LHRH sparing therapy in patients with chemotherapy-naïve, mCRPC treated with abiraterone acetate plus prednisone: results of the randomized phase II SPARE trial.

BACKGROUND: Although the benefit of androgen deprivation therapy (ADT) continuation in metastatic castration-resistant prostate cancer (mCRPC) remains controversial, clinical evidence is lacking. Recent results indicated that treatment with abiraterone acetate (AA) plus prednisone (P) further suppresses serum testosterone levels over ADT alone, suggesting that continuation of ADT in the treatment of mCRPC may not be necessary. METHODS: In this exploratory phase 2 study, mCRPC patients were randomized with a 1:1 ratio to receive either continued ADT plus AA + P (Arm A) or AA + P alone (Arm B). The primary endpoint was the rate of radiographic progression-free survival (rPFS) at month 12. Secondary endpoints included PSA-response rate, objective response, time to PSA progression and safety. RESULTS: A total of 68 patients were equally randomized between the two study arms. Median testosterone-levels remained below castrate-levels throughout treatment in all patients. According to the intention-to-treat analysis the rPFS rate was 0.84 in Arm A and 0.89 in Arm B. Moderate and severe treatment-emergent adverse events were reported for 72% of the patients in Arm A and for 85% of the patients in Arm B. CONCLUSIONS: AA + P treatment without ADT may be effective in mCRPC patients and ADT may not be necessary in patients receiving AA + P.

[Management of testosterone in advanced hormone-sensitive prostate cancer: still up to date?] / Ist das Testosteron-Management beim fortgeschrittenen hormonsensitiven Prostatakarzinom zeitgemäß?

Androgen-deprivation therapy (ADT) is the standard therapy used for advanced or metastatic prostate cancer, either alone or in association with additional procedures and substances. The optimum value of testosterone postulated more than 40 years ago was arbitrarily set to be < 50 ng/dL or < 1.7 nmol/L and, from today's perspective, was defined by more insensitive measurement methods. Since then, more and more data has been generated, suggesting that a value of < 20 ng/dL would be prognostically relevant. Yet no guideline has been changed so far despite the call for lowering the target value. Measuring testosterone to evaluate the response to androgen suppression is not yet established in clinical routine. There are no specific recommendations in national and international guidelines. Based on the evolving evidence, the question about testosterone management during ADT is gaining importance. The current data is summarised in this paper.

[TITAN study: evaluation of apalutamide in patients with metastatic hormone-sensitive prostate cancer - Treatment of metastatic hormone-sensitive prostate cancer (mHSPC)]. / TITAN-Studie ­ Evaluation von Apalutamid bei Patienten mit metastasiertem hormonsensitivem Prostatakarzinom.

The TITAN study, which compares apalutamide plus ADT with placebo plus ADT in an all-comers population of patients with metastatic hormone-sensitive prostate cancer (mHSPC), reached both primary endpoints, rPFS and OS, at the first planned interim analysis 1. After a median follow-up of 22.7 months, the risk of radiographic progression was reduced by 52 % (p < 0.001) 1. The rPFS benefit was observed in all subgroups and independently of tumour burden or docetaxel pre-treatment 1. The OS interim analysis showed a mortality risk reduced by 33 % in favour of apalutamide plus ADT (p = 0.0053) 1. The secondary endpoint of time to cytotoxic chemotherapy as well as the exploratory endpoints of time to PSA progression and second progression-free survival (PFS2), defined as time between randomisation and second disease progression or death under the first subsequent therapy, were also significantly improved 1 2. Overall, apalutamide showed good tolerability, with a higher rate of apalutamide-typical rash and hypothyroidism but no relevant increase in fatigue, falls or fractures compared with placebo, and with quality of life being maintained 1. Apalutamide plus ADT can thus be an effective and well-tolerated new treatment option in many patients with mHSPC.

Adherence Measures for Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone Acetate plus Prednisone: Results of a Prospective, Cluster-Randomized Trial.

Residual androgen production causes tumor progression in metastatic, castration-resistant prostate cancer (mCRPC) patients. Abiraterone acetate (AA), a prodrug of abiraterone, is an oral CYP-17 inhibitor that blocks androgen production. It was hypothesized that adherence-enhancing measures (AEM) might be beneficial for mCRPC patients receiving abiraterone acetate plus prednisone (AA + P). This multicenter, prospective, 2-arm trial allocated mCRPC patients who were progressive after docetaxel-based chemotherapy or asymptomatic/mildly symptomatic after failure of an androgen deprivation therapy to Arm A (with AEM) or Arm B (without AEM) by center-based cluster-randomization. The primary objective was to assess the influence of AEM on discontinuation rates and medication adherence in mCRPC patients treated with AA + P. A total of 360 patients were allocated to Arm A, and 315 patients to Arm B. At month 3, the rate of treatment discontinuation, not due to disease progression or the start of new cancer therapy, was low in both arms (A: 9.0% vs. B: 7.3%, OR = 1.230). Few patients had a medium/low Morisky Medication Adherence Scale (MMAS-4) score (A: 6.4% vs. B: 9.1%, OR = 0.685). The results obtained did not suggest any clear adherence difference between Arm A and Arm B. In patients with mCRPC taking AA + P medication, adherence seemed to be generally high.

Antigen-specific CD4 T cells are induced after intravesical BCG-instillation therapy in patients with bladder cancer and show similar cytokine profiles as in active tuberculosis.

Specific T cell immunity in patients with active tuberculosis is associated with a decrease in multifunctionality. However, it is unknown whether cytokine profiles differ in patients with primary infection and those with prior contact. We therefore used intravesical immunotherapy with attenuated live Bacille Calmette-Guérin (BCG) in patients with urothelial carcinoma as a model to characterise the induction of systemic immunity towards purified protein derivate (PPD) and to study whether cytokine profiles differ depending on pre-existing immunity. Eighteen patients with non-muscle invasive bladder cancer were recruited during the BCG-induction course. Fifty-four healthy individuals served as controls. Interferon (IFN)-γ and interleukin (IL)-2 producing PPD-specific CD4 T cells were analysed longitudinally before each instillation using a rapid flow-cytometric whole blood immunoassay. Baseline levels of IFN-γ producing PPD-specific T cells were comparable to controls. T cells showed a 5-fold increase to 0.23% by week 2/3, and further increased 8-fold by week 4/5 (to 0.42%, p=0.0007). Systemic immunity was induced in all patients, although the increase was less pronounced in patients with pre-existing immunity. As in active TB, cytokine profiling during therapy revealed a lower percentage of multifunctional IFN-γ/IL-2 double-positive T cells compared to controls (60.2% vs. 71.9%, p=0.0003). Of note, when comparing patients with and without pre-existing immunity, cytokine profiles in patients with primary immunity were shifted towards IL-2 single producing T cells (p=0.02), whereas those in patients with pre-existing immunity were shifted towards IFN-γ single-positivity (p=0.01). In conclusion, systemic T cell responses were induced after BCG-therapy, and their kinetics and cytokine profile depended on pre-existing immunity. Decreased functionality is a typical feature of specific immunity in both patients with active tuberculosis and BCG-therapy. Among patients with active infection, a shift towards IL-2 or IFN-γ single-positive cells may allow distinction between patients with primary infection and cases with boosted immunity after prior contact, respectively.

Abiraterone in metastatic prostate cancer without previous chemotherapy.

BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. METHODS: In this double-blind study, we randomly assigned 1088 patients to receive abiraterone acetate (1000 mg) plus prednisone (5 mg twice daily) or placebo plus prednisone. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was unblinded after a planned interim analysis that was performed after 43% of the expected deaths had occurred. The median radiographic progression-free survival was 16.5 months with abiraterone-prednisone and 8.3 months with prednisone alone (hazard ratio for abiraterone-prednisone vs. prednisone alone, 0.53; 95% confidence interval [CI], 0.45 to 0.62; P<0.001). Over a median follow-up period of 22.2 months, overall survival was improved with abiraterone-prednisone (median not reached, vs. 27.2 months for prednisone alone; hazard ratio, 0.75; 95% CI, 0.61 to 0.93; P=0.01) but did not cross the efficacy boundary. Abiraterone-prednisone showed superiority over prednisone alone with respect to time to initiation of cytotoxic chemotherapy, opiate use for cancer-related pain, prostate-specific antigen progression, and decline in performance status. Grade 3 or 4 mineralocorticoid-related adverse events and abnormalities on liver-function testing were more common with abiraterone-prednisone. CONCLUSIONS: Abiraterone improved radiographic progression-free survival, showed a trend toward improved overall survival, and significantly delayed clinical decline and initiation of chemotherapy in patients with metastatic castration-resistant prostate cancer. (Funded by Janssen Research and Development, formerly Cougar Biotechnology; ClinicalTrials.gov number, NCT00887198.).

Experimental orthotopic prostate tumor in nude mice: techniques for local cell inoculation and three-dimensional ultrasound monitoring.

OBJECTIVES: Orthotopic prostate cancer models are of great importance for cancer research. Orthotopic models in mice have been described previously. However, these studies lack a detailed methodological description and fail to define standards for local cell inoculation. Herein, we studied the effect of different protocols on tumor growth and report for the first time the use of high resolution ultrasound for monitoring of tumor growth. MATERIALS AND METHODS: Orthotopic inoculation of DU 145 MN1 prostate cancer cells was performed in 30 nude mice varying (1) the amount of cells (5 × 10(5) vs. 5 × 10(4)), (2) the number of puncture sites, and (3) the addition of matrigel. Surgical complications such as recoil of cells through the injection canal and rupture of the prostatic capsule were monitored. Animals were tracked by ultrasound imaging after 4, 5, and 6 weeks. Autopsy and histology confirmed local tumor growth. RESULTS: A take rate of 27/30 (90%) was observed. Growth of orthotopic prostate tumors was increased after inoculation of a large amount of cells under the capsule of 1 dorsal prostate lobe, but inoculation of small amounts of cells still induced local tumors. Noninvasive ultrasound examination allowed to identify orthotopic tumor formation and to monitor tumor growth in vivo. Addition of matrigel did not accelerate tumor growth. Complications like recoil (6.8%) or rupture of the prostate capsule (1.4%) were rare. CONCLUSIONS: Inoculation of DU 145 MN1 cells under the prostate capsule with a defined procedure results in very high take rates. Ultrasound screening is feasible to repetitively monitor tumor growth.

Novel options for the treatment of castration-resistant prostate cancer.

Docetaxel had been the only treatment of castration-resistant prostate cancer (CRPC) that demonstrated a survival benefit for the patients. After its approval, no considerable progress has been made for several years until cabazitaxel and abiraterone acetate demonstrated a significant survival benefit in phase III clinical trials. Apart from that several other new drugs appeared including inhibitors of the androgen receptor (MDV3100), endothelin receptor antagonists (atrasentan, zibotentan), bone-targeted drugs (denosumab, Alpharadin) and immunotherapies (sipuleucel-T) capable of improving the prognosis of patients with CRPC. Here, we review the most recent advances in the treatment of CRPC and highlight the most promising new agents currently being investigated in clinical trials.

Myeloid-derived suppressor cells in the peripheral blood of cancer patients contain a subset of immature neutrophils with impaired migratory properties.

In tumor-bearing mice, immunosuppressive granulocytic and monocytic MDSC have been identified. The identity and function of MDSC in cancer patients are less clear and need further characterization. We analyzed the peripheral blood of 103 patients with HNC, lung cancer, or cancers of bladder and ureter. Based on sedimentation properties in density gradients, a subset of LD-PMN was identified and analyzed. LD-PMN were expanded in the peripheral blood of cancer patients, suppressed proliferation, and IFN-γ production of polyclonally stimulated T cells and thus, qualify as human MDSC. Immunophenotyping and morphological analysis revealed the accumulation of immature PMN in the MDSC fraction. Neutrophilic MDSC showed altered surface marker expression, prolonged survival, and impaired effector functions when compared with conventional, mature PMN of regular density. MDSC displayed markedly reduced chemotaxis toward tumor-conditioned medium and lacked expression of chemokine receptors CXCR1 and CXCR2, which are normally required for PMN extravasation from the bloodstream and subsequent tissue infiltration. Collectively, our data suggest the accumulation and persistence of long-lived, immature granulocytic MDSC with T cell-suppressive function and impaired migratory properties in the peripheral blood of cancer patients.

Surgery for metastatic urothelial carcinoma with curative intent: the German experience (AUO AB 30/05).

BACKGROUND: Recent publications suggest a benefit from surgical removal of urothelial carcinoma metastases (UCM) for a subgroup of patients. OBJECTIVE: We report the combined experience and outcome of patients undergoing resection of UCM gained at 15 uro-oncologic centers in Germany. DESIGN, SETTING, AND PARTICIPANTS: Retrospective survey of 44 patients with distant UCM of the bladder or upper urinary tract who underwent complete resection of all detectable metastases in 15 different German uro-oncological centers between 1991 and 2008. INTERVENTION: Resected metastatic sites were the following: retroperitoneal lymph nodes (56.8%), distant lymph nodes (11.3%), lung (18.2%), bone (4.5%), adrenal gland (2.3%), brain (2.3%), small intestine (2.3%), and skin (2.3%). Systemic chemotherapy was administered in 35 of 44 patients (79.5%) before and/or after UCM surgery. MEASUREMENTS: Overall, cancer-specific and progression-free survival from time of diagnosis and metastasectomy of UCM. RESULTS AND LIMITATIONS: Median survival from initial diagnosis of UCM and subsequent resection was as follows: overall survival, 35 mo and 27 mo; cancer-specific survival, 38 mo and 34 mo; and progression-free survival, 19 mo and 15 mo. Overall 5-yr survival from metastasectomy for the entire cohort was 28%. Seventeen patients were still alive without progression at a median follow-up of 8 mo. Seven patients without disease progression survived for >2 yr and remained free from tumor progression at a median follow-up of 63 mo. No significant prognostic factors could be determined due to the limited patient number. CONCLUSIONS: Long-term cancer control and possible cure can be achieved in a subgroup of patients following surgical removal of UCM. Metastasectomy in patients with disseminated UCM remains investigational and should only be offered to those with limited disease as a combined-modality approach with systemic chemotherapy.

Combining 153Sm-lexidronam and docetaxel for the treatment of patients with hormone-refractory prostate cancer: first experience.

PURPOSE: 153Sm-lexidronam has been used for the palliation of symptoms from painful bone metastases for years, while docetaxel has recently been shown to improve the survival of patients with hormone-refractory prostate cancer (HRPC). The first clinical experience with the combination of both treatment modalities is reported. METHODS: Between 2005 and 2006, 12 patients with muliple bone metastases from HRPC were treated with a single application of 37 MBq/kg body weight 153Sm-lexidronam and 6 weekly infusions of 35 mg/m2 docetaxel. Data on survival, prostate-specific antigen (PSA) response, symptom palliation, toxicity, and scintigraphic follow-up are provided. RESULTS: Mean follow-up was 11.4 (range, 1.1-25.8) months, overall 1-year survival was 48.6%, and median survival was 11.5 months. A PSA response of >50% was documented in 50% of patients. The average pain score (visual analog scale: 1-10) was reduced from 5.1 to 1.4 (p = 0.016) with decrease of > or =2 in 58.3% of patients. The average World Health Organization medication level dropped from 1.6 to 1.1 (p = 0.5). Overall toxicity was moderate, but 1 patient died due to neutropenic sepsis. CONCLUSIONS: Our analysis demonstrates feasibility and therapeutic potential for the combination treatment and merits prospective investigation. Further studies will be planned with respect to the potentially synergistic hematologic toxicity of bone-seeking radiopharmaceuticals and chemotherapy.

Long-term survival in bilateral renal cell carcinoma: a retrospective single-institutional analysis of 101 patients after surgical treatment.

OBJECTIVES: Bilateral renal cell carcinomas (bRCC) account for <4% of all renal tumors. We report on the management, histopathologic results, and long-term follow-up of 101 patients with bRCC. METHODS: A total of 101 patients with bRCC who had undergone surgery from 1975 to 2005 at our institution were identified from our kidney tumor database and included in this retrospective analysis. Cancer-specific survival was assessed using the Kaplan-Meier method. Subgroups were compared using the log-rank test. Statistical analysis was performed with the Statistical Package for Social Sciences for Windows. RESULTS: Of 3097 kidney tumor patients, 101 (3.3%) had bRCC on final histopathologic examination. Synchronous tumors were found in 43 patients (42.6%) and metachronous tumors in 58 (57.4%). The cancer-specific survival rate of the entire cohort was 91.9%, 79.1%, and 56.7% after 5, 10, and 20 years, respectively. The survival of patients with synchronous or metachronous bRCCs did not differ significantly. Patients with metachronous bRCC were significantly younger at first diagnosis than those with synchronous bRCCs (median age 53.6 vs 58.7 years, P < .05). The histopathologic results revealed significantly greater rates of papillary bRCCs in synchronous tumors (P < .05). CONCLUSIONS: Standardized techniques of nephron-sparing surgery can achieve excellent survival rates in bRCC. Among other arguments for nephron-sparing surgery, kidney-preserving strategies are of particular importance in younger patients with unilateral RCC against the background of an increasing risk of developing a contralateral neoplasm with older age.

Antimicrobial peptides of the Cecropin-family show potent antitumor activity against bladder cancer cells.

BACKGROUND: This study evaluated the cytotoxic and antiproliferative efficacy of two well-characterized members of the Cecropin-family of antimicrobial peptides against bladder tumor cells and benign fibroblasts. METHODS: The antiproliferative and cytotoxic potential of the Cecropins A and B was quantified by colorimetric WST-1-, BrdU- and LDH-assays in four bladder cancer cell lines as well as in murine and human fibroblast cell lines. IC50 values were assessed by logarithmic extrapolation, representing the concentration at which cell viability was reduced by 50%. Scanning electron microscopy (SEM) was performed to visualize the morphological changes induced by Cecropin A and B in bladder tumor cells and fibroblasts. RESULTS: Cecropin A and B inhibit bladder cancer cell proliferation and viability in a dose-dependent fashion. The average IC50 values of Cecropin A and B against all bladder cancer cell lines ranged between 73.29 mug/ml and 220.05 mug/ml. In contrast, benign fibroblasts were significantly less or not at all susceptible to Cecropin A and B. Both Cecropins induced an increase in LDH release from bladder tumor cells whereas benign fibroblasts were not affected. SEM demonstrated lethal membrane disruption in bladder cancer cells as opposed to fibroblasts. CONCLUSION: Cecropin A and B exert selective cytotoxic and antiproliferative efficacy in bladder cancer cells while sparing targets of benign murine or human fibroblast origin. Both peptides may offer novel therapeutic strategies for the treatment of bladder cancer with limited cytotoxic effects on benign cells.

Improving the prognosis of patients after radical cystectomy. Part I: the role of lymph node dissection.

The first two reviews are from the same unit in Germany and describe the well-known but still much discussed ways of improving the prognosis of patients undergoing cystectomy for bladder cancer. The authors review the roles of lymph node dissection and perioperative chemotherapy, and draw conclusions which will be of help for patients having this form of therapy. In a further review, authors from Egypt debate the requirement for a refluxing or non-refluxing uretero-ileal anastomosis in low-pressure reservoirs, drawing on their extensive experience in this field. The optimum treatment for patients with muscle-invasive bladder cancer remains a matter of intense debate; some authors still question the role of radical cystectomy (RC) per se, as it can be a potentially mutilating procedure with subsequent impairment in quality of life. However, the impairment has not been investigated using validated quality-of-life studies. By contrast, it is commonly accepted that no alternative treatment yields similar long-term survival data to RC. However, survival rates after RC are far from satisfying, particularly for patients with >/= pT3 and/or pN+ disease. Therefore, various strategies were introduced to improve survival in these patients, i.e. extension of lymph node dissection during radical surgery and perioperative chemotherapy. Both strategies are analysed and discussed in two mini-reviews, based on data from current publications and from theoretical considerations.

Improving the prognosis of patients after radical cystectomy. Part II: the role of perioperative chemotherapy.

In this review we analyse the current status of perioperative systemic chemotherapy in the treatment of transitional cell carcinoma (TCC) of the bladder; instead of summarizing each neoadjuvant or adjuvant clinical trial we focus on the advantages and disadvantages of both strategies on the basis of theoretical considerations, and outline a rationale for a better design of future studies to confirm the efficacy of perioperative chemotherapy in TCC.

Thirty years of BCG immunotherapy for non-muscle invasive bladder cancer: a success story with room for improvement.

Over the last three decades, intravesical immunotherapy with the biological response modifier Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been established as the most effective adjuvant treatment for preventing local recurrences and tumor progression following transurethral resection of non-muscle invasive bladder cancer. A large number of clinical trials have established a major role for BCG immunotherapy in urological oncology. In parallel, the major principles of the immunological mechanism have been revealed. In spite of this success, questions still remain regarding its clinical use, mechanism of action and potential improvement. This review provides a comprehensive insight into the historical era of BCG immunotherapy, the current indications for clinical application, the complex mechanism of action and possible future developments.

Outcome of prostate cancer patients with initial PSA> or =20 ng/ml undergoing radical prostatectomy.

OBJECTIVES: To retrospectively assess the outcome of patients with initial PSA of 20 ng/ml or higher undergoing radical prostatectomy (RP) for prostate cancer (pCA). METHODS: Between January 1986 and June 2005, 275 patients with preoperative PSA> or =20 ng/ml underwent RP for pCA at our institution. Overall, disease-specific and biochemical progression-free survival rates for the entire cohort and for particular subgroups were determined. RESULTS: Median patient age at time of surgery was 64 yr (range: 44-75). Fifty-seven patients (20.7%) had pT2 stage, 206 (74.9%) pT3, and 10 (3.7%) pT4; 78 (28.4%) presented with local nodal metastases (pN+). To date, 40 patients have died (14.5%), 22 of pCA and 18 of other causes. Biochemical progression occurred in 92 patients (33.5%). Overall (and disease-specific) survivals at 5, 10, and 15 yr were 87% (93%), 70% (83%), and 58% (71%), respectively. These survival rates did not significantly differ between patients receiving immediate versus deferred hormonal therapy (in case of progression). Five-year PSA progression-free survival in patients on surveillance (receiving deferred hormonal treatment at the onset of rising PSA values) was 53%. For patients on immediate hormonal treatment following RP, the 5-yr hormone-refractory PSA progression rate was 76%. CONCLUSIONS: According to long-term follow-up results in this high-risk cohort of patients with preoperative PSA> or =20 ng/ml, RP can be considered a viable therapeutic option. With regard to combining immediate hormonal therapy with surgery, the optimal treatment following RP remains to be defined.

Transitional cell carcinoma of the ureter: prognostic factors influencing progression and survival.

OBJECTIVES: We retrospectively evaluated prognostic factors for progression-free and disease-specific survival in a large cohort of patients with transitional cell carcinoma (TCC) of the ureter. METHODS: A single-centre series of 145 consecutive patients treated with partial resection of the ureter or nephroureterectomy between 1975 and 2004 was evaluated. Median follow-up was 96 mo. Routine preoperative laboratory parameters as well as clinical and tumour-specific data were assessed. Univariate and multivariate statistical analyses were performed. RESULTS: Five-year disease-specific survival ranged from 96.1% for stages pTa to 28.6% for pT4. Grade1 tumours were associated with 5-yr disease-specific survival rates of 100% compared with 84% for G2, and 51.9% for G3 tumours, respectively. Univariate analyses identified pT stage and grade, tumour diameter, cM and pN categories, weight loss, the presence of synchronous tumour in the renal pelvis as well as elevated levels for humoral factors such as serum alkaline phosphatase (AP), white blood cell (WBC) count, platelet count, gamma-glutamyl transferase, creatinin, and blood urea nitrogen as prognostic factors. In multivariate analyses, tumour grade and WBC counts were predictive for low progression-free survival rates, whilst simultaneous tumour in the renal pelvis, high AP levels, and WBC counts were correlated with worse disease-specific survival. CONCLUSIONS: Our retrospective analysis provides clinical factors to identify patients with TCC of the ureter at high risk for progression and death of disease. Interestingly, humoral factors such as elevated serum AP levels and high WBC counts were demonstrated to be of paramount prognostic significance besides tumour stage, grade and multifocality.