Shah, Taimur Tariq; (2021) The role of minimally invasive ablative therapies in the treatment of primary and radio-recurrent prostate cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Focal cryotherapy and High Intensity Focused Ultrasound (HIFU) are emerging treatment modalities for men with prostate cancer both as a primary and radiorecurrent treatment. They aim to treat only the cancer within the prostate using minimally invasive surgical techniques whereby either cold or heat is applied in a focal manner to the cancerous areas whilst sparing adjacent structures. This process leads to control of the cancer whilst minimising treatment related side-effects particularly with regard to urinary and sexual function. My aim in primary disease was to assess the oncological and functional outcomes from focal cryotherapy before performing a comparative analysis of the oncological and functional outcomes against an established surgical treatment, radical prostatectomy. My aim in radiorecurrent disease was to assess outcomes from whole-gland salvage therapy, perform a systematic review on focal salvage therapies before presenting results from the FORECAST trial (FOcal RECurrent Assessment and Salvage Treatment, NCT01883128) and present oncological and functional outcomes in men who underwent focal salvage HIFU and Cryotherapy for both localised and metastatic radio-recurrent prostate. Primary Disease: An initial systematic review on focal cryotherapy confirmed good oncological outcomes in the short-medium term. When assessing intra-operative ice ball formation, using data from gel model experiments, I found that the -40oC lethal isotherm is approximately 1cm inside the leading edge of the ice-ball. The optimum distance between cryo-needles was 1.5 – 2 cm’s. At distances further apart the ice-balls had either a central core >-40oC or an hourglass shape. Subsequently analysis of a prospective registry-based case-series of 122 consecutive patients confirmed good early oncological control when treating predominantly anterior primary prostate with a 3-year failure free survival of 90.5% [95%CI 84.2-97.3]. Incontinence defined as any was 0/69 (0%) and erectile dysfunction was 5/31 (16.1%). Finally, a propensity score analysis was constructed using a combined focal cryotherapy and HIFU database versus a prospective radical prostatectomy database. After matching there were 246 patients in each arm with low-intermediate risk localised primary prostate cancer. Failure-free survival (95% CI) in the radical prostatectomy compared to focal therapy groups was 79% (73-86%) vs. 83% (76-90%) at 8 years (adjusted log rank p-value 0.12). Radiorecurrent Disease: Initial analysis of a 50-patient salvage HIFU showed a 5-year progression-free survival of 31% and 5-year overall survival (OS) of 87%. The main limitation was the adverse event profile with 3/50 (6%) developing a fistula, 27/50 (54%) needing further intervention for bladder outlet obstruction and 8/26 (31%) developing incontinence (any pad-use). A systemic review on focal salvage ablation showed that similar or better oncological outcomes could be obtained with focal salvage treatment with a superior side-effect profile. Results from the FORECAST trial showed that mpMRI for the detection of radiorecurrent disease had a sensitivity of 81% (95%CI 73-88%), specificity 88% (95%CI 73-98%), PPV 96% (95%CI 90-99%) and NPV 57% (95%CI 42-70%). Sensitivity of MRI-targeted biopsy in 87 men was 92% (95%CI 83-97%), specificity 75% (95%CI 45-92%), PPV 94% (95%CI 86-98%) and NPV 65% (95%CI 38-86%). Overall, 4/72 (6%) cancers were missed on systematic biopsies alone and 6/72 (8%) were missed on targeted biopsies alone. Subsequently, 93/181 underwent salvage focal therapy: HIFU (64/93) or cryotherapy (29/93). Probability of return of continence was 84% at 12-months. 73 underwent focal therapy for localised disease. Metastases Free Survival was 80% [95% CI 68 – 88] at 2-years. 20 underwent cytoreductive focal ablation in the presence of nodal/metastatic disease. All were alive at last follow-up. 4/20 had evidence of progression on whole-body imaging. The programme of work detailed above confirms both the good oncological and functional outcomes that can be achieved from focal therapy in primary and recurrent disease. This evidence provides the basis for future randomised controlled trials and whilst we await the results from these the presented data can be used to guide patients regarding their treatment options.

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