Additional Treatments to the Local tumour for metastatic prostate cancer-Assessment of Novel Treatment Algorithms (IP2-ATLANTA): protocol for a multicentre, phase II randomised controlled trial.

INTRODUCTION: Survival in men diagnosed with de novo synchronous metastatic prostate cancer has increased following the use of upfront systemic treatment, using chemotherapy and other novel androgen receptor targeted agents, in addition to standard androgen deprivation therapy (ADT). Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit. In this setting, IP2-ATLANTA will explore progression-free survival (PFS) outcomes with the addition of sequential multimodal local and metastasis-directed treatments compared with standard care alone. METHODS: A phase II, prospective, multicentre, three-arm randomised controlled trial incorporating an embedded feasibility pilot. All men with new histologically diagnosed, hormone-sensitive, metastatic prostate cancer, within 4 months of commencing ADT and of performance status 0 to 2 are eligible. Patients will be randomised to Control (standard of care (SOC)) OR Intervention 1 (minimally invasive ablative therapy to prostate±pelvic lymph node dissection (PLND)) OR Intervention 2 (cytoreductive radical prostatectomy±PLND OR prostate radiotherapy±pelvic lymph node radiotherapy (PLNRT)). Metastatic burden will be prespecified using the Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease (CHAARTED) definition. Men with low burden disease in intervention arms are eligible for metastasis-directed therapy, in the form of stereotactic ablative body radiotherapy (SABR) or surgery. Standard systemic therapy will be administered in all arms with ADT±upfront systemic chemotherapy or androgen receptor agents. Patients will be followed-up for a minimum of 2 years. PRIMARY OUTCOME: PFS. Secondary outcomes include predictive factors for PFS and overall survival; urinary, sexual and rectal side effects. Embedded feasibility sample size is 80, with 918 patients required in the main phase II component. Study recruitment commenced in April 2019, with planned follow-up completed by April 2024. ETHICS AND DISSEMINATION: Approved by the Health Research Authority (HRA) Research Ethics Committee Wales-5 (19/WA0005). Study results will be submitted for publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03763253; ISCRTN58401737.

Magnetic resonance imaging in the early detection of prostate cancer and review of the literature on magnetic resonance imaging-stratified clinical pathways.

INTRODUCTION: With level 1 evidence now available on the diagnostic accuracy of multiparametric magnetic resonance imaging (MRI) we must now utilise this data in developing an MRI-stratified diagnostic pathway for the early detection of prostate cancer. Areas covered: A literature review was conducted and identified seven randomised control trials (RCT's) assessing the diagnostic accuracy of such a pathway against the previously accepted systematic/random trans-rectal ultrasound guided (TRUS) biopsy pathway. The studies were heterogeneous in their design. Five studies assessed the addition of MRI-targeted biopsies to a standard care systematic TRUS biopsy pathway. Three of these studies showed either an increase in their diagnostic accuracy or the potential to remove systematic biopsies. Two studies looked specifically at a targeted biopsy only pathway and although the results were again mixed, there was no decrease in the diagnostic rate and overall significantly fewer biopsy cores were taken in the MRI group. Expert commentary: Results from these RCT's together with multiple retrospective and prospective studies point towards either an improved diagnostic rate for clinically significant cancer and/or a reduction in the need for systematic biopsies with a MRI-stratified pathway. The challenge for the urological community will be to implement pre-biopsy MRI into a routine clinical pathway with likely independent monitoring of standards.

Magnetic resonance imaging-transrectal ultrasound fusion focal cryotherapy of the prostate: A prospective development study.

OBJECTIVES: The use of software-based magnetic resonance-transrectal ultrasound fusion to deliver focal therapy may increase the precision of treatment. This is a prospective development study assessing the feasibility of Magnetic resonance imaging-transrectal ultrasound (MRI-TRUS) fusion focal cryotherapy. METHODS AND MATERIALS: Consecutive patients undergoing focal cryotherapy were included in an academic registry (December 2013-June 2014). MRI-TRUS fusion focal cryotherapy was offered to men with visible clinically significant prostate cancer (Galil SeedNet system). Eligibility was determined by multiparametric MRI (mpMRI), and transperineal template mapping or targeted biopsies. A rigid fusion platform (Biojet) was used with the operator ensuring the ice ball covered at least the lesion. Adverse events were scored using the NCICTC V4. Genitourinary toxicity was assessed using patient-reported outcome measures (IPSS, IIEF-15, and UCLA-EPIC). Early contrast-enhanced MRI and mpMRI at 6 to 12 months were used to assess extent of lesion ablation. RESULTS: Of 23 patients scheduled, 5 did not have image fusion owing to surgeon preference. Overall, 18 patients undergoing image-fusion cryotherapy had median age of 68 (interquartile range [IQR]: 65-73) years and median preoperative prostate-specific antigen = 9.54 (5.65-16)ng/ml. In all, 13 (72.2%) and 5 (27.8%) patients had intermediate and high-risk cancer, respectively. In total, 10 adverse events were reported with one of these as serious (grade 3) because of admission for hematuria requiring wash out only. There was no difference in the IIEF-15 between baseline and study end (P = 0.24). The IPSS remained stable (P = 0.12), whereas the UCLA-EPIC tended to improve (P = 0.065). The prostate-specific antigen level significantly decreased at 1.8 (1.04-2.93) ng/ml (P<0.001). Both early and late mpMRI showed no residual disease in the treated area. In 2 men, radiological progression of known contralateral disease was observed; both underwent focal high intensity focused ultrasound. CONCLUSION: MRI-TRUS fusion focal cryotherapy is feasible in most patients and seems to accurately guide ablation demonstrated by posttreatment imaging. Additional studies are needed to determine efficacy using postcryotherapy biopsy.

Technological aspects of delivering cryotherapy for prostate cancer.

Since the era of prostate specific antigen (PSA) testing, there has been a stage and grade migration seen with prostate cancer along with a reduction in mortality. Subsequently, concerns have been raised about the over treatment of patients following the diagnosis of localized prostate cancers. Cryotherapy, in which extremely low temperatures induce cell death via multiple mechanisms, has seen a drastic improvement in its technology since the 1800s. Such advances have improved oncological outcomes while reducing complication rates. Furthermore, technological advances have allowed the development of focal cryotherapy which aims to reduce morbidity associated with more radical whole-gland therapies. There is growing evidence that focal cryotherapy provides good oncological and morbidity rates when compared with traditional radical/whole-gland therapies.

Focal cryotherapy of localized prostate cancer: a systematic review of the literature.

Radical/whole gland treatment for prostate cancer has significant side-effects. Therefore focal treatments such as cryotherapy have been used to treat localized lesions whilst aiming to provide adequate cancer control with minimal side-effects. We performed a systematic review of Pubmed/Medline and Cochrane databases' to yield 9 papers for primary focal prostate cryotherapy and 2 papers for focal salvage treatment (radio-recurrent). The results of 1582 primary patients showed biochemical disease-free survival between 71-93% at 9-70 months follow-up. Incontinence rates were 0-3.6% and ED 0-42%. Recto-urethral fistula occurred in only 2 patients. Salvage focal cryotherapy had biochemical disease-free survival of 50-68% at 3 years. ED occurred in 60-71%. Focal cryotherapy appears to be an effective treatment for primary localized prostate cancer and compares favorably to radical/whole gland treatments in medium-term oncological outcomes and side-effects. Although more studies are needed it is also effective for radio-recurrent cancer with a low complications rates.

Key papers in prostate cancer.

Prostate cancer is the most common cancer and second leading cause of death in men. The evidence base for the diagnosis and treatment of prostate cancer is continually changing. We aim to review and discuss past and contemporary papers on these topics to provoke debate and highlight key dilemmas faced by the urological community. We review key papers on prostate-specific antigen screening, radical prostatectomy versus surveillance strategies, targeted therapies, timing of radiotherapy and alternative anti-androgen therapeutics. Previously, the majority of patients, irrespective of risk, underwent radical open surgical procedures associated with considerable morbidity and mortality. Evidence is emerging that not all prostate cancers are alike and that low-grade disease can be safely managed by surveillance strategies and localized treatment to the prostate. The question remains as to how to accurately stage the disease and ultimately choose which treatment pathway to follow.