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Web Resources: Cabazitaxel
Recent Research Publications

Web Resources: Cabazitaxel (5 links)

Recent Research Publications

Lange R, Heine RT, van Wieringen WN, et al.
Cytotoxic Effects of the Therapeutic Radionuclide Rhenium-188 Combined with Taxanes in Human Prostate Carcinoma Cell Lines.
Cancer Biother Radiopharm. 2017; 32(1):16-23 [PubMed] Related Publications
OBJECTIVE: Rhenium-188-HEDP is an effective radiopharmaceutical for the treatment of painful bone metastases from prostate cancer. The effectiveness of the β-radiation emitted by (188)Re might be enhanced by combination with chemotherapy, using the radiosensitization concept. Therefore, the authors investigated the combined treatment of the taxanes, docetaxel and cabazitaxel, with (188)Re in prostate carcinoma cell lines.
MATERIALS AND METHODS: The cytotoxic effects of single and combined treatment with taxanes and (188)Re were investigated in three human prostate carcinoma cell lines (PC-3, DU 145, and LNCaP), using the colony-forming assay. The half maximal effective concentration (EC50) of all individual agents was determined. The combined treatment was studied at 0.25, 0.5, 1, 2, and 4 times the EC50 of each agent. The interaction was investigated with a regression model.
RESULTS: The survival curves showed dose-dependent cell growth inhibition for both the taxanes and (188)Re. The regression model showed a good capability of explaining the data. It proved additivity in all combination experiments and confirmed a general trend to a slight subadditive effect.
CONCLUSIONS: This proof-of-mechanism study exploring radiosensitization by combining (188)Re and taxanes showed no synergism, but significant additivity. This encourages the design of in vivo studies. Future research should explore the potential added value of concomitant treatment of bone metastases with chemotherapy and (188)Re-HEDP.

Cicero G, De Luca R, Dorangricchia P, et al.
Cabazitaxel in Metastatic Castration-Resistant Prostate Cancer Patients Progressing after Docetaxel: A Prospective Single-Center Study.
Oncology. 2017; 92(2):94-100 [PubMed] Related Publications
PURPOSE: The present study aims to evaluate the efficacy of cabazitaxel in combination with prednisone treatment in Italian patients affected by hormone-refractory metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel plus prednisone.
METHODS: Thirty patients with mCRPC were enrolled between June 2013 and January 2016 (the last follow-up was in January 2016). Cabazitaxel was used according to the summary of product characteristics and administered at a dose of 25 mg/m2 every 3 weeks plus oral prednisone at a dose of 5-mg tablets twice a day continuously. The reduction in serum prostate-specific antigen (PSA) was the primary endpoint while reducing pain, safety, progression-free survival, response rate and overall survival (OS) were secondary endpoints.
RESULTS: Cabazitaxel was well tolerated, showing a manageable toxicity profile, associated with a modest objective response rate and a good reduction in PSA levels. Only 12 patients (40%) had a partial response, 10 patients (33%) showed stabilization of disease and 8 (27%) experienced disease progression. The median OS was 14.8 months (95% CI: 11.6-19.8). The linear regression analysis revealed that PSA response was an important predictor of OS, showing a positive correlation with OS (β = 0.377, p < 0.01).
CONCLUSIONS: Three-week treatment with cabazitaxel was found to be valid and was a well-tolerated treatment option for patients with mCRPC after a first-line docetaxel treatment.

Hotte SJ
Addressing taxane resistance in metastatic castration-resistant prostate cancer: a focus on chaperone proteins.
Future Oncol. 2017; 13(4):369-379 [PubMed] Related Publications
Despite the significant survival benefit of taxane therapy in metastatic castration-resistant prostate cancer (mCRPC), all patients inevitably develop treatment resistance. An understanding of resistance mechanisms has led to new therapies for prostate cancer (cabazitaxel, abiraterone and enzalutamide), all of which have improved survival following first-line docetaxel. Another treatment, currently in development, targets the prosurvival molecule clusterin. Custirsen, an antisense molecule that inhibits clusterin production, has shown promise in combination with docetaxel in mCRPC patients at risk for poor outcomes. Although optimal sequence and combination of available therapies is unclear, the heterogeneity of mCRPC suggests a continuing need for personalized treatment regimens and improved abilities to predict which patients will respond to the available treatment options.

Qu N, Lee RJ, Sun Y, et al.
Cabazitaxel-loaded human serum albumin nanoparticles as a therapeutic agent against prostate cancer.
Int J Nanomedicine. 2016; 11:3451-9 [PubMed] Free Access to Full Article Related Publications
Cabazitaxel-loaded human serum albumin nanoparticles (Cbz-NPs) were synthesized to overcome vehicle-related toxicity of current clinical formulation of the drug based on Tween-80 (Cbz-Tween). A salting-out method was used for NP synthesis that avoids the use of chlorinated organic solvent and is simpler compared to the methods based on emulsion-solvent evaporation. Cbz-NPs had a narrow particle size distribution, suitable drug loading content (4.9%), and superior blood biocompatibility based on in vitro hemolysis assay. Blood circulation, tumor uptake, and antitumor activity of Cbz-NPs were assessed in prostatic cancer xenograft-bearing nude mice. Cbz-NPs exhibited prolonged blood circulation and greater accumulation of Cbz in tumors along with reduced toxicity compared to Cbz-Tween. Moreover, hematoxylin and eosin histopathological staining of organs revealed consistent results. The levels of blood urea nitrogen and serum creatinine in drug-treated mice showed that Cbz-NPs were less toxic than Cbz-Tween to the kidneys. In conclusion, Cbz-NPs provide a promising therapeutic for prostate cancer.

Badrising SK, van der Noort V, Hamberg P, et al.
Enzalutamide as a Fourth- or Fifth-Line Treatment Option for Metastatic Castration-Resistant Prostate Cancer.
Oncology. 2016; 91(5):267-273 [PubMed] Related Publications
OBJECTIVE: To evaluate the efficacy of enzalutamide (Enz) as fourth- or fifth-line treatment in men with metastasized castration-resistant prostate cancer (mCRPC), by analyzing a retrospective cohort of heavily pretreated patients.
METHODS: We evaluated toxicity, overall survival (OS), progression-free survival (PFS) and time to prostate-specific antigen (PSA) progression data from 47 CRPC patients treated with fourth- or fifth-line Enz.
RESULTS: All patients were treated with docetaxel and abiraterone acetate and 42 patients (89%) with cabazitaxel. The median age of the patients was 69 years (IQR, 63-73.5), 79% had bone metastases, 55% had lymph node metastases, and 17% had visceral metastases. The median duration of Enz treatment was 12.0 weeks (IQR, 8.3-20.4), and 11 patients (23%) responded to Enz (maximum PSA decline ≥50%). In general, Enz was well tolerated, with the most frequently reported adverse events being fatigue and nausea. The median OS was 40.1 weeks (95% CI, 25.4-61.4), the median PFS was 12.1 weeks (95% CI, 9.9-14.0) and the median time to PSA progression was 15.7 weeks (95% CI, 14.0-28.7).
CONCLUSIONS: Analysis of this retrospective cohort suggests that Enz is well tolerated and that there is a 23% response rate in heavily pretreated CRPC patients, which is comparable with third-line treatment outcomes.

Gerwing M, Jacobsen C, Dyshlovoy S, et al.
Cabazitaxel overcomes cisplatin resistance in germ cell tumour cells.
J Cancer Res Clin Oncol. 2016; 142(9):1979-94 [PubMed] Related Publications
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: Cabazitaxel shows promising in vitro activity in GCT cells, independent of levels of cisplatin resistance.

Seisen T, Rouprêt M, Gomez F, et al.
A comprehensive review of genomic landscape, biomarkers and treatment sequencing in castration-resistant prostate cancer.
Cancer Treat Rev. 2016; 48:25-33 [PubMed] Related Publications
Hormone-naïve prostate cancer and its castration-resistant state (CRPC) are clinically and genetically heterogeneous diseases. From initiation of prostate carcinogenesis to its evolution towards therapeutic resistance, various combinations of genetic and epigenetic events occur. Schematically, progression to CRPC could be divided in two distinct pathways, either dependent or independent of the androgen receptor activity. Nevertheless, because the better knowledge of the genetic landscape of CRPC is under way, limited clinical applications are available at the moment, underlying the usefulness of prognostic and predictive biomarkers in daily practice. Despite the promising prognostic value of circulating tumor cells, no biomarker has been currently validated as a surrogate for overall survival in CRPC patients. Inversely, considerable interest has been generated with the recent finding of the splice variant AR-V7 that allows to predict resistance to abiraterone acetate and enzalutamide. However, other predictive biomarkers would be necessary to accurately guide personalized sequencing of CRPC treatment, which now includes numerous possibilities based on the six validated drugs, without accounting for those currently under investigation in the ongoing randomized controlled trials. As a consequence, only rational sequencing, which consists in choosing an agent that is not expected to have cross-resistance with previous therapy, can be currently advised.

Fujimoto N
Role of the Androgen-Androgen Receptor Axis in the Treatment Resistance of Advanced Prostate Cancer: From Androgen-Dependent to Castration Resistant and Further.
J UOEH. 2016; 38(2):129-38 [PubMed] Related Publications
After the introduction of prostate-specific antigen (PSA) screening, prostate cancer diagnosis has shifted to early and curative stages, although 10-20% of patients still present with metastatic and incurable cancer. Prostate cancer is androgen-dependent, and most patients with prostate cancer initially respond to androgen deprivation therapy (ADT). After 1-2 years of the treatment, advanced prostate cancer eventually progresses to castration resistant prostate cancer (CRPC). A variety of mechanisms of progression from androgen-dependent prostate cancer to CRPC under ADT have been postulated, and the key pathway is re-activation of the androgen-androgen receptor (AR) axis, for example, caused by AR mutation/overexpression/splice variants, altered expression of AR cofactors, and increased production of androgens. Recently approved new agents, such as the hormonal agents abiraterone and enzalutamide and the chemotherapeutic agent cabazitaxel, have demonstrated survival benefit in men with CRPC. However, the prolongation of survival times provided with these agents is limited because of the treatment resistance. Androgen-AR axis still plays a pivotal role in the resistance to the new agents for CRPC. To improve the prognosis of patients with CRPC, intensive research to identify effective agents, treatment strategies, and useful predictive biomarkers to select the patients who can benefit from such treatments are required. Additional clinical data, with a better understanding of the biology of CRPC, may provide better CRPC treatment outcomes. This article reviews the underlying mechanisms of treatment resistance and future direction of CRPC treatments.

Mizokami A, Izumi K, Konaka H, et al.
Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice.
Asian J Androl. 2017 Mar-Apr; 19(2):143-148 [PubMed] Free Access to Full Article Related Publications
Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC) has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen (PSA). However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.

Genestreti G, Di Battista M, Cavallo G, Brandes AA
New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.
Tumori. 2016; 102(4):361-6 [PubMed] Related Publications
Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

Süner A, Aydın D, Hacıoğlu MB, et al.
Effectiveness and safety of cabazitaxel chemotherapy for metastatic castration-resistant prostatic carcinoma on Turkish patients (The Anatolian Society of Medical Oncology).
Eur Rev Med Pharmacol Sci. 2016; 20(7):1238-43 [PubMed] Related Publications
OBJECTIVE: Prostate cancer is among the most common cancers in males. Prostate cancer is androgen dependent in the beginning, but as time progresses, it becomes refractory to androgen deprivation treatment. At this stage, docetaxel has been used as standard treatment for years. Cabazitaxel has become the first chemotherapeutic agent which has been shown to increase survival for patients with metastatic Castrate Resistant Prostate Cancer (mCRPC) that progresses after docetaxel. Phase 3 TROPIC study demonstrated that cabazitaxel prolongs survival.
PATIENTS AND METHODS: In this study, we evaluated a total of 103 patients who took cabazitaxel chemotherapy for mCRPC diagnosis in 21 centers of Turkey, retrospectively. This study included patients who progressed despite docetaxel treatments, had ECOG performance score between 0-2, and used cabazitaxel treatment. Patients received cabazitaxel 25 mg/m2 at every 3 weeks, and prednisolone 5 mg twice a day.
RESULTS: Median number of cabazitaxel cures was 5.03 (range: 1-17). Cabazitaxel response evaluation detected that 34% of the patients had a partial response, 22.3% had stable disease and 32% had a progressive disease. Grade 3-4 hematological toxicities were neutropenia (28.2%), neutropenic fever (14.5%), anemia (6.7%), and thrombocytopenia (3.8%). In our study, median progression-free survival (PFS) was 7.7 months and overall survival (OS) was 10.6 months.
CONCLUSIONS: This study reflects toxicity profile of Turkish patients as a Caucasian race. We suggest that cabazitaxel is a safe and effective treatment option for mCRPC patients who progress after docetaxel. Moreover, ethnicity may play important roles both in treatment response and in toxicity profile.

Di Lorenzo G, Pagliuca M, Perillo T, et al.
Docetaxel Rechallenge in a Heavily Pretreated Patient With Castration-Resistant Prostate Cancer: A Case Report and Review of Literature.
Medicine (Baltimore). 2016; 95(14):e2754 [PubMed] Free Access to Full Article Related Publications
Chemotherapy agents for patients with metastatic castration-resistant prostate cancer (mCRPC) include docetaxel and cabazitaxel. Although docetaxel is approved in the first-line treatment setting, a few studies have shown that selected patients can benefit from docetaxel rechallenge.We, here, report the case of a heavily pretreated mCRPC patient who reported clinical benefit from receiving docetaxel after previous exposure to docetaxel, cabazitaxel, abiraterone, and enzalutamide.After 4 cycles of treatment, patient's performance status had improved to 1, the hemoglobin level was 12.9 g/dL and his serum prostate specific antigen levels were reduced by >70%, with no treatment-related adverse events.Although docetaxel rechallenge is a therapeutic option for selected patients, the risk of cumulative toxicity described in literature must be carefully considered.As the risk of cabazitaxel-related cumulative toxicity is probably lower, retreatment with cabazitaxel rather than docetaxel may also be an option in the setting of heavily pretreated mCRPC patients.

Duran I, Hagen C, Arranz JÁ, et al.
SNPs associated with activity and toxicity of cabazitaxel in patients with advanced urothelial cell carcinoma.
Pharmacogenomics. 2016; 17(5):463-71 [PubMed] Related Publications
AIM: We aimed to identify SNPs associated with cabazitaxel toxicity and response within a Phase II clinical trial using this compound in advanced transitional cell carcinoma after progression to a platinum-based regimen.
PATIENTS & METHODS: Eleven SNPs in CYP3A4, CYP3A5, CYP2C8, ABCB1 and TUBB1 were genotyped in 45 patients.
RESULTS: CYP3A5 rs776746 A allele was associated with protection against gastrointestinal toxicity (odds ratio: 0.06, 95% CI: 0.007-0.63, p = 0.018) and with reduced progression-free survival (hazard ratio: 5.1, 95% CI: 1.7-15.1, p = 0.0038, multivariable analysis). ABCB1 SNPs were associated with total number of grade 3-4 toxicity events (p-values of 0.009, 0.041 and 0.043, respectively).
CONCLUSION: Polymorphisms in CYP3A5 and ABCB1 may define a subset of patients with different cabazitaxel toxicity and efficacy and therefore could be used as markers for treatment optimization.

Gunduz S, Bozcuk H, Yıldız M, et al.
Line of abiraterone acetate in castration-resistant metastatic prostate cancer--Does it matter? report of a multi-institutional experience.
Indian J Cancer. 2015 Oct-Dec; 52(4):658-60 [PubMed] Related Publications
OBJECTIVE: We present our data comparing retrospectively the efficacy of abiraterone and cabazitaxel in patients who progress after docetaxel treatment.
PATIENTS AND METHODS: The study included 56 patients diagnosed with hormone-refractory metastatic prostate cancer who were previously treated with abiraterone therapy at four oncology centers in Turkey.
RESULTS: With abiraterone, the patients had a median progression-free survival (PFS) of 5.9 months (95% confidence interval (CI) for hazard ratio (HR) (4.4-7.4)) and an overall survival of 13.4 months (95% CI for HR (5.5-21.3)). When we compared the disease-free survival (DFS) of reference patients treated with cabazitaxel as a second-line treatment with those receiving second-line abiraterone therapy, there was no significant difference. (PFS = 5.9 months with cabazitaxel vs. 6.7 months with abiraterone, P = 0.213).
CONCLUSION: This study has shown that in our experience abiraterone acetate is an effective agent in metastatic castration-resistant prostate cancer (mCRPC) regardless of the line of treatment.

Vignani F, Bertaglia V, Buttigliero C, et al.
Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer.
Cancer Treat Rev. 2016; 44:61-73 [PubMed] Related Publications
Incidence of bone metastases is very high in advanced prostate cancer patients. Bone metastases likely have a significant impact on functional status and quality of life, not only related to pain, but also to the relevant risk of skeletal-related events. A better understanding of mechanisms associated with bone metastatic disease secondary to prostate cancer and more specifically to the cross-talk between tumor cells and bone microenvironment in metastatic progression represented the background for the development of new effective bone-targeted therapies. Furthermore, a better knowledge of biological mechanisms driving disease progression led to significant advances in the treatment of castration-resistant prostate cancer, with the development and approval of new effective drugs. Aim of this review is to outline the physiopathology of bone metastases in prostate cancer and summarize the main results of clinical trials conducted with different drugs to control morbidity induced by skeletal metastases and bone disease progression. For each agent, therapeutic effect on bone metastases has been measured in terms of pain control and/or incidence of skeletal-related events, usually defined as a composite endpoint, including the need for local treatment (radiation therapy or surgery), spinal cord compression, pathological bone fractures. In details, data obtained with chemotherapy (mitoxantrone, docetaxel, cabazitaxel), new generation hormonal agents (abiraterone, enzalutamide), radium-223, bone-targeted agents (zoledronic acid, denosumab) and with several experimental agents (cabozantinib, dasatinib, anti-endothelin and other agents) in patients with castration-resistant prostate cancer are reviewed.

Zafeiriou Z, Jayaram A, Sharp A, de Bono JS
Managing Metastatic Castration-Resistant Prostate Cancer in the Pre-chemotherapy Setting: A Changing Approach in the Era of New Targeted Agents.
Drugs. 2016; 76(4):421-30 [PubMed] Related Publications
In recent years, the therapeutic options for treating men with metastatic castration-resistant prostate cancer have increased substantially. The hormonal treatments abiraterone acetate and enzalutamide, the chemotherapeutics docetaxel and cabazitaxel, the radiopharmaceutical alpharadin and the immunotherapeutic Sipuleucel-T have entered the field. Additionally, corticosteroids, which are used extensively, have documented activity but no documented survival benefit. Physicians treating patients with metastatic prostate cancer immediately after castration resistance develops currently have at least four different options to choose from for the first treatment. These therapeutic choices and their several possible ways of sequential use have not yet been compared to each other head-to-head and may never be. Therefore, there is an unmet need to inform their use with prospective clinical data. Additionally, the new indications of docetaxel for hormone naïve prostate cancer is changing the landscape of prostate cancer treatment and questions the traditional classifications 'pre-chemotherapy' and 'post-chemotherapy'. In this work we attempt to address these challenges in the treatment of metastatic castration-resistant prostate cancer with the focus mainly on the non-cytotoxic agents. We try to integrate available clinical and preclinical information to suggest optimal ways of treatment.

Cassinello J, Carballido Rodríguez J, Antón Aparicio L
Role of taxanes in advanced prostate cancer.
Clin Transl Oncol. 2016; 18(10):972-80 [PubMed] Related Publications
Advanced prostate cancer is an androgen-dependent disease for which the initial treatment is an androgen deprivation maneuver. However, some primary resistances to hormonal treatment occur with increasing incidence throughout the evolution of the disease. The taxanes, docetaxel and cabazitaxel, exert their action at multiple levels at the tumor cell: besides inhibiting the mitosis and inducing the cell death, they induce the nuclear accumulation of FOXO1, a potent nuclear factor that acts against the activation of androgen receptor inhibiting the transcription of AR-V7 variant associated with the development of resistances to abiraterone and enzalutamide. Docetaxel, as first-line therapy, and cabazitaxel, as second-line therapy, have demonstrated to increase the survival in castration-resistant prostate cancer. The results from last studies either on high-risk localized disease or on androgen-sensitive tumors demonstrate the increasing role of taxanes at earlier states of prostate cancer.

Meisel A, von Felten S, Vogt DR, et al.
Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial.
Eur J Cancer. 2016; 56:93-100 [PubMed] Related Publications
BACKGROUND: Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade ≥3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes.
METHODS: Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade ≥3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed.
FINDINGS: The occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43-0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40-0.79], p = 0.001) and a higher confirmed PSA response ≥50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade ≥3 neutropenia. Grade ≥3 neutropenia was more common in case of NLR <3 as compared with NLR ≥3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade ≥3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade ≥3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28-0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support.
INTERPRETATION: This post-hoc analysis of TROPIC suggests that the occurrence of grade ≥3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade ≥3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m(2) whenever possible.

Di Lorenzo G, Bracarda S, Gasparro D, et al.
Lack of Cumulative Toxicity Associated With Cabazitaxel Use in Prostate Cancer.
Medicine (Baltimore). 2016; 95(2):e2299 [PubMed] Free Access to Full Article Related Publications
Cabazitaxel provided a survival advantage compared with mitoxantrone in patients with castration-resistant prostate cancer refractory to docetaxel. Grade 3 to 4 (G3-4) neutropenia and febrile neutropenia were relatively frequent in the registrative XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer (TROPIC) trial, but their incidence was lower in the Expanded Access Program (EAP). Although cumulative doses of docetaxel are associated with neuropathy, the effect of cumulative doses of cabazitaxel is unknown. In this retrospective review of prospectively collected data, the authors assessed "per cycle" incidence and predictors of toxicity in the Italian cohort of the EAP, with a focus on the effect of cumulative doses of cabazitaxel.The study population consisted of 218 Italian patients enrolled in the cabazitaxel EAP. The influence of selected variables on the most relevant adverse events identified was assessed using a Generalized Estimating Equations model at univariate and multivariate analysis."Per cycle" incidence of G 3 to 4 neutropenia was 8.7%, whereas febrile neutropenia was reported in 0.9% of cycles. All events of febrile neutropenia occurred during the first 3 cycles. Multivariate logistic regression analysis showed that higher prior dose of cabazitaxel was associated with decreased odds of having G3 to 4 neutropenia (OR = 0.90; 95% CI: 0.86-0.93; P < 0.01), febrile neutropenia (OR = 0.52; 95% CI: 0.34-0.81; P < 0.01) and G3 to 4 anemia (OR = 0.93; 95% CI: 0.86-1; P = 0.07). Patients with a body surface area >2 m2 presented increased odds of having G 3 to 4 neutropenia (OR = 0.93; 95% CI: 0.86-1; P = 0.07), but decreased odds of having G3 to 4 anemia.Among the toxicities assessed, the authors did not identify any that appeared to be associated with a higher number of cabazitaxel cycles delivered. Prior cumulative dose was associated with reduced G3 to 4 neutropenia and anemia. The apparent protective effect associated with higher doses of cabazitaxel is likely to be affected by early dose reduction and early toxicity-related treatment discontinuation. Because this analysis is limited by its retrospective design, prospective trials are required to assess the optimal duration of cabazitaxel treatment.

Singapore Cancer Network (SCAN) Guidelines for the Management of Advanced Castrate-Resistant Prostate Cancer.
Ann Acad Med Singapore. 2015; 44(10):397-405 [PubMed] Related Publications
INTRODUCTION: The SCAN genitourinary cancer workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for the management of advanced castrate-resistant prostate cancer.
MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.
RESULTS: Five international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2014), the European Society of Medical Oncology (2013), the American Urological Association (2013), the National Institute of Health and Clinical Excellence (2014) and the American Society of Clinical Oncology and Cancer Care Ontario (2014). Recommendations on the management of advanced castrate-resistant prostate cancer were developed.
CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for the management of advanced castrate-resistant prostate cancer.

Moriceau G, Guillot A, Pacaut C, et al.
Translating Clinical Evidence-Based Medicine into the Real World: Single-Center Experience with Cabazitaxel in Metastatic Prostate Cancer Patients.
Chemotherapy. 2016; 61(3):127-33 [PubMed] Related Publications
BACKGROUND: We studied the efficacy and safety of cabazitaxel in unselected real-life patients.
PATIENTS AND METHODS: We retrospectively investigated all patients with metastatic prostate cancer (mPC) treated with cabazitaxel 25 mg/m2 i.v. every 3 weeks combined with oral prednisolone (10 mg once daily) after first-line docetaxel chemotherapy. Study issues were to report patient characteristics and cabazitaxel data in terms of tolerance and efficacy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. All data were compared with TROPIC results.
RESULTS: From 2011 to 2014, 41 patients received cabazitaxel; 15 patients (37%) had a performance status (PS) ≥2 versus 7% (p < 0.0001) in TROPIC, and 38 patients (93%) presented a Gleason score ≥7 at baseline (vs. 60%; p < 0.0001). All patients had metastatic disease at baseline. Previous therapies were radiotherapy in 17 patients (41 vs. 61%; p = 0.01) and surgery in 24 patients (59 vs. 52%; p = 0.4). The median number of cabazitaxel cycles was 5 (1-10) versus 6 (3-10) in TROPIC. Five patients completed 10 cycles of cabazitaxel (12%) versus 28% in TROPIC (p = 0.03). Toxicities were anemia (12 patients, 29%), diarrhea (9 patients, 22%), nausea (7 patients, 17%), pain (6 patients, 15%), sepsis (4 patients, 10%), neutropenia (3 patients, 7%) and urinary tract infection (1 patient, 2%). The tumor response rate was 19.5 versus 14.4% in TROPIC (nonsignificant). PFS was 4.5 months (95% CI 3.3-6.4) in our analysis and 2.8 months (95% CI 2.4-3.0) in TROPIC. OS was 12.1 months (95% CI 9.2 to not reached) and 15.1 months (95% CI 14.1-16.3), respectively.
CONCLUSION: In our unselected mPC patients with poorer baseline clinical conditions and aggressive disease, cabazitaxel seems efficient and not more toxic than in the TROPIC study.

Ramachandran K, Speer C, Nathanson L, et al.
Role of DNA Methylation in Cabazitaxel Resistance in Prostate Cancer.
Anticancer Res. 2016; 36(1):161-8 [PubMed] Related Publications
BACKGROUND/AIM: Cabazitaxel is an approved second-line treatment for docetaxel-refractory metastatic castration-resistant prostate cancer. However, the median time to progression on cabazitaxel is 2.8 months. We aimed to determine whether DNA methylation plays a role in cabazitaxel resistance.
MATERIALS AND METHODS: DU145 cells, resistant to docetaxel and cabaxitaxel (DU145 10DRCR), were generated from cells resistant to 10 nM docetaxel (DU145 10DR). The effect of pre-treatment with 5-azacytidine was determined with regards to cabazitaxel sensitivity. Gene expression profiling was carried-out on DU145 10DR, DU145 10DRCR and DU145 10DRCR treated with 5-azacytidine.
RESULTS: Pre-treatment of cells with 5-azacytidine resulted in enhanced sensitivity to cabazitaxel. Gene expression profiling identified a subset of genes that may be regulated by DNA methylation.
CONCLUSION: Our results indicate that DNA methylation of pro-apoptotic and cell-cycle regulatory genes may contribute to cabazitaxel resistance and pre-treatment with 5-azacytidine may restore sensitivity to cabazitaxel in prostate cancer cells.

Flaig TW, Potluri RC, Ng Y, et al.
Treatment evolution for metastatic castration-resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world data.
Cancer Med. 2016; 5(2):182-91 [PubMed] Free Access to Full Article Related Publications
Despite increasing drug treatment options for metastatic castration-resistant prostate cancer (mCRPC) patients, real-world treatment data are lacking. We conducted retrospective analyses of commercial claims and electronic medical record (EMR) databases to understand how treatment patterns for mCRPC have changed in a US-based real-world population. Truven Health Analytics MarketScan(®) (2000-2013) and EMR (2004-2013) databases were used to identify patients with an index prostate cancer diagnosis (ICD-9 codes 185X or 233.4X) and prescription claims for an mCRPC drug (mitoxantrone, estramustine, docetaxel, sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, or radium-223). Regimen analyses for first line of therapy (LOT1), second line of therapy, and beyond were performed among cohorts based on year of first mCRPC drug usage. mCRPC drug usage and treatment duration were compared across cohorts and age groups within each cohort. The commercial claims cohort yielded 3437 evaluable patients. Most men (91%) commencing mCRPC treatment had docetaxel as LOT1 in 2010; this number had declined to 15% in 2013. In 2013, 67% and 9% of patients used abiraterone acetate and enzalutamide, respectively, as LOT1. Among both commercial claims and EMR cohorts, treatment pattern changes were most pronounced in men aged >80 years, and median treatment duration for some mCRPC drugs was shorter than expected based on available clinical trial information. These results demonstrate a shift in mCRPC treatments during the past 5 years, with greater use of newer noncytotoxic treatments than docetaxel. These real-world data aid in understanding the changing role of chemotherapy in the management of mCRPC.

Ojima I, Lichtenthal B, Lee S, et al.
Taxane anticancer agents: a patent perspective.
Expert Opin Ther Pat. 2016; 26(1):1-20 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Paclitaxel and docetaxel were two epoch-making anticancer drugs and have been successfully used in chemotherapy for a variety of cancer types. In the year 2010, a new taxane, cabazitaxel, was approved by FDA for use in combination with prednisone for the treatment of metastatic hormone-refractory prostate cancer. Albumin-bound paclitaxel (nab™-paclitaxel; abraxane) nanodroplet formulation was another notable invention (FDA approval 2005 for refractory, metastatic, or relapsed breast cancer). Abraxane in combination with gemcitabine for the treatment of pancreatic cancer was approved by FDA in 2013. Accordingly, there have been a huge number of patent applications dealing with taxane anticancer agents in the last 5 years. Thus, it is a good time to review the progress in this area and find the next wave for new developments.
AREA COVERED: This review covers the patent literature from the year 2010 to early 2015 on various aspects of taxane-based chemotherapies and drug developments.
EXPERT OPINION: Three FDA-approved taxane anticancer drugs will continue to expand their therapeutic applications, especially through drug combinations and new formulations. Inspired by the success of abraxane, new nano-formulations are emerging. Highly potent new-generation taxanes will play a key role in the development of efficacious tumor-targeted drug delivery systems.

Martin SK, Pu H, Penticuff JC, et al.
Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer.
Cancer Res. 2016; 76(4):912-26 [PubMed] Free Access to Full Article Related Publications
Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial-mesenchymal transition (EMT) to mesenchymal-epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer.

Mizutani K, Tomoda M, Ohno Y, et al.
Effects of Cabazitaxel in Renal Cell Carcinoma Cell Lines.
Anticancer Res. 2015; 35(12):6671-7 [PubMed] Related Publications
BACKGROUND/AIM: Advanced renal cell carcinoma is treated with mammalian target of rapamycin (mTOR) inhibitors or tyrosine kinase inhibitors (TKIs). The effects of these drugs are, however, limited and novel treatment strategies are required. Clear-cell type renal cell carcinoma (ccRCC) is chemo-resistant, in part, due to expression of multidrug resistance proteins such as p-glycoprotein. Cabazitaxel, a tubulin-binding taxane drug used for castration-resistant prostate cancer, has less affinity for p-glycoprotein compared to docetaxel. In the current study, the effects of docetaxel and cabazitaxel on ccRCC cells were investigated.
MATERIALS AND METHODS: The expression of p-glycoprotein was evaluated in the ccRCC cell lines, Caki-1, KMRC-1 and OS-RC-2 by western blotting. Cells were treated with cabazitaxel or docetaxel, and growth kinetics and tubulin polymerization were determined by the WST-1 assay and cell-based tubulin polymerization assay, respectively. Intracellular drug concentrations were measured by chromatography. AKT activation after treatment was examined by western blotting.
RESULTS: All ccRCC cell lines expressed p-glycoprotein. Cabazitaxel inhibited cell growth and induced tubulin polymerization more potently than docetaxel. The intracellular concentration of cabazitaxel was much higher than docetaxel in all cell lines. Both docetaxel and cabazitaxel inhibit AKT phosphorylation at 5 min among three cells.
CONCLUSION: Cabazitaxel inhibits growth of ccRCC cells expressing p-glycoprotein and could thus be possibly used for advanced ccRCC patients in combination with targeted-therapy enhancing their effects.

Herden J, Heidegger I, Paffenholz P, Porres D
Systemic Medical Treatment in Men with Metastatic Castration-Resistant Prostate Cancer: Recommendations for Daily Routine.
Oncol Res Treat. 2015; 38(12):654-68 [PubMed] Related Publications
The approval or clinical evaluation of several new agents - cabazitaxel, abiraterone acetate, enzalutamide, sipuleucel-T, and radium-223 - has significantly changed the management of patients with metastatic castration-resistant prostate cancer (mCRPC) prior to or after docetaxel-based chemotherapy. All of these agents have resulted in a significant survival benefit as compared to their control group. However, treatment responses might differ depending on the associated comorbidities and the extent and biological aggressiveness of the disease. Furthermore, treatment-associated side effects differ between the various drugs. As new drugs become approved, new treatment strategies and markers to best select which patients will best respond to which drug are needed. It is the aim of the current article to i) summarize the data of established treatment options in mCRPC, ii) highlight new developments in medical treatment, iii) provide clinically useful algorithms for the daily routine, and iv) point out future developments in medical treatment.

Joerger M
Treatment regimens of classical and newer taxanes.
Cancer Chemother Pharmacol. 2016; 77(2):221-33 [PubMed] Related Publications
The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle-bound nab-paclitaxel are among the most widely used anticancer drugs. The taxanes share the characteristics of extensive hepatic metabolism and biliary excretion, the need for dose adaptation in patients with liver dysfunction, and a substantial pharmacokinetic variability even after taking into account known covariates. Data from clinical studies suggest that optimal scheduling of the taxanes is dependent not only on the specific taxane compound, but also on the tumor type and line of treatment. Still, the optimal dosing regimen (weekly vs 3 weekly) and optimal dose of the taxanes are controversial, as is the value of pharmacological personalization of taxane dosing. In this article, an overview is given on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics-pharmacodynamics and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most active and safe regimen, the recommended initial dose and the issue of therapeutic drug dosing.

dela Rama F, Pratz C
Navigating Treatment of Metastatic Castration- Resistant Prostate Cancer: Nursing Perspectives.
Clin J Oncol Nurs. 2015; 19(6):723-32 [PubMed] Related Publications
BACKGROUND: Treatment of metastatic castration-resistant prostate cancer (mCRPC) has evolved rapidly. In particular, five new treatments that extend survival in mCRPC have been approved since 2010, including the chemotherapy cabazitaxel (Jevtana®), hormonal agents abiraterone (Zytiga®) and enzalutamide (Xtandi®), vaccine sipuleucel-T (Provenge®), and radiopharmaceutical radium-223 (Xofigo®); all have different indications and toxicity profiles.
OBJECTIVES: This review discusses treatment advances in mCRPC, including considerations for side-effect management and treatment sequencing. Studies relating to quality of care in prostate cancer are also discussed.
METHODS: Nonsystematic searches were performed on published manuscripts and abstracts from major oncology or urology congresses, focusing on practical characteristics of the previously mentioned new treatments that extend survival in mCRPC, as well as studies relating to quality of care and the role of nurses in prostate cancer management.
FINDINGS: To ensure that patients derive optimal clinical benefit, assessing overall health and proactively managing expected side effects are essential. Treatment sequencing in mCRPC is an important consideration, but clinical data in this area are limited. Despite medical advances in mCRPC, studies have identified other aspects of care in which improvement is needed. Nurses can make major contributions to addressing supportive care needs, which has been shown to improve patient care and outcomes in prostate cancer. Although patient navigation programs have improved coordination of care, inconsistent implementation among centers has been identified for prostate cancer. Greater use of outcome measures can help to identify unmet patient needs.

Maughan BL, Antonarakis ES
Clinical Relevance of Androgen Receptor Splice Variants in Castration-Resistant Prostate Cancer.
Curr Treat Options Oncol. 2015; 16(12):57 [PubMed] Related Publications
OPINION STATEMENT: Metastatic castration-resistant prostate cancer (mCRPC) currently benefits from a wealth of treatment options, yet still remains lethal in the vast majority of patients. It is becoming increasingly understood that this disease entity continues to evolve over time, acquiring additional and diverse resistance mechanisms with each subsequent therapy used. This dynamic relationship between treatment pressure and disease resistance can be challenging for the managing clinician. The recent discovery of alternate splice variants of the androgen receptor (AR) is one potential mechanism of escape in mCRPC, and recognizing this resistance mechanism might be important for optimal treatment selection for our patients. AR-V7 appears to be the most relevant AR splice variant, and early clinical data suggest that it is a negative prognostic marker in mCRPC. Emerging evidence also suggests that detection of AR-V7 may be associated with resistance to novel hormonal therapy (abiraterone and enzalutamide) but may be compatible with sensitivity to taxane chemotherapy (docetaxel and cabazitaxel). Adding to this complexity is the observation that AR-V7 is a dynamic marker whose status may change across time and depending on selective pressures induced by different therapies. Finally, it is possible that AR-V7 may represent a therapeutic target in mCRPC if drugs can be designed that degrade or inhibit AR splice variants or block their transcriptional activity. Several such agents (including galeterone, EPI-506, and bromodomain/BET inhibitors) are now in clinical development.

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