Tumors strongly depend on their surrounding tumor microenvironment (TME) for growth and progression, since stromal elements are required to generate the optimal conditions for cancer cell proliferation, invasion, and possibly metastasis. Prostate cancer (PCa), though easily curable during primary stages, represents a clinical challenge in advanced stages because of the acquisition of resistance to anti-cancer treatments, especially androgen-deprivation therapies (ADT), which possibly lead to uncurable metastases such as those affecting the bone. An increasing number of studies is giving evidence that prostate TME components, especially cancer-associated fibroblasts (CAFs), which are the most abundant cell type, play a causal role in PCa since the very early disease stages, influencing therapy resistance and metastatic progression. This is highlighted by the prognostic value of the analysis of stromal markers, which may predict disease recurrence and metastasis. However, further investigations on the molecular mechanisms of tumor–stroma interactions are still needed to develop novel therapeutic approaches targeting stromal components. In this review, we report the current knowledge of the characteristics and functions of the stroma in prostate tumorigenesis, including relevant discussion of normal prostate homeostasis, chronic inflammatory conditions, pre-neoplastic lesions, and primary and metastatic tumors. Specifically, we focus on the role of CAFs, to point out their prognostic and therapeutic potential in PCa.

Systemic Therapy for Advanced or Metastatic Prostate cancer: Evaluation of Drug Efficacy (STAMPEDE) is a randomized controlled trial that follows a novel multi-arm, multi-stage (MAMS) design. We describe methodological and practical issues arising with (1) stopping recruitment to research arms following a pre-planned intermediate analysis and (2) adding a new research arm during the trial. STAMPEDE recruits men who have locally advanced or metastatic prostate cancer who are starting standard long-term hormone therapy. Originally there were five research and one control arms, each undergoing a pilot stage (focus: safety, feasibility), three intermediate ‘activity’ stages (focus: failure-free survival), and a final ‘efficacy’ stage (focus: overall survival). Lack-of-sufficient-activity guidelines support the pairwise interim comparisons of each research arm against the control arm; these pre-defined activity cut-off becomes increasingly stringent over the stages. Accrual of further patients continues to the control arm and to those research arms showing activity and an acceptable safety profile. The design facilitates adding new research arms should sufficiently interesting agents emerge. These new arms are compared only to contemporaneously recruited control arm patients using the same intermediate guidelines in a time-delayed manner. The addition of new research arms is subject to adequate recruitment rates to support the overall trial aims. (1) Stopping Existing Therapy: After the second intermediate activity analysis, recruitment was discontinued to two research arms for lack-of-sufficient activity. Detailed preparations meant that changes were implemented swiftly at 100 international centers and recruitment continued seamlessly into Activity Stage III with 3 remaining research arms and the control arm. Further regulatory and ethical approvals were not required because this was already included in the initial trial design. (2) Adding New Therapy: An application to add a new research arm was approved by the funder, (who also organized peer review), industrial partner and regulatory and ethical bodies. This was all done in advance of any decision to stop current therapies. The STAMPEDE experience shows that recruitment to a MAMS trial and mid-flow changes its design are achievable with good planning. This benefits patients and the scientific community as research treatments are evaluated in a more efficient and cost-effective manner. ISRCTN78818544, NCT00268476 First patient into trial: 17 October 2005 First patient into abiraterone comparison: 15 November 2011

In this retrospective nonrandomized study we compared the long-term outcome in patients with newly diagnosed stage T1G3 bladder cancer treated with transurethral resection and bacillus Calmette-Guerin or immediate cystectomy. Of 121 patients with a median age of 67 years (range 36 to 88) diagnosed with primary T1G3 bladder cancer between 1976 and 1999, 92 were treated by transureteral resection with additional intravesical bacillus Calmette-Guerin and 29 were treated with immediate cystectomy. Of the 92 patients treated with an organ preserving approach 29 remained disease-free, local recurrence developed in 33 (36%) and progression developed in 30 (33%) at a median followup of 6.9 years (range 0.6 to 16.5). Of these 92 patients 27 (29%) underwent deferred cystectomy at a median of 12.9 months (range 4.8 to 136), of whom 10 (37%) with a median postoperative followup of 19 months (range 2 to 173) died of progressive disease with a median survival of 13 months (range 3 to 34) after cystectomy. The majority of patients who died of progressive disease refused cystectomy, were referred too late for cystectomy, were inoperable or had upper urinary tract disease. Six of the 29 patients (21%) undergoing immediate cystectomy had progression at a median of 13.2 months (range 5.5 to 37). Overall and tumor specific survival at 5 years in patients treated with an organ preserving approach was 69% and 80%, and in those treated with immediate cystectomy it was 54% and 69%, respectively. The results of this analysis demonstrate that the concept of an organ preserving approach is acceptable and spares the bladder in approximately half of the patients with primary T1G3 bladder cancer. Of the patients 30% require deferred cystectomy, making meticulous, close followup mandatory.