P, et al.: Isochromosome 12p in mediastinal germ cell tumor. Cancer Genet Cytogenet 42 (2): 243-51, 1989.
19. Aly MS, Dal Cin P, Jiskoot P, et al.: Competitive in situ hybridization in a mediastinal germ cell tumor. Cancer Genet Cytogenet 73 (1): 53-6, 1994.
20. 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.
21. McKenney JK, Heerema-McKenney A, Rouse RV: Extragonadal germ cell tumors: a review with emphasis on pathologic features, clinical prognostic variables, and differential diagnostic considerations. Adv Anat Pathol 14 (2): 69-92, 2007.
22. Dexeus FH, Logothetis CJ, Chong C, et al.: Genetic abnormalities in men with germ cell tumors. J Urol 140 (1): 80-4, 1988.
23. 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.
24. Lachman MF, Kim K, Koo BC: Mediastinal teratoma associated with Klinefelter's syndrome. Arch Pathol Lab Med 110 (11): 1067-71, 1986.
25. Coutin AS, Hamy A, Fondevilla M, et al.: [Pure 46XY gonadal dysgenesis] J Gynecol Obstet Biol Reprod (Paris) 25 (8): 792-6, 1996.
26. Amice V, Amice J, Bercovici JP, et al.: Gonadal tumor and H-Y antigen in 46,XY pure gonadal dysgenesis. Cancer 57 (7): 1313-7, 1986.

Stage Information for Childhood Extracranial GCTs

As with other childhood solid tumors, stage directly impacts the outcome of patients with malignant germ cell tumors (GCTs).[1,2,3] The most commonly used staging system in the United States is described below.[4] Retroperitoneal lymph node dissection has not been required in pediatric germ cell trials to stage males younger than 15 years. Data on adolescent males with testicular GCTs are limited. Retroperitoneal lymph node dissection is used for both staging and treatment in adult testicular GCT trials.[5] (Refer to the PDQ summary on Testicular Cancer Treatment for more information about the staging of adult testicular GCTs.)

Nonseminoma Testicular GCT Staging From Children's Oncology Group

  • Stage I: Limited to testis, complete resection by high inguinal orchiectomy or transscrotally with no tumor spillage. There must be no evidence of disease beyond the testis by radiologic scans or pathology. Tumor markers must normalize in appropriate half-life after resection.
  • Stage II: Transscrotal orchiectomy with spillage of tumor, microscopic disease in scrotum or high in spermatic cord (>0.5 cm), tumor markers fail to normalize or increase.
  • Stage III: Gross residual disease, retroperitoneal lymph node involvement (>2 cm in boys < age 10 years).
  • Stage IV: Distant metastases, including liver.

Ovarian GCT Staging From Children's Oncology Group

  • Stage I: Localized disease, completely resected without microscopic disease in the resected margins or in regional lymph nodes.
  • Stage II: Microscopic residual disease, capsular invasion, or microscopic lymph node involvement.
  • Stage III: Gross residual disease, gross lymph node involvement (>2 cm), or cytologic evidence of tumor cells in ascites.
  • Stage IV: Disseminated disease involving lungs, liver, brain, or bone.

Ovarian GCT Staging From FIGO

Another staging system used frequently by gynecologic oncologists is the International Federation of Gynecologic Oncologists (FIGO) staging system, which is based on an adequate staging operation at the time of diagnosis.[6] (Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.) This system has also been used by some pediatric centers,[2] and is as follows:

Stage I: Tumor limited to the ovaries

  • IA: One ovary, no ascites, intact capsule.
  • IB: Both ovaries, no ascites, intact capsule.
  • IC: Ruptured capsule, capsular involvement, positive peritoneal washings, or malignant ascites.

Stage II: Ovarian tumor with pelvic extension

  • IIA: Pelvic extension to uterus or tubes.
  • IIB: Pelvic extension to other pelvic organs (bladder, rectum, or vagina).
  • IIC: Pelvic extension, plus findings indicated for stage IC.

Stage III: Tumor outside the pelvis, or positive nodes

  • IIIA: Microscopic seeding outside the true pelvis.
  • IIIB: Gross deposit 2 cm or smaller.
  • IIIC: Gross deposits larger than 2 cm or positive nodes.

Stage IV: Distant organ involvement, including liver parenchyma or pleural space

Extragonadal Extracranial GCT Staging From Children's Oncology Group

  • Stage I: Localized disease, complete resection with no microscopic disease at margins or in regional lymph nodes; tumor markers must normalize in appropriate half-life after resection; complete coccygectomy for sacrococcygeal site.
  • Stage II: Microscopic residual disease, capsular invasion, and/or microscopic lymph node involvement; tumor markers fail to normalize or increase.
  • Stage III: Gross residual disease and gross lymph node involvement (>2 cm).
  • Stage IV: Distant metastases, including liver.

References:

1. Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991.
2. Mann JR, Pearson D, Barrett A, et al.: Results of the United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies. Cancer 63 (9): 1657-67, 1989.
3. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.
4. Brodeur GM, Howarth CB, Pratt CB, et al.: Malignant germ cell tumors in 57 children and adolescents. Cancer 48 (8): 1890-8, 1981.
5. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006.
6. Cannistra SA: Cancer of the ovary. N Engl J Med 329 (21): 1550-9, 1993.

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]

Table 4. Comparison of Pediatric PEB and JEB Chemotherapy Dosing Schedulesa

Regimen Bleomycin Etoposide Cisplatin Carboplatin References
GFR = glomerular filtration rate; JEB = carboplatin, etoposide, and bleomycin; PEB = cisplatin, etoposide, and bleomycin.
a Adult doses of PEB and JEB chemotherapy are different from pediatric doses.
Pediatric PEB (every 21 days) 15 units/m², day 1 100 mg/m², days 1–5 20 mg/m², days 1–5   [6,7]
Pediatric JEB (every 21–28 days) 15 units/m², day 3 120 mg/m², days 1–3   600 mg/m² or GFR-based dosing, day 2 [8]

Table 5 provides an overview of standard treatment options for children with extracranial GCTs. Treatment requires a multidisciplinary approach with various surgical subspecialties and pediatric oncologists. Specific details of treatment by primary site and clinical condition are described in subsequent sections.

Table 5. Standard Treatment Approaches for Infants and Children Younger Than 15 Years With Germ Cell Tumors by Histology, Stage, and Primary Site

Histology Primary Site Stage Treatment
PEB = cisplatin, etoposide, and bleomycin.
a Patients aged 15 years and older with stage IV testicular tumors and all patients with stages III and IV extragonadal tumors treated with PEB have suboptimal outcome and should be considered for more intensive therapies.
b The role for observation after surgery has not been well established for stage I ovarian germ cell tumors and should be reserved for a clinical trial.
c 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.
Mature teratoma All sites Localized Surgery + Observation
Immature teratoma All sites Localized Surgery + Observation
Malignant germ cell tumors Testicular Stage I Surgery + Observation
Stages II–IVa Surgery + PEB
  Ovarian Stage Ib Surgery + PEB
Stages II–IV Surgery + PEB
Extragonadal Stages I–II Surgeryc + PEB
Stages III–IVa Surgeryc + PEB

Non-GCT Malignant Elements

The treatment of GCTs with other non-GCT elements is complex and scant data exist to inform treatment. Specific treatment for both the malignant GCT and non-GCT elements may be required.[18] However, the optimal treatment strategy for other malignant elements found in GCT has not been determined.

References:

1. Kurman RJ, Norris HJ: Endodermal sinus tumor of the ovary: a clinical and pathologic analysis of 71 cases. Cancer 38 (6): 2404-19, 1976.
2. Chretien PB, Milam JD, Foote FW, et al.: Embryonal adenocarcinomas (a type of malignant teratoma) of the sacrococcygeal region. Clinical and pathologic aspects of 21 cases. Cancer 26 (3): 522-35, 1970.
3. Billmire DF, Grosfeld JL: Teratomas in childhood: analysis of 142 cases. J Pediatr Surg 21 (6): 548-51, 1986.
4. Hawkins EP, Finegold MJ, Hawkins HK, et al.: Nongerminomatous malignant germ cell tumors in children. A review of 89 cases from the Pediatric Oncology Group, 1971-1984. Cancer 58 (12): 2579-84, 1986.
5. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.
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.
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.
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.
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.
10. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.
11. 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.
12. 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.
13. 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.
14. 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.
15. Stern JW, Bunin N: Prospective study of carboplatin-based chemotherapy for pediatric germ cell tumors. Med Pediatr Oncol 39 (3): 163-7, 2002.
16. Horwich A, Sleijfer DT, Fosså SD, et al.: Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in good-prognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 15 (5): 1844-52, 1997.
17. Marina N, Chang KW, Malogolowkin M, et al.: Amifostine does not protect against the ototoxicity of high-dose cisplatin combined with etoposide and bleomycin in pediatric germ-cell tumors: a Children's Oncology Group study. Cancer 104 (4): 841-7, 2005.
18. Ehrlich Y, Beck SD, Ulbright TM, et al.: Outcome analysis of patients with transformed teratoma to primitive neuroectodermal tumor. Ann Oncol 21 (9): 1846-50, 2010.

Treatment of Mature and Immature Teratomas in Children

Mature and immature teratomas arise primarily in the sacrococcygeal region of neonates and young children and in the ovaries of pubescent girls. These tumors are also less commonly found in the testicular region of boys younger than 4 years, the mediastinum of adolescents, and other sites.[1,2,3]

Sacrococcygeal Tumors in Children

Standard treatment options

The sacrococcygeal region is the primary tumor site for the majority of benign and malignant germ cell tumors (GCTs) diagnosed in neonates, infants, and children younger than 4 years. These tumors occur more often in girls than in boys; ratios of 3:1 to 4:1 have been reported.[4] Sacrococcygeal tumors present in two clinical patterns related to the child's age, tumor location, and likelihood of tumor malignancy. Neonatal tumors present at birth protruding from the sacral site are usually mature or immature teratomas. Among infants and young children, the tumor presents as a palpable mass in the sacropelvic region compressing the bladder or rectum.[1] These pelvic tumors have a greater likelihood of being malignant. An early survey found that the rate of tumor malignancy was 48% for girls and 67% for boys older than 2 months at the time of sacrococcygeal tumor diagnosis, compared with a malignant tumor incidence of 7% for girls and 10% for boys younger than 2 months at the time of diagnosis.[5] The pelvic site of the primary tumor has been reported to be an adverse prognostic factor, which may be due to either delayed diagnosis because it was unappreciated at birth or incomplete resection at the time of original surgery.[5,6,7,8]

After successful resection, neonates diagnosed with benign mature and immature teratomas are observed with close follow-up exams and serial serum alpha-fetoprotein (AFP) determinations for several years to ensure that the expected physiological normalization of AFP levels occurs and to facilitate early detection of tumor relapse.[9] A significant rate of recurrence among these benign tumors has been reported by several groups, ranging from 10% to 21%, with most relapses occurring within 3 years of resection.[4,9,10,11] While there is no standard follow-up schedule, follow-up should include scans and tumor markers for 3 years. Importantly, 43% to 50% of these recurrent tumors will be malignant and require adjuvant chemotherapy. With early detection, these malignant GCTs can be treated successfully with surgery and chemotherapy (overall survival, 92%).[12] Complete resection of the coccyx is vital to minimize the likelihood of tumor recurrence;[2] however, one study reported that 11 out of 12 patients with microscopic residual benign immature teratoma had no recurrence.[13] Long-term survivors should be monitored for complications of extensive surgery, which include constipation, fecal and urinary incontinence, and psychologically unacceptable cosmetic scars.[14]

Nonsacrococcygeal Teratomas in Children

Standard treatment options

Mature teratoma and epidermoid cyst in the prepubertal testis are relatively common benign lesions and may be amenable to testis-sparing surgery.[15] Children with mature teratomas, including mature teratomas of the mediastinum, can be treated with surgery and observation with an excellent prognosis.[1,16] In a review of 153 children with nontesticular mature teratoma, the 6-year relapse-free survival for completely resected disease was 96% versus 55% for incomplete resection.[2] Head and neck GCTs in neonates should be cared for by a multidisciplinary team. While most are benign, they do present significant challenges to surgeons. Some tumors develop malignant elements, which may change the treatment strategy.[17]

In infants and young children, immature teratomas have benign clinical behavior if they can be resected.[10,18,19] In a single institution retrospective study, immature teratomas had a mortality rate (16.2%) twice that of yolk sac tumors (7.4%) and reflects the few patients with immature teratomas (unfavorable sites) that could not be resected. Immature teratomas generally do not respond to chemotherapy.[20] In adults, immature teratomas (primarily ovarian) reportedly have an aggressive clinical behavior [21] requiring surgery and chemotherapy. The benefit of adjuvant chemotherapy for children was questioned in a study by the Pediatric Oncology Group and Children's Cancer Group that evaluated the use of surgical resection followed by careful observation for patients with immature teratomas. Surgery alone was curative for most children and adolescents with resected ovarian immature teratoma of any grade, even when elevated levels of serum AFP or microscopic foci of yolk sac tumor were present. The study demonstrated a 3-year event-free survival of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively.[22] It is important to emphasize that the number of pediatric patients with residual teratomas and immature teratomas is very small. There may be a role for surgical removal of residual benign lesions.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood teratoma. 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. Rescorla FJ: Pediatric germ cell tumors. Semin Surg Oncol 16 (2): 144-58, 1999.
2. Göbel U, Calaminus G, Engert J, et al.: Teratomas in infancy and childhood. Med Pediatr Oncol 31 (1): 8-15, 1998.
3. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.
4. 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.
5. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974.
6. Ablin AR, Krailo MD, Ramsay NK, et al.: Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group. J Clin Oncol 9 (10): 1782-92, 1991.
7. Marina N, Fontanesi J, Kun L, et al.: Treatment of childhood germ cell tumors. Review of the St. Jude experience from 1979 to 1988. Cancer 70 (10): 2568-75, 1992.
8. 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.
9. Huddart SN, Mann JR, Robinson K, et al.: Sacrococcygeal teratomas: the UK Children's Cancer Study Group's experience. I. Neonatal. Pediatr Surg Int 19 (1-2): 47-51, 2003.
10. Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102 (8): 420-5, 1978.
11. Gabra HO, Jesudason EC, McDowell HP, et al.: Sacrococcygeal teratoma--a 25-year experience in a UK regional center. J Pediatr Surg 41 (9): 1513-6, 2006.
12. De Corti F, Sarnacki S, Patte C, et al.: Prognosis of malignant sacrococcygeal germ cell tumours according to their natural history and surgical management. Surg Oncol 21 (2): e31-7, 2012.
13. De Backer A, Madern GC, Hakvoort-Cammel FG, et al.: Study of the factors associated with recurrence in children with sacrococcygeal teratoma. J Pediatr Surg 41 (1): 173-81; discussion 173-81, 2006.
14. Derikx JP, De Backer A, van de Schoot L, et al.: Long-term functional sequelae of sacrococcygeal teratoma: a national study in The Netherlands. J Pediatr Surg 42 (6): 1122-6, 2007.
15. Metcalfe PD, Farivar-Mohseni H, Farhat W, et al.: Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 170 (6 Pt 1): 2412-5; discussion 2415-6, 2003.
16. 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.
17. 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.
18. Valdiserri RO, Yunis EJ: Sacrococcygeal teratomas: a review of 68 cases. Cancer 48 (1): 217-21, 1981.
19. Carter D, Bibro MC, Touloukian RJ: Benign clinical behavior of immature mediastinal teratoma in infancy and childhood: report of two cases and review of the literature. Cancer 49 (2): 398-402, 1982.
20. Mann JR, Gray ES, Thornton C, et al.: Mature and immature extracranial teratomas in children: the UK Children's Cancer Study Group Experience. J Clin Oncol 26 (21): 3590-7, 2008.
21. Norris HJ, Zirkin HJ, Benson WL: Immature (malignant) teratoma of the ovary: a clinical and pathologic study of 58 cases. Cancer 37 (5): 2359-72, 1976.
22. 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.

Treatment of Malignant Gonadal GCTs

Childhood Malignant Testicular GCTs

Testicular GCTs in young boys

Testicular germ cell tumors (GCTs) in children occur almost exclusively in boys younger than 4 years.[1,2] The initial 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] Retroperitoneal dissection of lymph nodes is not beneficial in the staging of testicular GCTs in young boys. Computed tomography or magnetic resonance imaging evaluation, with the additional information provided by elevated tumor markers, appears adequate for staging.[3,4] Therefore, there is no reason to risk the potential morbidity (e.g., impotence and retrograde ejaculation) related to lymph node dissection.[6,7]

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. This treatment strategy resulted in a 6-year event-free survival (EFS) of 82%; those boys who developed recurrent disease were salvaged with four cycles of standard-dose cisplatin, etoposide, and bleomycin (PEB), with a 6-year survival of 100%.[3,4] Boys younger than 10 years with stage II tumors were treated after diagnosis with four cycles of PEB.[8] Boys and adolescents (age not limited to 10 years or younger) with stage III and IV testicular tumors were treated with surgical resection followed by four cycles of standard or high-dose (HD)-PEB therapy. The 6-year survival outcome for males younger than 15 years with stage III and IV tumors was 100%, with 6-year EFS of 100% and 94%, respectively.[9] The use of HD-PEB therapy did not improve the outcome for these boys but did cause increased incidence of ototoxicity. Excellent outcomes for boys with testicular GCTs using surgery and observation for stage I tumors and carboplatin, etoposide, and bleomycin (JEB) and other cisplatin-containing chemotherapy regimens for stage II, III, and IV tumors have also been reported by European investigators.[6,10] Thus, surgery followed by standard-dose platinum-based chemotherapy is the recommended approach for stages II, III, and IV testicular GCTs in children younger than 15 years.

Standard treatment options

Surgery: The role of surgery at diagnosis for GCTs is age- and site-dependent and must be individualized. Primary resection is appropriate when feasible without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is biopsy for diagnosis followed by subsequent excision in selected patients who have residual masses following chemotherapy.

Stage I

  • Surgery and close follow-up observation are indicated to document that a normalization of the tumor markers occurs after resection.[10,3]

Stages II through IV

  • Surgery and treatment with four to six cycles of standard PEB. These patients have an overall survival (OS) outcome greater than 90% with this regimen, suggesting that a reduction in therapy could be considered.[8,9]
  • Surgery and treatment with six cycles of JEB.[10]

Treatment options under clinical evaluation for stages I through IV in patients younger than 15 years

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 United Kingdom CCG trial is studying reducing the total JEB cycles.

Testicular GCTs in adolescents and young adult males

Because the biology of testicular GCTs among adolescents and young adult males is different from that of testicular tumors arising in infants and young boys, the treatment guidelines described above for young boys may not be strictly applicable to adolescent males. In particular, the use of retroperitoneal lymph node dissection may play a crucial role both in 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, but if a sarcomatous component is found in a metastatic lesion, survival is likely to be compromised.[14]

(Refer to the PDQ summary on Testicular Cancer Treatment for more information.)

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 and 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.

Childhood Malignant Ovarian GCT

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 dysgerminomas (seminomatous) and nonseminomatous malignant GCTs (i.e., immature teratomas, yolk sac carcinomas, mixed GCTs, choriocarcinoma, and embryonal carcinomas). (For information on childhood mature and immature teratomas arising in the ovary, see the Nonsacrococcygeal Teratomas in Children section of this summary. Refer to the PDQ summary on Ovarian Germ Cell Tumors Treatment for more information.)

For stage I ovarian dysgerminomas and immature teratomas, cure can usually be achieved by unilateral salpingo-oophorectomy, conserving the uterus and opposite ovary, and close follow-up observation.[10,15,16,17,18] Chemotherapy can be given if tumor markers do not normalize or if tumors recur.

While advanced-stage ovarian dysgerminomas similar to 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 maintenance of menstrual function and fertility in most patients with dysgerminomas.[21,23]

For ovarian malignant GCTs other than dysgerminomas or immature teratomas, treatment generally involves surgical resection and adjuvant chemotherapy.[24,25] Platinum-based chemotherapy regimens such as PEB or JEB have been used successfully in children,[8,9,10,15] and PEB is a common regimen in young women with ovarian GCTs.[26,27] This approach results in a high rate of cure and the maintenance of menstrual function and fertility in most patients with nondysgerminomas.[25,28] A few small studies have suggested that observation after surgery may be an option, but only as part of a clinical trial with strict adherence to surgical guidelines.[10,28]

A multidisciplinary approach is essential for treatment of ovarian GCTs. Various surgical subspecialties 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. In a completed pediatric intergroup trial, pediatric patients with ovarian GCTs (stages I-IV) had excellent survival with PEB and conservative surgery, rather than the strict guidelines proposed originally in the study.[29] The role of laparoscopy in children with ovarian GCTs has not been well studied.

Standard treatment options

Surgery: The role for surgery at diagnosis is age- and site-dependent and must be individualized. Primary resection is appropriate when feasible without undue risk of damage to adjacent structures; otherwise, an appropriate strategy is biopsy for diagnosis followed by subsequent surgery in selected patients who have residual masses following chemotherapy.

Stages I through IV

  • Surgery and treatment with four to six cycles of standard PEB, with the exception of patients with stage I ovarian GCTs for whom observation is currently being evaluated. These patients have an OS outcome greater than 90% with this regimen, suggesting that a reduction in therapy could be considered.[8,9,29]
  • Surgery and treatment with six cycles of JEB.[10,29]

Treatment options under clinical evaluation for stages I through III

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 United Kingdom CCG trial is studying the reduction of total JEB cycles.

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 March 28, 2013.
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.
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.
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.
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.
7. Pinkerton CR: Malignant germ cell tumours in childhood. Eur J Cancer 33 (6): 895-901; discussion 901-2, 1997.
8. 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.
9. 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.
10. 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.
11. de Wit R, Fizazi K: Controversies in the management of clinical stage I testis cancer. J Clin Oncol 24 (35): 5482-92, 2006.
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.
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.
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.
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.
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.
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.
18. Gershenson DM: Chemotherapy of ovarian germ cell tumors and sex cord stromal tumors. Semin Surg Oncol 10 (4): 290-8, 1994 Jul-Aug.
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.
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.
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.
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.
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.
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.
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.
26. Williams SD: Ovarian germ cell tumors: an update. Semin Oncol 25 (3): 407-13, 1998.
27. 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.
28. 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.
29. 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.

Treatment of Childhood Malignant Extragonadal GCTs

Extragonadal germ cell tumors (GCTs) (i.e., sacrococcygeal, mediastinal, and retroperitoneal) are more common in children than adults.[1] 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.[4] 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.[5,6,7,8]

Sacrococcygeal GCTs are very common extragonadal tumors that occur in very young children, predominately young females.[9] 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.[9] 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.[5] 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.[6] Children with mediastinal teratomas are treated with tumor resection, which is curative in almost all patients.[6] 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%.[4,15,16,17]; [18]Level of evidence: 3iiA (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.[19] 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.[19]

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.[20][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.[2,21]
  • Surgery and treatment with six cycles of JEB.[5]

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.[2]
  • Surgery and treatment with six cycles of JEB yield similar OS.[5]

Treatment Options Under Clinical Evaluation

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.

Current Clinical Trials

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:

1. Pantoja E, Llobet R, Gonzalez-Flores B: Retroperitoneal teratoma: historical review. J Urol 115 (5): 520-3, 1976.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Altman RP, Randolph JG, Lilly JR: Sacrococcygeal teratoma: American Academy of Pediatrics Surgical Section Survey-1973. J Pediatr Surg 9 (3): 389-98, 1974.
10. 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.
11. 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.
12. 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.
13. 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.
14. Billmire D, Vinocur C, Rescorla F, et al.: Malignant mediastinal germ cell tumors: an intergroup study. J Pediatr Surg 36 (1): 18-24, 2001.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.

Treatment of Recurrent Childhood Malignant GCTs

Only a small number of children and adolescents with extracranial germ cell tumors (GCTs) relapse.[1,2] However, the approach to recurrent disease and its success depend on the initial treatment regimen and on the response of the tumor to treatment.

Boys with stage I testicular disease originally treated with surgical resection and observation can usually be salvaged, if relapse occurs, by further surgical excision and standard cisplatin, etoposide, and bleomycin (PEB) or carboplatin, etoposide, and bleomycin (JEB) chemotherapy.[3,4] Several European studies also have reported encouraging salvage rates for stage I ovarian GCT patients originally treated with surgery and observation.[5,6]

Most children with recurrent sacrococcygeal tumors will recur locally at the primary tumor site. For these children, complete surgical resection of the recurrent tumor and the coccyx is the basis of salvage treatment; preoperative chemotherapy may assist the surgical resection. In patients in whom a complete salvage resection is not achieved, postoperative local irradiation should be considered.[7]

Despite overall cure rates greater than 80%, children with extracranial GCTs who have disease recurrence after surgery and three-agent platinum-based combination chemotherapy (PEB or JEB) have an unfavorable prognosis. Reports regarding the treatment and outcome of these children include small patient samples.[7] Reports of salvage treatment strategies used in adult recurrent GCTs include larger numbers of patients, but the differences between children and adults regarding the location of the primary GCT site, pattern of relapse, and the biology of childhood GCTs may limit the applicability of adult salvage approaches to children.

In adults with recurrent GCTs, several chemotherapy combinations have achieved relatively good disease-free status.[8,9,10,11,12,13] A combination of paclitaxel and gemcitabine has demonstrated activity in adults with testicular GCTs who relapsed after high-dose (HD) chemotherapy and hematopoietic stem cell transplant (SCT).[14]

HD chemotherapy with autologous stem cell rescue has been explored in adults with recurrent testicular GCTs. HD chemotherapy plus hematopoietic stem cell rescue has been reported to cure adult patients with relapsed testicular GCTs, even as third-line therapy and in cisplatin-refractory patients.[15] While several other studies support this approach,[16,17,14,18,19] others do not.[20,21] Salvage attempts using HD-chemotherapy regimens may be of little benefit if the patient is not clinically disease free at the time of hematopoietic SCT.[15,22]

The role of HD chemotherapy and hematopoietic stem cell rescue for recurrent pediatric GCTs is not established, despite anecdotal reports. (Refer to the Autologous Hematopoietic Cell Transplantation section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation). In one European series, 10 of 23 children with relapsed extragonadal GCTs achieved long-term (median follow-up 66 months) disease-free survival by using HD chemotherapy with stem cell support.[23] Further study is needed in children and adolescents.

Standard Treatment Options

There are no standard treatment options for recurrent pediatric GCTs. The role for surgery in selected patients who have recurrent GCTs has not been established but should be considered. Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood malignant 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. 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.
2. 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.
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.
4. 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.
5. Baranzelli MC, Bouffet E, Quintana E, et al.: Non-seminomatous ovarian germ cell tumours in children. Eur J Cancer 36 (3): 376-83, 2000.
6. 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.
7. Schneider DT, Wessalowski R, Calaminus G, et al.: Treatment of recurrent malignant sacrococcygeal germ cell tumors: analysis of 22 patients registered in the German protocols MAKEI 83/86, 89, and 96. J Clin Oncol 19 (7): 1951-60, 2001.
8. Loehrer PJ Sr, Gonin R, Nichols CR, et al.: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 16 (7): 2500-4, 1998.
9. Motzer RJ, Sheinfeld J, Mazumdar M, et al.: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 18 (12): 2413-8, 2000.
10. Hartmann JT, Einhorn L, Nichols CR, et al.: Second-line chemotherapy in patients with relapsed extragonadal nonseminomatous germ cell tumors: results of an international multicenter analysis. J Clin Oncol 19 (6): 1641-8, 2001.
11. Mandanas RA, Saez RA, Epstein RB, et al.: Long-term results of autologous marrow transplantation for relapsed or refractory male or female germ cell tumors. Bone Marrow Transplant 21 (6): 569-76, 1998.
12. Kondagunta GV, Bacik J, Sheinfeld J, et al.: Paclitaxel plus Ifosfamide followed by high-dose carboplatin plus etoposide in previously treated germ cell tumors. J Clin Oncol 25 (1): 85-90, 2007.
13. Schmoll HJ, Kollmannsberger C, Metzner B, et al.: Long-term results of first-line sequential high-dose etoposide, ifosfamide, and cisplatin chemotherapy plus autologous stem cell support for patients with advanced metastatic germ cell cancer: an extended phase I/II study of the German Testicular Cancer Study Group. J Clin Oncol 21 (22): 4083-91, 2003.
14. Einhorn LH, Brames MJ, Juliar B, et al.: Phase II study of paclitaxel plus gemcitabine salvage chemotherapy for germ cell tumors after progression following high-dose chemotherapy with tandem transplant. J Clin Oncol 25 (5): 513-6, 2007.
15. Einhorn LH, Williams SD, Chamness A, et al.: High-dose chemotherapy and stem-cell rescue for metastatic germ-cell tumors. N Engl J Med 357 (4): 340-8, 2007.
16. Bhatia S, Abonour R, Porcu P, et al.: High-dose chemotherapy as initial salvage chemotherapy in patients with relapsed testicular cancer. J Clin Oncol 18 (19): 3346-51, 2000.
17. Motzer RJ, Mazumdar M, Sheinfeld J, et al.: Sequential dose-intensive paclitaxel, ifosfamide, carboplatin, and etoposide salvage therapy for germ cell tumor patients. J Clin Oncol 18 (6): 1173-80, 2000.
18. Rick O, Bokemeyer C, Beyer J, et al.: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 19 (1): 81-8, 2001.
19. Feldman DR, Sheinfeld J, Bajorin DF, et al.: TI-CE high-dose chemotherapy for patients with previously treated germ cell tumors: results and prognostic factor analysis. J Clin Oncol 28 (10): 1706-13, 2010.
20. Beyer J, Rick O, Siegert W, et al.: Salvage chemotherapy in relapsed germ cell tumors. World J Urol 19 (2): 90-3, 2001.
21. Beyer J, Kramar A, Mandanas R, et al.: High-dose chemotherapy as salvage treatment in germ cell tumors: a multivariate analysis of prognostic variables. J Clin Oncol 14 (10): 2638-45, 1996.
22. Rick O, Bokemeyer C, Weinknecht S, et al.: Residual tumor resection after high-dose chemotherapy in patients with relapsed or refractory germ cell cancer. J Clin Oncol 22 (18): 3713-9, 2004.
23. De Giorgi U, Rosti G, Slavin S, et al.: Salvage high-dose chemotherapy for children with extragonadal germ-cell tumours. Br J Cancer 93 (4): 412-7, 2005.

Changes to This Summary (03 / 29 / 2013)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Pediatric GCT Biology

Added Poynter et al. as reference 3.

Treatment of Recurrent Childhood Malignant GCTs

Added a link to the Autologous Hematopoietic Cell Transplantation section of the PDQ summary on Childhood Hematopoietic Cell Transplantation for more information about transplantation.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood extracranial germ cell tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Extracranial Germ Cell Tumors Treatment are:

  • Thomas A. Olson, MD (AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus)
  • R. Beverly Raney, MD (Consultant)
  • Stephen J. Shochat, MD (St. Jude Children's Research Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Extracranial Germ Cell Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/extracranial-germ-cell/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov Web site can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the Web site's Contact Form.

Get More Information From NCI

Call 1-800-4-CANCER

For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 8:00 a.m. to 8:00 p.m., Eastern Time. A trained Cancer Information Specialist is available to answer your questions.

Chat online

The NCI's LiveHelp® online chat service provides Internet users with the ability to chat online with an Information Specialist. The service is available from 8:00 a.m. to 11:00 p.m. Eastern time, Monday through Friday. Information Specialists can help Internet users find information on NCI Web sites and answer questions about cancer.

Write to us

For more information from the NCI, please write to this address:

NCI Public Inquiries Office
Suite 3036A
6116 Executive Boulevard, MSC8322
Bethesda, MD 20892-8322

Search the NCI Web site

The NCI Web site provides online access to information on cancer, clinical trials, and other Web sites and organizations that offer support and resources for cancer patients and their families. For a quick search, use the search box in the upper right corner of each Web page. The results for a wide range of search terms will include a list of "Best Bets," editorially chosen Web pages that are most closely related to the search term entered.

There are also many other places to get materials and information about cancer treatment and services. Hospitals in your area may have information about local and regional agencies that have information on finances, getting to and from treatment, receiving care at home, and dealing with problems related to cancer treatment.

Find Publications

The NCI has booklets and other materials for patients, health professionals, and the public. These publications discuss types of cancer, methods of cancer treatment, coping with cancer, and clinical trials. Some publications provide information on tests for cancer, cancer causes and prevention, cancer statistics, and NCI research activities. NCI materials on these and other topics may be ordered online or printed directly from the NCI Publications Locator. These materials can also be ordered by telephone from the Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237).

Last Revised: 2013-03-29

This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use. How this information was developed to help you make better health decisions.

Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.