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

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Extragonadal Germ Cell Tumors Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of extragonadal germ cell tumors. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Cellular classification.
  • Staging.
  • Treatment options for different types of tumors.

This summary 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.

Some of the reference citations in the 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 Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Note: Separate PDQ summaries on Ovarian Germ Cell Tumors Treatment and Testicular Cancer Treatment are also available.

Extragonadal germ cell tumors are rare and account for only a small percentage of all germ cell tumors. However, the true incidence of these tumors may conceivably be higher than originally thought because of failure to diagnose them properly.

Cellular Classification

Extragonadal germ cell tumors can be benign (teratoma) or malignant. The latter group can be divided into seminoma and nonseminoma germ cell tumors, which include embryonal carcinomas, malignant teratomas, endodermal sinus tumors, choriocarcinomas, and mixed germ cell tumors.

Extragonadal germ cell tumors occur much more commonly in males than in females [1] and are usually seen in young adults. They are aggressive neoplasms and can arise virtually anywhere, but typically the site of origin is in the midline (mediastinum, retroperitoneum, or pineal gland). Gonadal origin should be excluded by careful testicular examination and ultrasound. The diagnosis can be difficult and should be considered in any patient with a poorly defined epithelial malignancy, particularly young individuals with midline masses.[2,3]

An international germ cell tumor prognostic classification has been developed based on a retrospective analysis of 5,202 patients with metastatic nonseminomatous germ cell tumors and 660 patients with metastatic seminomatous germ cell tumors.[4] All patients received treatment with cisplatin-containing or carboplatin-containing therapy as their first chemotherapy course. The prognostic classification, shown below, was agreed on in early 1997 by all major clinical trial groups worldwide and should be used for the reporting of clinical trials' results of patients with extragonadal germ cell tumors.

Good Prognosis

Nonseminoma

  • Testis/retroperitoneal primary

    and

  • No nonpulmonary visceral metastases

    and

  • Good markers - all of:
    • AFP less than 1,000 ng/mL

      and

    • hCG less than 5,000 iu/L (1,000 ng/mL)

      and

    • LDH less than 1.5 x upper limit of normal

56% of nonseminomas

5-year progression-free survival (PFS) rate of 89%

5-year survival rate of 92%

Seminoma

  • Any primary site

    and

  • No nonpulmonary visceral metastases

    and

  • Normal AFP, any hCG, any LDH

90% of seminomas

5-year PFS rate of 82%

5-year survival rate of 86%

Intermediate Prognosis

Nonseminoma

  • Testis/retroperitoneal primary

    and

  • No nonpulmonary visceral metastases

    and

  • Intermediate markers - any of:
    • AFP 1,000 ng/mL or greater and 10,000 ng/mL or less

      or

    • hCG 5,000 iu/L or greater and 50,000 iu/L or less

      or

    • LDH 1.5 × N or greater and 10 × N or less

28% of nonseminomas

5-year PFS rate of 75%

5-year survival rate of 80%

Seminoma

  • Any primary site

    and

  • Nonpulmonary visceral metastases

    and

  • Normal AFP, any hCG, any LDH

10% of seminomas

5-year PFS rate of 67%

5-year survival rate of 72%

Poor Prognosis

Nonseminoma

  • Mediastinal primary

    or

  • Nonpulmonary visceral metastases

    or

  • Poor markers - any of:
    • AFP greater than 10,000 ng/mL

      or

    • hCG greater than 50,000 iu/L (1,000 ng/mL)

      or

    • LDH greater than 10 × upper limit of normal

16% of nonseminomas

5-year PFS rate of 41%

5-year survival rate of 48%

Seminoma

No patients are classified as poor prognosis.

References:

1. Mayordomo JI, Paz-Ares L, Rivera F, et al.: Ovarian and extragonadal malignant germ-cell tumors in females: a single-institution experience with 43 patients. Ann Oncol 5 (3): 225-31, 1994.
2. Greco FA, Vaughn WK, Hainsworth JD: Advanced poorly differentiated carcinoma of unknown primary site: recognition of a treatable syndrome. Ann Intern Med 104 (4): 547-53, 1986.
3. Hainsworth JD, Greco FA: Extragonadal germ cell tumors and unrecognized germ cell tumors. Semin Oncol 19 (2): 119-27, 1992.
4. International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group. J Clin Oncol 15 (2): 594-603, 1997.

Benign Teratoma

Benign teratomas are treated with surgical excision only. These tumors are frequently very large, and the surgical procedure can be formidable.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with benign 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.

Seminoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

The diagnosis of seminoma requires that the serum alpha fetoprotein (AFP) be normal, and no other germ cells be present. Management decisions in patients presenting with these tumors can sometimes be difficult.

As in testicular seminoma, these tumors are very radiosensitive. About 60% to 80% of patients will remain disease free after treatment with radiation therapy.[1] Craniospinal radiation therapy for intracranial germinomas (the intracranial counterpart of seminoma) is associated with relapse-free and overall survival rates of 90% to 95% at 5 years as evidenced in the MAKEI-83/86/89 trial, for example.[2][Level of evidence: 3iiiA]

Initial chemotherapy with regimens used in nonseminoma testicular cancer is also very efficacious. Practically speaking, patients with localized relatively small tumors are usually treated initially with radiation, while those with very bulky tumors or nonlocalized tumors are treated with etoposide-based and cisplatin-based chemotherapy regimens.

As in testicular seminoma, many patients will be left with a residual mass posttreatment. If the residual mass is smaller than 3.0 cm, the majority of experts agree that observation is appropriate. In those with larger residual masses, some experts favor surgical excision while others favor observation.[3,4]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extragonadal seminoma. 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. Clamon GH: Management of primary mediastinal seminoma. Chest 83 (2): 263-7, 1983.
2. Bamberg M, Kortmann RD, Calaminus G, et al.: Radiation therapy for intracranial germinoma: results of the German cooperative prospective trials MAKEI 83/86/89. J Clin Oncol 17 (8): 2585-92, 1999.
3. Motzer R, Bosl G, Heelan R, et al.: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 5 (7): 1064-70, 1987.
4. Schultz SM, Einhorn LH, Conces DJ Jr, et al.: Management of postchemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 7 (10): 1497-503, 1989.

Nonseminoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Patients with nonseminomas should receive chemotherapy at diagnosis. These patients tend to have a very large tumor volume at diagnosis and are usually symptomatic. Initial debulking surgery is rarely useful. Many high-risk patients qualify for clinical trials. Standard therapy would generally be considered to be four courses of BEP (bleomycin, etoposide, and cisplatin).[1,2]

A randomized study comparing four courses of BEP with four courses of VIP (etoposide, ifosfamide, and cisplatin) showed similar overall survival and time-to-treatment failure for the two regimens in patients with advanced disseminated germ cell tumors who had not received previous chemotherapy.[3,4][Level of evidence: 1iiA] Of the 304 patients on this study, 66 patients had extragonadal primary tumors, and in this subset of patients, responses were similar on the two regimens. Hematologic toxic effects in the overall study were substantially worse with the VIP regimen than with the BEP regimen.

Patients with a residual mass after chemotherapy may achieve long-term disease-free survival after postchemotherapy surgery with resection of all residual disease.[5][Level of evidence: 3iiiDii] Patients with nonseminomatous extragonadal germ cell tumors who relapse after front-line chemotherapy generally have poor prognoses with poor responses to salvage chemotherapy regimens, including autologous bone marrow transplantation, that have had success for recurrent testicular cancer.[6,7,8] Such patients, therefore, are candidates for studies of new approaches.

Mediastinal Nonseminoma

Mediastinal nonseminomas have certain unique aspects. The tumors are more frequent in individuals with Klinefelter syndrome and are associated with a risk of subsequent development of hematologic neoplasia that is not treatment related.[9,10] Approximately 50% of patients with mediastinal nonseminomas will survive with appropriate management.[11] High risk is partially related to tumor bulk, to chemotherapy resistance, and to a predisposition to develop hematologic neoplasia and other nongerm cell malignancies. In an uncontrolled study, some patients with a postchemotherapy residual mediastinal mass achieved long-term disease-free survival after complete resection, even when serum tumor markers were elevated.[5][Level of evidence: 3iiiDii] Patient selection factors may play a role in these favorable outcomes.

Retroperitoneal Nonseminoma

The prognosis of retroperitoneal nonseminoma is reasonably good and, similar to the situation with nodal metastasis from a testicular primary, is related to tumor volume.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with malignant extragonadal non-seminomatous 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. Williams SD, Birch R, Einhorn LH, et al.: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 316 (23): 1435-40, 1987.
2. Bosl GJ, Gluckman R, Geller NL, et al.: VAB-6: an effective chemotherapy regimen for patients with germ-cell tumors. J Clin Oncol 4 (10): 1493-9, 1986.
3. Nichols CR, Catalano PJ, Crawford ED, et al.: Randomized comparison of cisplatin and etoposide and either bleomycin or ifosfamide in treatment of advanced disseminated germ cell tumors: an Eastern Cooperative Oncology Group, Southwest Oncology Group, and Cancer and Leukemia Group B Study. J Clin Oncol 16 (4): 1287-93, 1998.
4. Hinton S, Catalano PJ, Einhorn LH, et al.: Cisplatin, etoposide and either bleomycin or ifosfamide in the treatment of disseminated germ cell tumors: final analysis of an intergroup trial. Cancer 97 (8): 1869-75, 2003.
5. Schneider BP, Kesler KA, Brooks JA, et al.: Outcome of patients with residual germ cell or non-germ cell malignancy after resection of primary mediastinal nonseminomatous germ cell cancer. J Clin Oncol 22 (7): 1195-200, 2004.
6. Saxman SB, Nichols CR, Einhorn LH: Salvage chemotherapy in patients with extragonadal nonseminomatous germ cell tumors: the Indiana University experience. J Clin Oncol 12 (7): 1390-3, 1994.
7. 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.
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. 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.
10. Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.
11. Nichols CR, Saxman S, Williams SD, et al.: Primary mediastinal nonseminomatous germ cell tumors. A modern single institution experience. Cancer 65 (7): 1641-6, 1990.

Recurrent or Refractory Extragonadal Germ Cell Tumors

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

A randomized controlled trial compared conventional doses of salvage chemotherapy to high-dose chemotherapy with autologous marrow rescue in 263 patients with recurrent or refractory germ cell tumors. Of the 263 patients, 43 of whom had extragonadal primary tumors, more toxic effects and treatment-related deaths were seen in the high-dose arm without any improvement in response rate or overall survival.[1][Level of evidence: 1iiA]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent 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. Pico JL, Rosti G, Kramar A, et al.: A randomised trial of high-dose chemotherapy in the salvage treatment of patients failing first-line platinum chemotherapy for advanced germ cell tumours. Ann Oncol 16 (7): 1152-9, 2005.

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Changes to This Summary (05 / 16 / 2008)

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.

Editorial changes were made to this summary.

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Date Last Modified: 2008-05-16

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