cabazitaxel and Liver-Neoplasms

Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first and second lines. Vinflunine is the only treatment approved in this setting by the European Medicines Agency and taxanes are also widely used in second line. Cabazitaxel is a taxane with activity in docetaxel-refractory cancers. A randomized study was conducted to compare its efficacy versus vinflunine.. This is a multicenter, randomized, open-label, phase II/III study, following a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II. ECOG Performance Status, anaemia and liver metastases were stratification factors. Primary objectives were overall response rate for the phase II and overall survival for the phase III.. Seventy patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Three patients (13%) obtained a partial response on cabazitaxel (95% CI 2.7-32.4) and six patients (30%) in the vinflunine arm (95% CI 11.9-54.3). Median progression-free survival for cabazitaxel was 1.9 versus 2.9 months for vinflunine (P = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for overall survival benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3- to 4-related adverse events were seen in 41% patients with no difference between the two arms.. This phase II/III second line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those known previously.. NCT01830231.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Transitional Cell; Disease Progression; Disease-Free Survival; Europe; Female; Humans; Liver Neoplasms; Male; Middle Aged; Survival Analysis; Taxoids; Time Factors; Treatment Outcome; Urinary Bladder Neoplasms; Urothelium; Vinblastine

Pegfilgrastim is a long-acting, granulocyte colony-stimulating factor approved in Japan for the prevention of neutropenia caused by antineoplastic agents. Severe thrombocytopenia was reported with pegfilgrastim, however, the factors associated with thrombocytopenia are unclear. This study aimed to explore the factors associated with thrombocytopenia in patients with metastatic castration-resistant prostate cancer treated with pegfilgrastim for primary prophylaxis of febrile neutropenia (FN) with cabazitaxel.. This study included metastatic castration-resistant prostate cancer patients who received pegfilgrastim for primary prophylaxis of FN with cabazitaxel. The timing and severity of thrombocytopenia and factors associated with the reduction rate of platelets were examined in patients who received pegfilgrastim for the primary prevention of FN during the first course of cabazitaxel and by multiple regression analysis.. Thrombocytopenia was most common within 7 days of pegfilgrastim administration, with 32 cases of grade 1 and 6 cases of grade 2 as per the Common Terminology Criteria for Adverse Events version 5.0. Multiple regression analysis revealed that the reduction rate of platelets after pegfilgrastim administration was significantly positively correlated with monocytes. In contrast, the presence of liver metastases and neutrophils was significantly negatively correlated with the reduction rate of platelets.. Thrombocytopenia due to pegfilgrastim administered as primary prophylaxis for FN with cabazitaxel was most likely to occur within one week after pegfilgrastim administration, suggesting that monocytes, neutrophils, and liver metastases were associated with a reduction in platelets.

Topics: Antineoplastic Combined Chemotherapy Protocols; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Liver Neoplasms; Male; Polyethylene Glycols; Prostatic Neoplasms, Castration-Resistant; Recombinant Proteins; Thrombocytopenia

We aimed to evaluate relationships between clinical outcomes and explanatory variables by network clustering analysis using data from a post marketing surveillance (PMS) study of castration-resistant prostate cancer (CRPC) patients.. The PMS was a prospective, multicenter, observational study of patients with metastatic, docetaxel-refractory CRPC treated with cabazitaxel in Japan after its launch in 2014. Graphical Markov (GM) model-based simulations and network clustering in 'R' package were conducted to identify correlations between clinical factors and outcomes. Factors shown to be associated with overall survival (OS) in the machine learning analysis were confirmed according to the clinical outcomes observed in the PMS.. Among the 660 patients analyzed, median patient age was 70.0 years, and median OS and time-to-treatment failure (TTF) were 319 and 116 days, respectively. In GM-based simulations, factors associated with OS were liver metastases, performance status (PS), TTF, and neutropenia (threshold 0.05), and liver metastases, PS, and TTF (threshold 0.01). Factors associated with TTF were OS and relative dose intensity (threshold 0.05), and OS (threshold 0.01). In network clustering in 'R' package, factors associated with OS were number of treatment cycles, discontinuation due to disease progression, and TTF (threshold 0.05), and liver and lung metastases, PS, discontinuation due to adverse events, and febrile neutropenia (threshold 0.01). Kaplan-Meier analysis of patient subgroups demonstrated that visceral metastases and poor PS at baseline were associated with worse OS, while neutropenia or febrile neutropenia and higher number of cabazitaxel cycles were associated with better OS.. Neutropenia may be a predictive factor for treatment efficacy in terms of survival. Poor PS and distant metastases to the liver and lungs were shown to be associated with worse outcomes, while factors related to treatment duration were shown to positively correlate with better OS.

Topics: Aged; Febrile Neutropenia; Humans; Liver Neoplasms; Machine Learning; Male; Product Surveillance, Postmarketing; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Taxoids

Adrenocortical cancer (ACC) is a rare and aggressive malignancy with a poor prognosis. The overall 5-year survival rate of patients with ENS@T stage IV ACC is less than 15%. Systemic antineoplastic therapies have a limited efficacy and new drugs are urgently needed. Human ACC primary cultures and cell lines were used to assess the cytotoxic effect of cabazitaxel, and the role of P-glycoprotein in mediating this effect. Cabazitaxel reduced ACC cell viability, both in ACC cell lines and in ACC primary cell cultures. Molecular and pharmacological targeting of ABCB1/P-gp did not modify its cytotoxic effect in NCI-H295R cells, while it increased the paclitaxel-induced toxicity. Cabazitaxel modified the expression of proteins involved in cellular physiology, such as apoptosis and cell cycle regulation. The drug combination cabazitaxel/mitotane exerted an additive/moderate synergism in different ACC cell experimental models. These results provide a rationale for testing cabazitaxel in a clinical study.

Topics: Adrenal Cortex Neoplasms; Adrenocortical Carcinoma; Adult; Aged; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Proliferation; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Primary Cell Culture; Taxoids; Tumor Cells, Cultured

Polymer-lipid hybrid nanoparticles, PMONPs, were developed to improve the oral absorption of cabazitaxel (CTX), a semi-synthetic taxane derivative, by overcoming multiple gastrointestinal barriers. The nano-carrier is comprised of a poly(ε-caprolactone) (PCL) and chain triglyceride (MCT) hybrid core for drug loading, and a positively charged surface while slightly concealed with a polyethylene oxide (PEO) shell by insertion of poloxamer 188, with the aim of improving the intestinal mucus permeation and epithelial cell uptake. The CTX-loaded PMONPs (CTX-PMONPs) were optimized with 10% MCT content in the core, and characterization showed they were on the nanoscale with a size of 170.2±5.7nm, zeta potential of +40.90±3.05mV, drug loading of 11.5%, and sustained release property. Enhanced mucus permeation of PMONPs were confirmed in a bulk permeation test, in situ SPIP and intestinal distribution study, and is likely attributed to the combined effect of positive charge and hydrophilic PEO layer on the surface. Meanwhile, promoted cellular uptake was found in mucus-secreting cells evaluation, in which potential adsorptive transcytosis, caused by positively charged surface, played a key role. Furthermore, lymphatic transport was positively demonstrated, contributing to the high oral absorption of CTX-PMONPs. The oral bioavailability of CTX was elevated from 7.7% (CTX solution (CTX-Sol)) to 56.6% after oral administration of CTX-PMONPs, approximately 7.3 times higher than that of CTX-Sol. An in vivo anticancer efficiency study showed that CTX-PMONPs orally exhibited a good tumor inhibition effect, and reduced the CTX-caused systemic toxicity compared with intravenous CTX-Sol. In conclusion, PMONPs are able to efficiently orally deliver the anticancer drug, CTX, into systemic circulation, and can achieve the desired oral anticancer effect. This surface modified polymer-lipid hybrid nanoparticle is likely to be a promising carrier for oral delivery of small molecule anticancer drugs.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Cell Line; Drug Carriers; Drug Liberation; Humans; Intestinal Absorption; Intestinal Mucosa; Lipids; Liver Neoplasms; Male; Mice; Mucus; Nanoparticles; Polyethylene Glycols; Rats, Sprague-Dawley; Taxoids; Treatment Outcome

To evaluate the association between prostate-specific antigen (PSA) response and progression-free and overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated with cabazitaxel.. Of the 527 men (median age 72 years), 266 received ≥ 4 cycles of cabazitaxel and had PSA response data. After four cycles, 34.6% of men achieved a PSA decrease ≥ 50% and 49.6% a decrease ≥ 30%. Median progression-free survival was 7.7 (95% CI 6.2, 9.5) months, and overall survival was 19.5 (95% CI 16.0, 30.9) months, corresponding to 1-year event rates of 39.4 and 78.8%, respectively. Median progression-free survival was longer in PSA responders versus non-responders (15.7 vs 5.5 months at 50% cut-off; 15.7 vs 5.3 months for 30% cut-off; both P < 0.0001). Overall survival (50% cut-off) was 23.3 months in responders and 16.0 months in non-responders (P = 0.068); corresponding data at the 30% cut-off are 21.7 and 16.0 months (P = 0.057). Overall, 55.4% of men experienced ≥ 1 adverse event, 59.6% of whom had a serious adverse event.. PSA response after four cycles of cabazitaxel is associated with improved progression-free survival in men with mCRPC treated with cabazitaxel plus prednis(ol)one.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bone Neoplasms; Disease-Free Survival; Humans; Kallikreins; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Prostate-Specific Antigen; Prostatic Neoplasms, Castration-Resistant; Taxoids; Treatment Outcome

We report the case of a 51-year-old patient with metastatic prostate cancer at diagnosis and primary refractoriness to both androgen ablation therapy and docetaxel. At the time of cabazitaxel initiation, the patient had only osseous metastases and was constrained to a wheelchair because of bone pain. Ten cycles of cabazitaxel were administered, and a remarkable response was achieved, with improvement in biochemical markers, performance status, and bone scan findings. Two months after suspension of treatment by choice, the patient developed jaundice because of massive hepatic metastases and died after a few days because of hepatic failure.

Topics: Humans; Liver Neoplasms; Male; Middle Aged; Prostatic Neoplasms, Castration-Resistant; Taxoids

Interactive case studies formed a key feature of the third annual Interactive Genitourinary Cancer Conference held in April/May 2011 in Budapest, Hungary. These cases were used to discuss the practical aspects of the management of metastatic castration-resistant prostate cancer (mCRPC). Particular emphasis was placed on audience participation with potential management options posed as interactive questions to the delegates. This paper summarises these case studies and the related discussion. Docetaxel is the standard first-line chemotherapeutic agent for patients with mCRPC and, until recently, second-line therapeutic options were limited. Results from the recently completed TROPIC trial showed a statistically and clinically significant improvement in overall survival with the microtubule inhibitor cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to be well tolerated and has been approved in Europe and the USA as second-line chemotherapy for mCRPC. Prognostic factors have a potential benefit in individualised patient management in mCRPC. Pretreatment prognostic factors, including PSA doubling time, pain, visceral metastases, anaemia and progression of osseous metastases, have been shown to predict survival outcomes and can be used to guide treatment strategies, including appropriate timing of chemotherapy.   Multiple treatment options and significant heterogeneity among patients with advanced prostate cancer necessitate multidisciplinary team management in addition to patient education, as part of a patient-centred approach. The development of second-line chemotherapeutic agents together with the use of prognostic factors and a patient-centred multidisciplinary team approach provide encouraging new management prospects for patients with mCRPC.

Topics: Aged; Androgen Antagonists; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Congresses as Topic; Docetaxel; Drug Resistance, Neoplasm; Humans; Liver Neoplasms; Male; Palliative Care; Patient-Centered Care; Prognosis; Prostatectomy; Prostatic Neoplasms; Radiotherapy, Adjuvant; Taxoids