**9. Monitoring of patients after focal HIFU**

**7. HIFU Therapy for prostate cancer: Its role in focal therapy**

reporting data after a median follow up of 94 months [29].

**functional preservation**

USA) [26].

6 Updates on Cancer Treatment

HIFU for the treatment of localized prostate cancer was developed in 1990. Nowadays there are two available devices for the treatment of prostate cancer: the Ablatherm™ (EDAP TMS S.A., Vaulx-en-Velin, France) and the Sonablate™ (Focus Surgery, Inc, Indianapolis, Indiana,

Both of them have a simultaneous imaging technique coupled to the treatment device. They differ by patient positioning and the degree of manual control of power. Currently, the technique is used among many cancer centers despite the fact that available guidelines do not recommend it for the treatment of localized prostate cancer. In 2010, the Cancer Care Ontario group excluded HIFU from its recommendations due to lack of randomized controlled clinical trials and short follow up [27]. The NICE guidelines in 2012 considered HIFU as an experi‐ mental technique with further studies needed in order to conclude [28]. In 2014, the FDA bans the use of HIFU for whole-gland primary treatment of clinically localized prostate cancer. At present, high quality evidence on efficacy and safety of HIFU is based on uncontrolled case series with a significant overlap of patients among series. There are no direct comparisons with active surveillance or whole gland radical therapies. Furthermore, the technique is not standardized and patient selection is not unanimous. The ideal candidate is defined as a patient aged > 70 years of age, with clinical stage T1-T2 N0M0, a Gleason score<7, a PSA level <15 ng/ ml and a prostate volume of <40 ml, in particular if the patient is unsuitable for or refuse radical therapy [26]. A prostate volume of >40 ml and the presence of large calcifications are a contraindications for HIFU. In such cases where the volume exceed 40 ml a TURP or a cytoreductive androgen deprivation therapy or a 5 alpha reductase inhibitor before HIFU is recommended to reduce the volume of the prostate. The number of HIFU treatment per patient varies between one and five. The median follow up time is short with the longest series

HIFU could be used as a primary treatment or as a salvage therapy in recurrent prostate cancer after radiotherapy failure. The field could involve a whole gland ablation or a more focal therapy. For technical considerations, Hemiablation HIFU of an entire lobe delivered with intention to treat is currently used for focal therapy. The technique was demonstrated to be feasible and

functional and disease control outcomes were encouraging at 3 years of follow up.

**8. The principle rationale of tissue preservation is harm reduction and**

Adverse events affecting the urinary tract are reported in 2-58% of whole gland HIFU therapy in the literature. Rectal toxicities ranged from 0 to 15%. Erectile dysfunction is reported in 0 to 39% of cases [30]. Toxicity rates are believed to be lower after focal therapy. In our case series, 31 consecutive patients with unilateral organ confined prostate cancer were primarily treated by hemiablation HIFU. Early self-resolving LUTS were the most common complications and no rectal toxicities were reported. The strategy was well tolerated in the genitourinary functional domains: all patients were pad free continent despite a high number of apical lesions

In the literature, there is no consensus on whether cancer control in focal therapy should be considered the absence of any cancer or the absence of clinically significant cancer and whether this should be limited to the treated or untreated area. In addition there is no standard follow up protocol for the assessment of clinical failure. In our opinion, histologic confirmation of complete ablation within the treated area appears to be essential in focal therapy. That's why any positive biopsy in the treated lobe independently of the percentage of core involvement should be considered a clinical failure. In contrast, controlateral positive biopsy should not be considered as a clinical failure but as a technical limitation. As a surrogate, although PSA testing is accepted as a valid outcome in standard therapy, there are no validated biochemical measures in tissue preservation. Furthermore, PSA values are difficult to interpret in the follow up because many factors influence post treatment values (the proportion of initial PSA that was due to tumor, amount of residual prostate tissue, progression of BPH, TURP...). Definitions that are currently used and validated for biochemical failure in whole gland radiation therapy (ASTRO, Phoenix, Stuttgart...) are used, without any evidence or validation, in whole gland HIFU and focal therapy [31]. Phoenix criteria should not be considered as response criteria to define failure but as a threshold to offer biopsy. We believe that a specific PSA based definition is unlikely to be derived and multiparametric MRI will play a major role in the future in the definition of failure if it is validated against histology outcomes.

## **10. Oncologic outcomes**

Following whole gland ablation therapy, negative biopsy rates at 3 month of 51-96% and 64-87% with Ablatherm and Sonablate respectively were reported [32-36]. Overall survival rates and prostate cancer specific survival rates were 90% and 100% at 5 years and 83% and 98% at 8 years, respectively. The actuarial biochemical failure–free survival rates at 5 and 7 years were 77% and 69%, respectively. The actuarial disease–free survival rate at 5 and 7 years were 66% and 59%, respectively [32-36]. Biochemical success or failure rate was stratified against risk category according to the D'Amico classification in the majority of reports and was uniformly more favourable for the low and intermediate risk category compared to the high risk category. Some authors have argued that HIFU is a coagulative technology that unlike radiation therapy results in complete cell destruction independently of Gleason score. However, high grade tumours in prostate cancer are associated with increased neoangiogen‐ esis responsible of a heat sink phenomenon that is tissue cooling by blood flow that causes thermal loss. The tissue under ablation in high grade tumour may be inadequately ablated and is a high risk site for persistent residual progressive disease and metastatic spread. Following focal therapy, we demonstrated a biochemical recurrence free survival of 100%, 89%, 82.7% at 1, 2 and 3 years respectively, with an overall and cancer specific survival of 100% [19].
