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Aims: The intermittent administration of chemotherapy is a means of preserving patients' quality of life (QL). The aim of this study was to verify whether the intermittent administration of docetaxel (DOC) improves the patients' QL., Patients & Methods: All patients received DOC 70 mg/m(2) every 3 weeks for eight cycles. The patients were randomized to receive DOC continuously or with a fixed 3-month interval after the first four DOC courses., Results: The study involved 148 patients. There was no difference in QL between the groups receiving intermittent or continuous treatment. Intermittence had no detrimental effects on disease control., Conclusion: Although feasible and not detrimental, our results showed that true intermittent chemotherapy in metastatic castration-resistant prostate cancer patients failed to improve the patients' QL.

The standard of care for patients with local advanced or metastatic urothelial carcinoma is chemotherapy. However, results with this are rather disappointing, and validated prognostic factors and biomarkers of tumor response, which are useful in the decision-making process, are still lacking. PubMed databases were searched for articles published until November 2013. Several promising clinical and biological candidate prognostic factors or markers of tumor response to first- or second-line therapy, such as hemoglobin, performance status, visceral metastasis and ERCC1, hENT1 and EMT markers, have been identified and described in this article. In summary, clinical parameters and molecular profiling could revolutionize the management of local advanced or metastatic urothelial cancer, but an improvement in individualized therapeutic approaches still seems distant.

Background: The objective of this study was to analyze the impact of visceral metastases in castration-resistant prostate cancer (CRPC) treated with abiraterone., Materials & Methods: All CRPC patients received abiraterone 1000 mg daily plus prednisone 10 mg orally daily. Liver and lung metastases were considered as visceral metastases., Results: Of 265 CRPC patients, 49 had visceral metastases. Results on progression-free survival were not significantly different in patients with or without visceral metastases. Conversely, the median overall survival between the two groups was 12.4 and 18.5 months (p = 0.01), respectively, and median overall survival of patients with liver-only disease versus other sites was 10.5 versus 18.5 months (p = 0.006), respectively., Conclusion: Visceral disease appears to be an important predictor of clinical outcome in CRPC patients treated with abiraterone.

The availability of active new drugs for the treatment of advanced castration-resistant prostate cancer has significantly prolonged overall survival, thus changing the natural history of the disease and raising the likelihood of observing metastases in atypical sites. This review of the literature describes the frequency, clinical-pathological features and presenting symptoms of non-liver gastrointestinal metastases (GIm) from prostate cancer. Its purpose is to increase clinical awareness of the increasing incidence of such GIm, contributing to the early detection, accurate diagnosis and, when feasible, appropriate management.

Purpose: A correlation, power and benchmarking analysis between progression-free and overall survival (PFS, OS) of randomized trials with targeted agents or immunotherapy for advanced renal cell carcinoma (RCC) was performed to provide a practical tool for clinical trial design., Results: For 1st-line of treatment, a significant correlation was observed between 6-month PFS and 12-month OS, between 3-month PFS and 9-month OS and between the distributions of the cumulative PFS and OS estimates. According to the regression equation derived for 1st-line targeted agents, 7859, 2873, 712, and 190 patients would be required to determine a 3%, 5%, 10% and 20% PFS advantage at 6 months, corresponding to an absolute increase in 12-month OS rates of 2%, 3%, 6% and 11%, respectively., Conclusions: These data support PFS as a reliable endpoint for advanced RCC receiving up-front therapies. Benchmarking and power analyses, on the basis of the updated survival expectations, may represent practical tools for future trial' design., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Adenocarcinoma of the paraurethral glands represents a very rare neoplasm of the urinary tract. Due to the rarity of this disease, there is no standard therapeutic approach. We report a case of adenocarcinoma of the paraurethral glands in a 56-year-old woman, presenting with abnormal serous vaginal discharges. The radiologic examination revealed a 5-cm mass around the urethra, which underwent surgical resection. After surgical resection, the histology revealed a moderately differentiated adenocarcinoma, probably arising from the paraurethral glands. One month later, a pelvic recurrent mass was radiologically diagnosed; consequently, an anterior pelvic exenteration with lymph node dissection was performed. Histological examination revealed a moderately differentiated adenocarcinoma, with glandular and micropapillary architecture, with multiple lymph node metastases. The absence of modifications such as urethritis cystic glandularis on the urethral mucosa, as well as the lack of a lesion in situ, associated with the immunohistochemical expression of PAX8 and negativity for GATA3 and S100p, suggested that the adenocarcinoma originated from the paraurethral glands rather than from the urethral mucosa. Post-surgery CT scans revealed no evidence of metastatic disease. The patient received 6 courses of adjuvant chemotherapy with carboplatin and paclitaxel. One year after the pelvic exenteration, because of inguinal lymph node progression, an inguinal lymphadenectomy was performed. Four months later, a TC-PET revealed a multidistrectual lymph node and a lung micronodule disease progression. Invasive micropapillary carcinomas have been characterized as a rare distinctive variant of carcinomas in several anatomic sites and are distinguished by a marked tendency to lymphovascular invasion, justifying the association with high-stage disease and poor prognosis. In the present case, both the poor prognosis connected with micropapillary structure and the lymph node involvement, encouraged adjuvant cisplatinum-based chemotherapy.

Background: Enzalutamide is active in advanced castration-resistant prostate cancer (CRPC) patients, in whom it has shown to be able to increase survival. We report the enzalutamide effect on primary prostate tumors, assessed by changes of metabolic tumor activity detected by (18)F-fluorocholine-positron emission tomography/computerized tomography ((18)F-FCH PET/CT)., Patients and Methods: We treated 31 patients with pretreated metastatic CRPC in an enzalutamide named-patient program. All patients were initially evaluated and then followed up by means of repeated (18)F-FCH PET/CT examinations. We identified most radiotracer-avid lesions, which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum radiotracer standardized uptake value (SUVmax) and the threshold-based volume of interest (VOI) with a cutoff SUV value ≥ 2.5. In the 12 patients who did not receive a radical treatment for localized disease, the prostate was also considered an ROI., Results: The baseline prostate median SUVmax of 7.25 showed reductions of 25% (P = .012) and 43% (P = .009) after 3 and 7 months of enzalutamide treatment, respectively. The baseline median prostate VOI of 12.73 cm(3) showed a reduction of 73% (P = .002) at 3 months and a reduction of 90% (P = .005) at 7 months., Conclusion: In addition to the metabolic changes of metastatic lesions observed with enzalutamide in CRPC patients, our data have shown significant volume reductions of the primary tumors according to (18)F-FCH PET/CT evaluation. These results could suggest the potential of enzalutamide therapy for localized prostate cancer., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Aim: To identify factors predicting primary resistance to new-generation hormonal agents (NHAs), abiraterone acetate and enzalutamide in patients with castration-resistant prostate cancer (CRPC)., Patients & Methods: Our hospital has conducted two successive named patient NHA programs. A total of 57 patients with progressive CRPC previously treated with first-line docetaxel-based chemotherapy received standard NHA doses: abiraterone acetate 1000 mg once-daily combined with prednisone (5 mg twice daily) or enzalutamide 160 mg once-daily. Patients, who were assessed monthly to check their hematological parameters and prostate-specific antigen (PSA) levels, also underwent imaging investigations every 3-4 months. In total, 24 variables were assessed as potential predictors of primary NHA resistance., Results: Univariate analysis indicated that baseline pain and lactate dehydrogenase levels, and PSA levels after 1 month's treatment were predictive of primary NHA resistance. Only the predictive value of PSA levels after 1 month of treatment was confirmed at multivariate analysis. This factor strongly predicted progression-free and overall survival., Conclusion: RESULTS suggest the use of a simple and rapid method of identifying patients with primary resistance to NHAs: patients not achieving a ≥ 50% reduction in PSA levels within the first treatment month should undergo intensive investigations to verify whether they have primary resistance to NHAs.

Tumor-associated macrophages (TAMs) derived from peripheral blood monocytes recruited into the renal cell carcinoma (RCC) microenvironment. In response to inflammatory stimuli, macrophages undergo M1 (classical) or M2 (alternative) activation. M1 cells produce high levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin (IL)-12, IL-23 and IL-6, while M2 cells produce anti-inflammatory cytokines, such as IL-10, thus contributing to RCC-related immune dysfunction. The presence of extensive TAM infiltration in RCC microenvironment contributes to cancer progression and metastasis by stimulating angiogenesis, tumor growth, and cellular migration and invasion. Moreover, TAMs are involved in epithelial-mesenchymal transition of RCC cancer cells and in the development of tumor resistance to targeted agents. Interestingly, macrophage autophagy seems to play an important role in RCC. Based on this scenario, TAMs represent a promising and effective target for cancer therapy in RCC. Several strategies have been proposed to suppress TAM recruitment, to deplete their number, to switch M2 TAMs into antitumor M1 phenotype and to inhibit TAM-associated molecules. In this review, we summarize current data on the essential role of TAMs in RCC angiogenesis, invasion, impaired anti-tumor immune response and development of drug resistance, thus describing the emerging TAM-centered therapies for RCC patients.

Background: Although data from ongoing trials with targeted agents are awaited, we used a meta-analytical approach to explore whether cytokines (CK), vaccines (VAX), or other therapies may differentially influence patients' outcomes., Materials and Methods: The objective was to determine whether significant interactions exist according to treatment (CK vs. VAX vs. other), in the context of a literature-based meta-analysis. Fourteen trials (3380 patients) were identified, with 10 randomized clinical trials (RCTs) (2257 patients) providing data for the primary outcome--5-year relapse-free survival (RFS). The primary selected end point was 5-year RFS; secondary end points were 5- and 2-year overall survival (OS) and 2-year RFS. Event-based relative risk (RR) ratios with 95% confidence intervals (CI) were extracted and cumulated according to a random-effect model from articles/presentations. Testing for heterogeneity was performed as well., Results: Although not statistically significant, an effect in favor of a qualitative interaction according to treatment was found for 5-year RFS, with a likely detrimental effect in CK (P = .42) in contrast to that found in VAX subpopulation (P = .76). For the secondary end points, a similar effect in favor of a quantitative significant interaction according to treatment was found for 5-year OS, regardless of the approach adopted, with a different magnitude of treatment effect. In addition, a borderline significant (P = .05) detrimental effect in terms of 2-year OS against the use of adjuvant treatment was determined in the CK subpopulation (RR, 1.24; 95% CI, 0.99, 1.54)., Conclusion: The effect in favor of a qualitative interaction according to the adopted strategy is intriguing and suggests potential implications for trial design with targeted agents., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To describe the incidence and clinical relevance of biochemical and objective responses to abiraterone acetate (AA) withdrawal (AAWD) in patients with castration-resistant prostate cancer (CRPC)., Materials and Methods: Twenty-six patients with progressive CRPC treated with first-line docetaxel-based chemotherapy were administered with AA at the standard dose of 1000 mg/day in combination with prednisone until progression. The patients were regularly followed up during treatment and after AAWD., Results: Nineteen of the 26 patients discontinued AA because of progression. Three of the patients undergoing AAWD experienced a biochemical response, which was accompanied by a metabolic and radiological response as revealed by choline positron emission tomography in 2 cases., Conclusion: Regardless of the underlying molecular bases, AAWD response does not occur rarely. It is sometimes long-lasting and accompanied by a metabolic and radiographic improvement. AAWD response should be taken into account when further therapeutic strategies are planned in patients with CRPC with progressive disease during abiraterone therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed.

The rapid approval of several novel agents has given prostate cancer patients and their treating physicians many new and effective therapeutic options. Four new medical therapies were recently approved on the basis of prolonged overall survival in castration-resistant prostate cancer (CRPC) patients: sipuleucel-T, cabazitaxel, abiraterone acetate and MDV3100. Additionally, there are several other promising prostate cancer agents in late-stage development, including PROSTVAC-VF, orteronel and radium-223 chloride, each with a novel mechanism of action. The treatment paradigm for these patients is rapidly evolving, with future study needed to define the optimal sequencing and potential combinations of these new agents. In this review, we discuss the recent progress in understanding the biology of this disease and examining the development of a variety of new agents with promising activity and a favorable toxicity profile, that have been investigated in the setting of hormonal, cytotoxic, immune and targeted therapy. In this new therapeutic setting of CRPC, clinicians will have an opportunity to balance benefits and harms of these new agents in an individual context.