Paclitaxel-Bleomycin/Etoposide/Cisplatin vs Bleomycin/Etoposide/Cisplatin in Poor-prognosis Non-seminomatous Germ Cell Tumors (NSGCT) and Unfavorable Tumor Marker Decline: Randomized Phase II Trial

Screening procedures:

• AFP, b-HCG, LDH - ≤7 days before enrollment;
• Complete blood counts;
• Blood chemistry;
• Urinalysis;
• Chest, abdominal and pelvic CT-scan with IV enhancement;
• Electrocardiogram;
• Brain MRI scan as clinically indicated (neurologic symptoms, post-orchiectomy serum beta-hCG > 5000 IU/L or extensive lung metastasis)

Treatment:

After registration patients will receive first cycle of standard BEP chemotherapy: cisplatin 20 mg/m² IV days 1-5, etoposide 100 mg/m² IV days 1-5, bleomycin 30 mg IV days 1, 8 and 15 OR days 1, 3 and 5 + G-CSF 5 mcg/kg subcutaneous day 6, until post-nadir absolute neutrophil count ≥ 1.0 x 10^9. In patients with ultra-high level of tumor markers and/or poor performance status (eg, ECOG3-4) administration of a disease stabilizing chemotherapy first cycle of chemotherapy is allowed.

After 1st cycle of BEP tumor markers will be reassessed between days 18 and 21, and their kinetics will be centrally calculated (App: Tumor marker decline calculator poor-risk GCT - http://www.gustaveroussy.fr/calculation-tumor/NSGCT.html).

Patients with favorable tumor markers for both AFP and B-HCG decline will receive three subsequent cycles of BEP.

Patients with unfavorable tumor markers decline will be centrally randomized stratified by center, mediastinum primary tumor, 1st cycle in stabilizing schedule, and brain metastasis to the following arms.

• three additional cycles of T-BEP: paclitaxel 175 mg/m2 IV days 1, cisplatin 20 mg/m² IV days 1-5, etoposide 100 mg/m² IV days 1-5, bleomycin 30 mg IV days 1, 8 and 15 OR days 1, 3 and 5 + G-CSF 5 mcg/kg subcutaneous day 6, until post-nadir absolute neutrophil count ≥ 1.0 x 10^9 - cycled every 21 days (experimental arm).
• Three additional cycles of BEP: cisplatin 20 mg/m² IV days 1-5, etoposide 100 mg/m² IV days 1-5, bleomycin 30 mg IV days 1, 8 and 15 OR days 1, 3 and 5 + G-CSF 5 mcg/kg subcutaneous day 6, until post-nadir absolute neutrophil count ≥ 1.0 x 10^9 (standard arm).

Patients with complete response radiological and marker response after completion of chemotherapy to be followed without additional therapy (surveillance according to guidelines). Patients with radiographically detectable residual masses (eg, retroperitoneal lymph nodes, mediastinal lymph nodes, lung metastases) ≥10 mm and normal STMs (partial remission with negative STMs) should undergo surgery with goal to remove all the residual disease. If the patient considered to have unresectable tumor or to be medically inoperable the treatment approach is to be selected individually.

Patients with viable GCTs in completely resected masses (except for mature teratoma) will be managed with 2 more cycles of EP or TIP chemotherapy.

Patients are following for at least 3 years according to the following schedule: once every 2 months for 2 years, once every 4 months in the third year, once every 6 months in the fourth year, and once every year after the fourth year. Surveillance includes a clinical examination, AFP, b-HCG, LDH, creatinine, blood count, and a CT scan of the initially involved sites every 4 months for 2 years, and then once yearly in the next 3 years.