Overview
GETUG-13 study has prospectively confirmed poor outcomes in advanced germ cell tumors (GCT) patients with unfavorable decrease of tumor markers after 1 cycle of BEP chemotherapy. There is an unmet medical need to improve outcomes in this subset of patients, however the dose-dense regimen proposed in the above-mentioned trial cannot be implemented in routine clinical practice. T-BEP regimen may have advantage over the traditional BEP regimen as first-line therapy for poor-risk GCT Treatment escalation with T-BEP regimen may be an effective and tolerable therapeutic option for advanced GCT patients with unfavorable tumor markers decline.
Description
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.
Eligibility
Inclusion Criteria:
- Age ≥16 years;
- Evidence of NSGCT based on histologic examination or clinical evidence (high serum HCG or AFP levels - in case of clinical emergency due to bulky disease, therapy can be started without pathological confirmation of the disease);
- Testicular, retroperitoneal, or mediastinal primary site;
- Disease classified as poor prognosis according to IGCCCG criteria:
- Primary mediastinal NSGCT or
- Non-pulmonary visceral metastases or
- HCG \> 50,000 UI/l, or AFP \> 10,000 ng/ml, or LDH \> 10 times the upper normal value.
- No prior chemotherapy;
- No concurrent malignancies which may have an impact of anticipated lifespan (ie, malignancies other than basal-cell skin carcinoma, in situ carcinomas, borderline ovarian tumors etc);
- Adequate renal function: measured or calculated glomerular filtration rate \> 60 ml/min.
- Absolute baseline granulocyte count ≥0.5\10\^9, platelets ≥100\10\^9, bilirubin ≤1.5 ULN.
- Unfavorable tumor marker decline after 1st cycle of standard BEP chemotherapy calculated according to time to normalization from the K. Fizazi study in JCO 2004.
- Signed informed consent before protocol-specific procedures.
Exclusion Criteria:
- Primary intracranial germ-cell tumors;
- Patients with seminomas or dysgerminomas;
- Patients with normal range of serum tumor markers before starting treatment;
- Patients with favorable tumor markers decline;
- Patients infected by the Human Immunodeficiency Virus (HIV);
- Patients with contraindications to taxane agents (hypersensitivity to paclitaxel);
- Patients who do not fit inclusion criteria.
