Stephanie Guillaumier

Harnessing the immunomodulatory effect of thermal and non-thermal ablative therapies for cancer treatment

Minimally invasive interventional therapies are evolving rapidly and their use for the treatment of solid tumours is becoming more extensive. The in situ destruction of solid tumours by such therapies is thought to release antigens that can prime an antitumour immune response. In this review, we offer an overview of the current evidence for immune response activation associated with the utilisation of the main thermal and non-thermal ablation therapies currently in use today. This is followed by an assessment of the hypothesised mechanisms behind this immune response priming and by a discussion of potential methods of harnessing this specific response, which may subsequently be applicable in the treatment of cancer patients. References were identified through searches of PubMed/MEDLINE and Cochrane databases to identify peer-reviewed original articles, meta-analyses and reviews. Papers were searched from 1850 until October 2014. Articles were also identified through searches of the authors’ files. Only papers published in English were reviewed. Thermal and non-thermal therapies have the potential to stimulate antitumour immunity although the current body of evidence is based mostly on murine trials or small-scale phase 1 human trials. The evidence for this immune-modulatory response is currently the strongest in relation to cryotherapy and radiotherapy, although data is accumulating for related ablative treatments such as high-intensity focused ultrasound, radiofrequency ablation and irreversible electroporation. This effect may be greatly enhanced by combining these therapies with other immunostimulatory interventions. Evidence is emerging into the immunomodulatory effect associated with thermal and non-thermal ablative therapies used in cancer treatment in addition to the mechanism behind this effect and how it may be harnessed for therapeutic use. A potential exists for treatment approaches that combine ablation of the primary tumour with control and possible eradication of persistent, locally recurrent and metastatic disease. However, more work is needed into each of these modalities, initially in further animal studies and then subsequently in large-scale prospective human studies.

The Effects of Focal Therapy for Prostate Cancer on Sexual Function: A Combined Analysis of Three Prospective Trials.

BACKGROUND Tissue preservation by means of focal therapy offers some men with clinically significant prostate cancer an alternative to standard care that appears to confer favourable genito-urinary outcomes. The precise estimates of these outcomes have so far been based on small series. OBJECTIVE This analysis pools the sexual domain related patient reported outcomes from three prospective, registered studies that represent a range of inclusion criteria. DESIGN, SETTING, AND PARTICIPANTS One-hundred and eighteen men with localised prostate cancer (prostate specific antigen ≤ 15ng/ml, Gleason ≤ 4+3, stage ≤ T3aN0M0) treated in a tissue-preserving manner using high intensity focused ultrasound from three registered studies were included. Data on International Index of Erectile Function (IIEF-5) scores and use of phosphodiesterase-5-inhibitors were collected at baseline, and 1 mo, 3 mo, 6 mo, 9 mo, and 12 mo postoperatively. The IIEF-15 total and individual domain scores were used to assess overall sexual function. Urinary function was assessed with the International Prostate Symptom Score (IPSS), IPSS quality-of-life, and UCLA-Expanded Prostate Cancer Index Composite continence questionnaires. General health status was derived by means of the Charlson score. Multiple linear regression was used to assess whether age, grade, stage, qualitative scores (IIEF, IPSS, Expanded Prostate Cancer Index Composite, Charlson), or focal therapy type duration were associated with IIEF-5 and IIEF-15 scores at 12 mo. RESULTS AND LIMITATIONS Median age was 63 yr (interquartile range [IQR] 52-70 yr). Median IIEF-erectile score at baseline was 23 (IQR 11-28). This declined significantly to 9 (IQR 3-22, p<0.01) at 1 mo, but improved to 20 (IQR 9-29, p=0.30) at 1 yr posttreatment. Changes in total IIEF and other IIEF domains were only significantly different from preoperative values at 1 mo and 3 mo postoperatively. In the same period, the proportion of men using phosphodiesterase-5-inhibitors was 10% preoperatively, reaching 43% and 42% at 6 mo and 9 months before declining to 37% at 1 yr. The only baseline determinants of postoperative erectile function were total IIEF and IIEF-erectile function scores (p=0.002). The primary limitation of our study is the relatively short follow-up of 1 yr. CONCLUSION Men who received a range of tissue preserving therapies from the three pertinent studies experienced small decreases in total IIEF, erectile, and individual sexual domain scores that are not significantly different to those recorded at baseline. The only determinant of erectile dysfunction after tissue preserving therapy was preoperative erectile dysfunction status. Tissue preservation confers a high probability of maintaining erectile function that appears independent of all perioperative factors with the exception of baseline status. PATIENT SUMMARY In this report, the largest prospectively collected and published set of patients with erectile dysfunction outcomes post-focal therapy for prostate cancer, we have found a return to baseline International Index of Erectile Function-erectile and total International Index of Erectile Function scores by 6 mo post-focal therapy which was maintained at 1 yr, with the majority of patients not on any form of medical treatment for their erectile dysfunction at that point. Focal therapy may represent a suitable alternative for men of any age or comorbidity wishing to maintain erectile function.

A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating Clinically Significant Nonmetastatic Prostate Cancer

Background Clinically significant nonmetastatic prostate cancer (PCa) is currently treated using whole-gland therapy. This approach is effective but can have urinary, sexual, and rectal side effects. Objective To report on 5-yr PCa control following focal high-intensity focused ultrasound (HIFU) therapy to treat individual areas of cancer within the prostate. Design, setting, and participants This was a prospective study of 625 consecutive patients with nonmetastatic clinically significant PCa undergoing focal HIFU therapy (Sonablate) in secondary care centres between January 1, 2006 and December 31, 2015. A minimum of 6-mo follow-up was available for599 patients. Intermediate- or high-risk PCa was found in 505 patients (84%). Intervention Disease was localised using multiparametric magnetic resonance imaging (mpMRI) combined with targeted and systematic biopsies, or transperineal mapping biopsies. Areas of significant disease were treated. Follow-up included prostate-specific antigen (PSA) measurement, mpMRI, and biopsies. Outcome measurements and statistical analysis The primary endpoint, failure-free survival (FFS), was defined as freedom from radical or systemic therapy, metastases, and cancer-specific mortality. Results and limitations The median follow-up was 56 mo (interquartile range [IQR] 35–70). The median age was 65 yr (IQR 61–71) and median preoperative PSA was 7.2 ng/ml (IQR 5.2–10.0). FFS was 99% (95% confidence interval [CI] 98–100%) at 1 yr, 92% (95% CI 90–95%) at 3 yr, and 88% (95% 85–91%) at 5 yr. For the whole patient cohort, metastasis-free, cancer-specific, and overall survival at 5 yr was 98% (95% CI 97–99%), 100%, and 99% (95% CI 97–100%), respectively. Among patients who returned validated questionnaires, 241/247 (98%) achieved complete pad-free urinary continence and none required more than 1 pad/d. Limitations include the lack of long-term follow-up. Conclusions Focal therapy for select patients with clinically significant nonmetastatic prostate cancer is effective in the medium term and has a low probability of side effects. Patient summary In this multicentre study of 625 patients undergoing focal therapy using high-intensity focused ultrasound (HIFU), failure-free survival, metastasis-free survival, cancer-specific survival, and overall survival were 88%, 98%, 100%, and 99%, respectively. Urinary incontinence (any pad use) was 2%. Focal HIFU therapy for patients with clinically significant prostate cancer that has not spread has a low probability of side effects and is effective at 5 yr.

MP30-10 HIFU DOSE ESCALATION LEADS TO FEWER RECURRENCES IN FOLLOWING FOCAL HIFU IN PROSTATE CANCER

CONCLUSION HIFU dose escalation leads to fewer recurrences in following focal HIFU in prostate cancer P. M. Huber 1,4,6, N. Afzal 8, M. Arya 4,6,7, S. Boxler 1, S. Charman 3, A. Cornaby 3, T. Dudderidge 9, M. Emberton 3,4, S. Guillaumier 3,4, R. J. Hindley 10, L. Leemann 2, H. Lewi 11, N. McCartan 3,4, C. M. Moore 3,4, R. Nigam 12, C. Ogden 13, R. Persad 14, K. Shah 3, G. N. Thalmann 1, J. Virdi 7, M. Winkler 6, H. U. Ahmed 3,5,6 1. Department of Urology, University Hospital Inselspital Berne, CH; 2. Department of Political Science, University of Zurich, CH; 3. Division of Surgery and Interventional Sciences, University College London, London, UK; 4. Department of Urology, UCLH NHS Foundation Trust, London, UK; 5. Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK; 6. Imperial Urology, Charing Cross Hospital, Imperial College Healthcare NHS Trust, London, UK; 7. Department of Urology, The Princess Alexandra Hospital NHS Trust, Harlow, UK; 8. Department of Urology, Dorset County Hospital NHS Trust, Dorset, UK; 9. Department of Urology, University Hospital Southampton NHS Trust, Southampton, UK; 10. Department of Urology, Basingstoke and North Hampshire Hospital, Hampshire Hospitals NHS Foundation Trust, UK; 11. Springfield Hospital, Chelmsford, Essex, UK; 12. Department of Urology, Royal County Surrey Hospital NHS Trust, Surrey, UK; 13. Department of Academic Urology, The Royal Marsden Hospital NHS Foundation Trust, London, UK; 14. Department of Urology, Southmead Hospital, North Bristol NHS Trust, Bristol, UK

High-Intensity Focused Ultrasound for Prostate Cancer

Prostate cancer is the most common cancer in males and the second-leading cancer-related cause of death in the Western world. Prostate-specific antigen (PSA) screening, and changes in the diagnostic pathway of prostate cancer, has resulted in proportionally more men being diagnosed with early stage prostate cancer still confined to the prostate. Patients are faced with an overwhelming choice of treatment options to treat their disease. Standard options include radical prostatectomy (RP) and external-beam radiotherapy (ERBT) which, although provide good long-term cancer control, are associated with significant side effects affecting the quality of life of these patients.

Reply from Authors re: Giorgio Gandaglia, Alberto Briganti, Andrea Salonia, Francesco Montorsi. Excellent Erectile Function Recovery after Focal Therapy: Is This Enough? Eur Urol 2016;69:852–3: Focal Therapy Preserves Erectile Function in Men with Prostate Cancer

erectile function among patients treated with these approaches, for which there were significant differences in the amount of healthy prostatic tissue spared [3]. The similar functional outcomes observed in patients receiving ablation of different amounts of prostatic tissue suggest that sparing at least one NVB might be sufficient to obtain satisfactory erectile function after treatment. Again, this can be safely obtained using other well-established treatment modalities. In particular, a meticulous surgical approach allows preservation of anatomic structures responsible for erections and continence [5,7], even in patients with more aggressive disease characteristics [8]. Finally, these excellent functional results are presented in the absence of solid oncologic data at long-term followup [1]. The introduction of novel treatment approaches will substantially improve our ability to manage patients with clinically localized PCa and reduce the risk of treatmentrelated side effects. Nonetheless, efficacy data on oncologic endpoints are needed before these therapies can be routinely implemented in the clinical setting. Although the study by Yap et al [3] demonstrates that focal therapy is associated with excellent recovery of erectile function, longterm results from ongoing trials evaluating the outcomes of this technique are needed to clarify its role in the management of PCa patients. Meanwhile, we should remember that other well-established treatment approaches can provide optimal long-term recovery of erectile function in selected patients without compromising oncologic outcomes [5–10].

Focal or Multifocal Therapy in Prostate Cancer: New Technologies and Strategies

New surgical techniques are continuously being developed in the field of prostate cancer, more so with the ever-increasing interest in minimally invasive techniques to treat solid organ cancers. This has been triggered by the current state of play with treating a disease that has a long natural history in which the benefits and risks of radical therapy are not quite right. In other words, whole-gland radical therapy or radiotherapy can cause significant complications that are a direct result of damage to surrounding structures, including erectile dysfunction (30–70 %), urinary incontinence (5–20 %) and bowel toxicity (5–10 %). Focal therapy aims to reduce the complication profile by focusing the therapy to the cancer lesion and preserving surrounding tissues, thus improving functional outcome.

Reply from Authors re: Giorgio Gandaglia, Alberto Briganti, Andrea Salonia, Francesco Montorsi. Excellent Erectile Function Recovery after Focal Therapy: Is This Enough? Eur Urol. In press. http://dx.doi.org/10.1016/j.eururo.2015.11.014: Focal Therapy Preserves Erectile Function in Men with Prostate Cancer

erectile function among patients treated with these approaches, for which there were significant differences in the amount of healthy prostatic tissue spared [3]. The similar functional outcomes observed in patients receiving ablation of different amounts of prostatic tissue suggest that sparing at least one NVB might be sufficient to obtain satisfactory erectile function after treatment. Again, this can be safely obtained using other well-established treatment modalities. In particular, a meticulous surgical approach allows preservation of anatomic structures responsible for erections and continence [5,7], even in patients with more aggressive disease characteristics [8]. Finally, these excellent functional results are presented in the absence of solid oncologic data at long-term followup [1]. The introduction of novel treatment approaches will substantially improve our ability to manage patients with clinically localized PCa and reduce the risk of treatmentrelated side effects. Nonetheless, efficacy data on oncologic endpoints are needed before these therapies can be routinely implemented in the clinical setting. Although the study by Yap et al [3] demonstrates that focal therapy is associated with excellent recovery of erectile function, longterm results from ongoing trials evaluating the outcomes of this technique are needed to clarify its role in the management of PCa patients. Meanwhile, we should remember that other well-established treatment approaches can provide optimal long-term recovery of erectile function in selected patients without compromising oncologic outcomes [5–10].