cabazitaxel and Testicular-Neoplasms

Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting.. To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed.. The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated.

Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Resistance, Neoplasm; Humans; Male; Molecular Targeted Therapy; Neoplasms, Germ Cell and Embryonal; Taxoids; Testicular Neoplasms; Treatment Outcome

This review will describe the contemporary management of castration-resistant prostate cancer in the context of multiple recent advances.. Two novel agents have been added to the therapeutic armamentarium including cabazitaxel and sipuleucel-T. Cabazitaxel, a novel taxane extended survival in men with progressive metastatic CRPC following conventional docetaxel-based chemotherapy. Sipuleucel-T, an autologous dendritic cell based vaccine extended survival in men with relatively asymptomatic metastatic CRPC without visceral metastasis. A third agent, abiraterone acetate, an orally administered CYP17 inhibitor, which suppresses androgen synthesis has been preliminarily reported to significantly prolong survival following prior docetaxel and approval by regulatory agencies is anticipated. Baseline and early changes in circulating tumor cells appear useful as a prognostic factor. Additionally, data demonstrated the superiority of denosumab, a RANK-ligand antagonist, compared to zoledronic acid in the prevention of skeletal related events in men with bone metastases.. Cabazitaxel, sipuleucel-T and denosumab were approved in 2010 by regulatory agencies in the USA for men with metastatic CRPC, and approval of abiraterone acetate is anticipated based on the results of a phase III trial. The evaluation of circulating tumor cells assists in determining prognosis, although its utility for clinical decision-making entails validation.

Topics: Androstenes; Androstenols; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Castration; Denosumab; Drug Therapy; Humans; Male; Prostatic Neoplasms; RANK Ligand; Taxoids; Testicular Neoplasms; Tissue Extracts

Outcomes of multiply relapsed, refractory germ-cell tumour (GCT) patients remain poor with an overall survival (OS) of a few months only. Thus, new therapeutic advances are urgently needed. Cabazitaxel has shown preclinical activity in platinum-resistant GCT models. Here, we report the first clinical case series of cabazitaxel treatment for platinum-refractory GCT.. Data of multiply relapsed GCT patients receiving single-agent cabazitaxel were retrospectively analysed. Endpoints included 12-week progression-free survival (PFS) rate, disease control rate, tumour marker responses, median PFS and OS, and toxicity.. Cabazitaxel showed limited activity in 13 heavily pre-treated GCT patients. After a median follow-up of 23 weeks (IQR 29), 69% of patients were deceased. A median of 2 cycles of cabazitaxel (range 1-7) were applied. The 12-week PFS rate was 31%. Median PFS and OS were 7 and 23 weeks, respectively. Two patients achieved objective responses (15%), three patients (23%) achieved a tumour marker decline ≥ 50%, and the disease control rate was 39%. Cabazitaxel was well tolerated. CTCAE° III-IV haemato-toxicity was most common (54%), and dose reductions were scarce (15%).. In this case series, cabazitaxel showed limited activity in heavily pre-treated GCT patients. Two-phase II studies are underway (NCT02115165, NCT02478502) prospectively assessing cabazitaxel in multiply relapsed GCTs.

Topics: Adult; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Male; Mediastinal Neoplasms; Neoplasm Metastasis; Neoplasms, Germ Cell and Embryonal; Retroperitoneal Neoplasms; Retrospective Studies; Taxoids; Testicular Neoplasms

Cisplatin-based chemotherapy is highly effective in metastasized germ cell tumours (GCT). However, 10-30 % of patients develop resistance to cisplatin, requiring salvage therapy. We investigated the in vitro activity of paclitaxel and the novel taxane cabazitaxel in cisplatin-sensitive and -resistant GCT cell lines.. In vitro activity of paclitaxel and cabazitaxel was determined by proliferation assays, and mode of action of cabazitaxel was assessed by western blotting and two screening approaches, i.e. whole proteome analysis and a human apoptosis array.. Activity of paclitaxel and cabazitaxel was not affected by cisplatin resistance, suggesting that there is no cross-resistance between these agents in vitro. Cabazitaxel treatment showed a strong inhibitory effect on colony formation capacity. Cabazitaxel induced classical apoptosis in all cell lines, reflected by cleavage of PARP and caspase 3, without inducing specific changes in the cell cycle distribution. Using the proteomic and human apoptosis array screening approaches, differential regulation of several proteins, including members of the bcl-2 family, was found, giving first insights into the mode of action of cabazitaxel in GCT.. Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.

Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Humans; Male; Neoplasms, Germ Cell and Embryonal; Paclitaxel; Taxoids; Testicular Neoplasms