Intensive induction chemotherapy with C-BOP/BEP for intermediate- and poor-risk metastatic germ cell tumours (EORTC trial 30948)

New chemotherapy regimens are continuously explored in patients with high-risk malignant germ cell tumours (MGCTs). This multicentre phase II trial assessed the efficacy and toxicity of C-BOP/BEP chemotherapy in intermediate and poor prognosis MGCT (IGCCCG criteria). C-BOP/BEP treatment consisted of cycles of cisplatin, vincristine, bleomycin and carboplatin, followed by one cycle of vincristine and bleomycin and three cycles of BEP (bleomycon, etoposide, cisplatin). The trial was designed to demonstrate a 1-year progression-free survival rate of 80%, that is, to exclude a 1-year rate of 70% or less, with a one-sided significance level of 5%. Secondary end points included toxicity, overall survival and the postchemotherapy complete response rate. In total, 16 European hospitals entered 66 eligible patients (intermediate prognosis group: 37; poor prognosis group: 29). A total of 45 patients (68.2%, 95% confidence interval (95% CI): 56.9–79.4%) achieved a complete response (intermediate prognosis: 30; poor prognosis: 15). After a median observation time of 40.4 months (range: 13.7–66.3), the 1-year progression-free survival rate was 81.8% 95% CI: 72.5–91.1%). The 2-year overall survival was 84.5% (95% CI: 75.6–93.3%). In all, 51 patients experienced at least one episode of WHO grade 3/4 leucopenia, and at least one event of grade 3/4 thrombocytopenia occurred in 30 patients. There was no toxic death. With an 82% 1-year progression-free survival and a lower limit of the 95% CI above 70%, the efficacy of C-BOP/BEP is comparable to that of published alternative chemotherapy schedules in high-risk MGCT patients. The treatment's toxicity is manageable in a multicentre setting. In poor prognosis patients, C-BOP/BEP should be compared to standard chemotherapy of four cycles of BEP

Bleomycin, vincristine, cisplatin/bleomycin, etoposide, cisplatin chemotherapy: an alternating, dose intense regimen producing promising results in untreated patients with intermediate or poor prognosis malignant germ-cell tumours

Patients with poor and intermediate prognosis metastatic germ-cell tumours (MGCTs) are at a significant risk of relapse after standard platinum-based chemotherapy. Novel treatment regimens are required to improve survival. Dose intense, alternating combinations of drugs with known activity in germ-cell tumours represents one approach. In all, 43 patients with IGCCCG intermediate/poor prognosis MGCT were treated with a dose intense regimen alternating bleomycin, vincristine, cisplatin (BOP) with bleomycin, etoposide, cisplatin (BEP) to a maximum of three cycles. Data were collected on the maintenance of dose intensity, toxicity, response, progression-free (PFS) and overall survival (OS). The complete response rate was 58%; a further 7% of patients being rendered disease free by resection of viable residual tumour. With a median follow-up of more than 4 years in surviving patients, 3-year OS and PFS rates of 81% (95% CI: 66-91%) and 72% (95% CI: 56-83%) are seen, respectively. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) was well tolerated, with 86% of patients completing all planned courses. Toxicity was predominantly haematological with common toxicity criteria grade III neutropenia in 90% of patients. Cisplatin neuropathy and bleomycin-induced pulmonary toxicity represented the most significant nonhaematological toxicity. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) represents a practicable, well-tolerated, dose intense chemotherapy regimen with significant activity in intermediate and poor prognosis MGCT

Gene therapy vectors containing CArG elements from the Egr1 gene are activated by neutron irradiation, cisplatin and doxorubicin

Combining gene therapy with radiotherapy and chemotherapy holds potential to increase the efficacy of cancer treatment, while minimizing side effects. We tested the responsiveness of synthetic gene promoters containing CArG elements from the Early Growth Response 1 (Egr1) gene after neutron irradiation, doxorubicin and cisplatin. Human MCF-7 breast adenocarcinoma and U373-MG glioblastoma cells were transfected with plasmids containing CArG promoters controlling the expression of the green fluorescent protein (GFP). Exposing the cells to neutrons, doxorubicin or cisplatin resulted in a significant induction of transgene expression. Therapeutic advantage was demonstrated by replacing the reporter with the herpes simplex virus thymidine kinase (HSVtk), able to convert the prodrug ganciclovir (GCV) into a cytotoxin. A 1.3 Gy neutron dose caused 49% growth inhibition in MCF-7 cells, which increased to 63% in irradiated CArG-HSVtk-transfectants treated with GCV. Exposure to 0.5 mM cisplatin or 0.01 mM doxorubicin induced a growth inhibition of 25 - 30% in MCF-7 cells. In the presence of GCV, this value increased to 65 - 70% in cells transfected with the CArG promoter constructs driving the expression of HSVtk. These data indicate that combining CArG-mediated HSVtk/ GCV suicide gene therapy with radio- and chemotherapy can enhance antitumor toxicity, and validates future in vivo investigations