EvaluatioN of HIFU Hemiablation and Short Term AndrogeN Deprivation Therapy Combination to Enhance Prostate Cancer Control.

Prostate Cancer (PCa) is a multifocal disease in up to 90% of men with heterogeneity among different cancer foci in the same prostate gland. An index/dominant lesion has been proposed, namely the largest tumor nodule that often correlates with the highest Gleason score (GS) and, consequently, with the clinical behavior of the tumor. However, this concept is not always applicable as highest GS, largest tumor volume and extraprostatic extension may be present in different PCa foci in up to 10% of the cases. Focal therapies (FT) for localized PCa emerged to reduce the adverse effects of radical treatments,including a30-90% for erectile dysfunction and 5-20% for incontinence and rectal toxicity, while maintaining comparable oncological efficacy. Amongst organ-sparing strategies, high-intensity focused ultrasound (HIFU) is widely used and yields promising cancer control rates and relatively low morbidity. In our recently published prospective study of HIFU hemiablation for localized PCa with one year follow up, 25.4% of patients demonstrated PCa cores at 12 months post-treatment biopsy (Feijo et al, Eur Urol, 2016). Among them 11.5% of patients showed cancer in the contralateral untreated lobe. At 3 months, all patients were continent and 11 out of 21 preoperatively potent patients maintained adequate sexual functions. Minor adverse effects were reported in 8%, while 2.8% of patients experienced Clavien-Dindo grade-3 events. Although FT has proven to be effective and less morbid treatment for localized PCa, an area for improvement still exists and a gap in cancer control needs to be filled by adding additional form of treatment so as to improve oncological outcomes and minimize treatment failures. Research Rationale Previous studies have shown approximately 20% of men continue to harbour cancer at 12 months after HIFU FT for localized PCa. This finding could be in part attributed to undetectable (invisible) remote cancer foci owing to limitations of the currently available imaging and biopsy techniques and representing an appealing argument against FT. Another point is tumor microenvironment, defined as the myriad of multiple interactions amongst tumour and surrounding cells including immune cells, stromal fibroblasts, mesenchymal stem cells and blood vessels. It is not completely clear whether at least part of FT recurrences may be related to non-aggressive lesions taking the position of an index PCa focus and/or PCa index lesion signalling altering benign tissues behaviour. Androgen deprivation therapy (ADT) modifies tumour microenvironment and suppresses PCa growth and progression. Short-term ADT has been reported to increase the overall survival in men with localized intermediate- to high-risk PCa when combined with external beam radiation therapy (EBRT) or RP. Short term ADT has been also investigated in the context of active surveillance; other trials are under way. However, to date, there is no prospective data assessing the role of HIFU/ADT combination therapy for the treatment of localized PCa in terms of cancer control. The current study aims to examine the hypothesis that combining the focal effects of HIFU with the systemic effects of androgen deprivation therapy might eradicate the prostatic cancer cells by targeting the 'visible' index focus (by HIFU) and the tumour surrounding microenvironment which may contain 'invisible' foci and aberrant PCa related signalling (by androgen deprivation therapy) to enhance oncological outcomes of HIFU hemi-ablation in men with localized PCa, and consequently reducing treatment failures, without significantly increasing toxicity and/or complications.