Approximately 5-7% of germ cell tumors in adults are of extragonadal origin.  Primary sites include central nervous system, mediastinum and retroperitoneal.  The serologic and histologic characteristics of EGGCT’s are similar to their gonadal counterparts but the biology and clinical outcomes are markedly different.

CNS GCT’s
1-2% of CNS neoplasms are germ cell tumors.  Pure seminomas (germinomas) are associated with 90% 5 year survival with radiation alone.  Because of radiation associated neurotoxicity concerns, use of neoadjuvant chemotherapy is employed and appears to allow reduced volume of brain radiated.  However, craniospinal RT is still employed as needed.  Studies have demonstrated 100% 5 year survivals.  Nonseminomas (nongerminomas) are radioresistant and require aggressive cisplatin based chemotherapy combined with IMRT/conformal RT.  There is greater than 50% progression.  Second look surgery and resection, if possible, is recommeneded.

Mediastinal and retroperitoneal GCT’s
PMNSGCT’s are considered poor risk by IGCCCG and are associated with only 30-60% long term survival despite cisplatin based therapy and aggressive resection of masses followed by therapy based upon histology and STM’s.  All patients should be considered for clinical trials. 

PRNSGCT’s are associated with 59-61% 5 year survivals depending upon IGCCCG risk stratification.  Therapy involves cisplatin chemotherapy.  Presence of persistently abnormal STM’s and residual masses determine the need for consolidation/clinical trial participation as well as resection of residual masses.

PMGCT’s and PRGCT’s have been associated with 88% long term survivals when initial therapy is cisplatin based.  Radiation therapy as initial therapy has been associated with inferior survivals.

Stages 1A, 1B, and 1S

Early stage seminoma is a radiosensitive tumor. Patients with disease in stages 1A, 1B, and 1S are treated with radiation (20-30 Gy) to the infradiaphragmatic area including pare-aortic lymph nodes.

Between 15% and 20% of seminoma patients relapse during surveillance if they do not receive adjuvant radiation therapy after orchiectomy.

Stages 11A and 11B

For patients with stage 11A or 11B disease, 35 to 40 Gy is administered to the infradiaphragmatic area including para-aortic and ipsilateral iliac lymph nodes (Tees-3).

Stage, III

EP x 4

BEP x 3

Intermediate or High risk
BEP x4 or clinical trail.

Stage 1A Nonseminoma

Two management options exist for patients with stage 1A disease: 1) observation (in complaint patients) or 2) nerve-sparing retroperitoneal lymph node dissection (RPLND). The cure rate with either approach exceeds 95%.

Noncompliant patients are managed with RPLND.

Stage 1B tumors have three treatment options: RPLND, chemotherapy, or observation. The preferred treatment option is nerve-sparing RPLND. If a suitable surgeon is not available to perform RPLND, then chemotherapy-with two cycles of cisplatin, etoposide, and bleomycin (BEP) is a reasonable treatment option.

Stage 11C patients are categorized as good-risk, intermediate-risk, or poor-risk, depending upon serum tumor marker levels. Stage 11C disease is treated with initial chemotherapy according to risk status. If there is a residual mass after treatment and negative tumor markers, RPLND is performed or the patient may be observed. RPLND is generally preferred if markers are negative and there is no residual mass on CT scan.

Stage 11A and 11B Nonseminoma

Treatment for patients with stage11A nonseminoma depends upon serum tumor levels. When the levels of tumor markers are persistently elevated, patients are treated with chemotherapy. When the tumor marker levels are negative, two treatment options are available. Patients can undergo RPLND, or receive primary chemotherapy). Primary chemotherapy with 4 cycles of EP or 3 cycles of BEP is appropriate if the patient was multifocal disease. Adjuvant chemotherapy is preferred for those who received primary management by RPLND and primary tumor has been completely resected and includes high volume, completely resected disease (stage11A, pN2). Tow cycles of chemotherapy result in nearly 100% relapse free survival rate.

Stage11C

Good Risk-
EP x 4 cycles or BEPx3 cycles

Int. Risk-
BEP x 4 cycles or clinical trail

Poor Risk-
Clinical trail (preferred) or BEP x 4 cycles

Good-Risk Patients (Stage 111A Nonseminoma)

Treatment programs for good-risk germ cell tumors were designed to decrease toxicity while maintaining maximal efficacy.
Two regimens are considered standard treatment programs in the United States for good-risk germ cell tumors: 4 cycles of EP, or 3 cycles of BEP. Either regimen is well tolerated and cures approximately 90% of good-risk patients.

Intermediate (Stage 111B Nonseminoma) and Poor Risk (Stage111C Nonseminoma)

Between 20% and 30% of all patients with metastatic germ cell tumors are not cured with conventional cisplatin therapy. Poor prognostic features at diagnosis that can be used to identify these patients include nonpulmonary visceral metastases and high serum tumor marker concentrations and/or mediastinal primary site in patients with nonseminoma.  In patients with these prognostic factors, clinical trails are directed at improving efficacy.
For intermediate-risk patients, the cure rate is approximately 70% for standard therapy with four cycles of BEP. In patients with poor-risk germ cell tumors (stage IIIC), less than one half achieve a durable complete response to four cycles of BEP and treatment in a clinical trail is preferred.

Chemotherapy for Advanced Disease

Patients with stage IIC and stage III disease are treated with primary chemotherapy regimens based on risk status. Also, patients with an extragonadal primary site, whether retroperitoneal or mediastinal, are treated with initial chemotherapy.
Cisplatin, vinblastine, and bleomycin achieved a complete response in 70% to 80% of patients with metastatic germ cell tumors.

Stage IIIA

Good risk-
EP x 4 cycles or BEP x 3 cycles

Intermediate risk-
BEP x 4 cycles or clinical trail

Poor risk-
Clinical trial (preferred) or BEP x4 cycles

Brain Metastases-
Primary chemotherapy+ RT+ surgery, if clinically indicated.

References:

• Jones RH, Vassey PA Part I: Testicular cancer-management of early disease. The Lancet Oncology 2003; 4(12): 730-737.
• Gospodarowicz M, Sturgeon JFG, Jewitt MAS. Early stage and advanced seminoma: Role of radiation therapy, surgery, and chemotherapy. Semin Oncol 1998; 25:160-173
• Bayley A, Warde P, Milosevic M et al. Surveillance for stage I testicular seminoma: a review. Urologic Oncology 2001; 6:139-143
• Warde P, Gospodarowicz MK, Panzarella T et al. Stage I testicular seminoma: Results of adjuvant irradiation and surveillance. J Clin Oncol 1995; 13:2255-2262
• Thijssens K, Vaneerdeweg W, Schrijvers D et al. Retroperitoneal lymph node dissection as adjuvant therapy in the treatment of non-seminomatous testicular cancer. Acta Chir Belg 2003; 103(6): 599-602
• Oldenburg J, Alfsen GC, Lien HH, Aass N et al. Post chemotherapy retroperitoneal surgery remains necessary in patients with non-seminomatous testicular cancer and minimal residual tumor masses. J Clin Onc 2003; 21(17): 3310-3317
• Jones RH, Vassey PA. Part II: Testicular cancer-management of advanced disease. The Lancet Oncology 2003; 4(12): 738-4