Taimur T. Shah

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.

Histological outcomes after focal high-intensity focused ultrasound and cryotherapy.

IntroductionFocal therapy has increasingly become an accepted treatment option for patients with localised prostate cancer. Most follow-up protocols use a mixture of protocol biopsies or “for cause” biopsies triggered by a rising PSA. In this paper, we discuss the histological outcomes from these biopsies and their use in guiding subsequent management and trial development.MethodsWe conducted a literature search and reviewed the post-treatment biopsy results from studies on focal HIFU and focal cryotherapy. We subsequently reviewed the results of three recently published consensus statements released discussing many of the issues concerning focal therapy.ResultsResearch suggests that 1 in 5 of all post-treatment biopsies after focal therapy are positive. However, the majority of these seemed to be from the untreated portion of the gland or met criteria for clinically insignificant disease. The histological outcomes from focal therapy are promising and confirm its effectiveness in the short to medium term. Furthermore re-treatment is possible whilst maintaining a low-side-effect profile.ConclusionDebate is ongoing about the clinical significance of various levels of residual disease after focal therapy and the exact threshold at which to call failure within a patient who has had focal therapy.

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.

Modeling Cryotherapy Ice Ball Dimensions and Isotherms in a Novel Gel-based Model to Determine Optimal Cryo-needle Configurations and Settings for Potential Use in Clinical Practice

Objective To gain a better understanding of ice ball dimensions and temperature isotherms relevant for cell kill when using combinations of cryo-needles we set out to answer 4 questions: (1) what type of cryo-needle? (2) how many needles? (3) best spatial configuration? and (4) correct duty cycle percentage? Methods We conducted laboratory experiments to monitor ice ball dimensions and create multi-needle planar isotherm maps for 17G and 10G cryo-needles using a novel multi-needle thermocouple fixture within gel at body temperature. We tested configurations of 1-4 cryo-needles at duty cycles of 20%-100% with 1-2.5 cm spacing. Results Analysis of various combinations shows that a central core of ≤−40°C develops at a distance of ~1 cm around the cryo-needles. Temperature increases linearly from this point to the ice ball leading edge (0°C), which is a further ≈1 cm away. Thus, the −40°C isotherm is approximately 1 cm inside the leading edge of the ice ball. The optimum distance between cryo-needles was 1.5-2 cm, at duty cycle settings of 70%-100%. At distances further apart or with lower duty cycle settings, ice balls either had a central core >−40°C or had an hourglass shape. Conclusion In answer to questions 1-3, tumor length, diameter, and shape will ultimately determine the number of needles and their configuration. However, we propose a conservative distance for cryo-needle placement between 1 and 1.5 cm should be adopted for clinical practice. In answer to question 4, using low duty cycle settings runs the risk of incomplete −40°C isotherm coverage of the tumor, and thus in routine practice we suggest that settings of 70%-100% are most appropriate.

Development and Phantom Validation of a 3-D-Ultrasound-Guided System for Targeting MRI-Visible Lesions During Transrectal Prostate Biopsy

Objective: Three- and four-dimensional transrectal ultrasound transducers are now available from most major ultrasound equipment manufacturers, but currently are incorporated into only one commercial prostate biopsy guidance system. Such transducers offer the benefits of rapid volumetric imaging, but can cause substantial measurement distortion in electromagnetic tracking sensors, which are commonly used to enable 3-D navigation. In this paper, we describe the design, development, and validation of a 3-D-ultrasound-guided transrectal prostate biopsy system that employs high-accuracy optical tracking to localize the ultrasound probe and prostate targets in 3-D physical space. Methods: The accuracy of the system was validated by evaluating the targeted needle placement error after inserting a biopsy needle to sample planned targets in a phantom using standard 2-D ultrasound guidance versus real-time 3-D guidance provided by the new system. Results: The overall mean needle-segment-to-target distance error was 3.6 ± 4.0 mm and mean needle-to-target distance was 3.2 ± 2.4 mm. Conclusion: A significant increase in needle placement accuracy was observed when using the 3-D guidance system compared with visual targeting of invisible (virtual) lesions using a standard B-mode ultrasound-guided biopsy technique.

Multivariable model development and internal validation for prostate cancer specific survival and overall survival after whole-gland salvage Iodine-125 prostate brachytherapy

BACKGROUND Whole-gland salvage Iodine-125-brachytherapy is a potentially curative treatment strategy for localised prostate cancer (PCa) recurrences after radiotherapy. Prognostic factors influencing PCa-specific and overall survival (PCaSS & OS) are not known. The objective of this study was to develop a multivariable, internally validated prognostic model for survival after whole-gland salvage I-125-brachytherapy. MATERIALS AND METHODS Whole-gland salvage I-125-brachytherapy patients treated in the Netherlands from 1993-2010 were included. Eligible patients had a transrectal ultrasound-guided biopsy-confirmed localised recurrence after biochemical failure (clinical judgement, ASTRO or Phoenix-definition). Recurrences were assessed clinically and with CT and/or MRI. Metastases were excluded using CT/MRI and technetium-99m scintigraphy. Multivariable Cox-regression was used to assess the predictive value of clinical characteristics in relation to PCa-specific and overall mortality. PCa-specific mortality was defined as patients dying with distant metastases present. Missing data were handled using multiple imputation (20 imputed sets). Internal validation was performed and the C-statistic calculated. Calibration plots were created to visually assess the goodness-of-fit of the final model. Optimism-corrected survival proportions were calculated. All analyses were performed according to the TRIPOD statement. RESULTS Median total follow-up was 78months (range 5-139). A total of 62 patients were treated, of which 28 (45%) died from PCa after mean (±SD) 82 (±36) months. Overall, 36 patients (58%) patients died after mean 84 (±40) months. PSA doubling time (PSADT) remained a predictive factor for both types of mortality (PCa-specific and overall): corrected hazard ratios (HRs) 0.92 (95% CI: 0.86-0.98, p=0.02) and 0.94 (95% CI: 0.90-0.99, p=0.01), respectively (C-statistics 0.71 and 0.69, respectively). Calibration was accurate up to 96month follow-up. Over 80% of patients can survive 8years if PSADT>24months (PCaSS) and >33months (OS). Only approximately 50% survival is achieved with a PSADT of 12months. CONCLUSION A PSADT of respectively >24months and >33months can result in >80% probability of PCa- specific and overall survival 8years after whole-gland salvage I-125-brachytherapy. Survival should be weighed against toxicity from a salvage procedure. Larger series and external validation are necessary.

PSA nadir as a predictive factor for biochemical disease-free survival and overall survival following whole-gland salvage HIFU following radiotherapy failure

Background:Treatment options for radio-recurrent prostate cancer are either androgen-deprivation therapy or salvage prostatectomy. Whole-gland high-intensity focussed ultrasound (HIFU) might have a role in this setting.Methods:An independent HIFU registry collated consecutive cases of HIFU. Between 2005 and 2012, we identified 50 men who underwent whole-gland HIFU following histological confirmation of localised disease following prior external beam radiotherapy (2005–2012). No upper threshold was applied for risk category, PSA or Gleason grade either at presentation or at the time of failure. Progression was defined as a composite with biochemical failure (Phoenix criteria (PSA>nadir+2 ng ml−1)), start of systemic therapies or metastases.Results:Median age (interquartile range (IQR)), pretreatment PSA (IQR) and Gleason score (range) were 68 years (64–72), 5.9 ng ml−1 (2.2–11.3) and 7 (6–9), respectively. Median follow-up was 64 months (49–84). In all, 24/50 (48%) avoided androgen-deprivation therapies. Also, a total of 28/50 (56%) achieved a PSA nadir <0.5 ng ml−1, 15/50 (30%) had a nadir ⩾0.5 ng ml−1 and 7/50 (14%) did not nadir (PSA non-responders). Actuarial 1, 3 and 5-year progression-free survival (PFS) was 72, 40 and 31%, respectively. Actuarial 1, 3 and 5-year overall survival (OS) was 100, 94 and 87%, respectively. When comparing patients with PSA nadir <0.5 ng ml−1, nadir ⩾0.5 and non-responders, a statistically significant difference in PFS was seen (P<0.0001). Three-year PFS in each group was 57, 20 and 0%, respectively. Five-year OS was 96, 100 and 38%, respectively. Early in the learning curve, between 2005 and 2007, 3/50 (6%) developed a fistula. Intervention for bladder outlet obstruction was needed in 27/50 (54%). Patient-reported outcome measure questionnaires showed incontinence (any pad-use) as 8/26 (31%).Conclusions:In our series of high-risk patients, in whom 30–50% may have micro-metastases, disease control rates were promising in PSA responders, however, with significant morbidity. Additionally, post-HIFU PSA nadir appears to be an important predictor for both progression and survival. Further research on focal salvage ablation in order to reduce toxicity while retaining disease control rates is required.

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.

The British Urology Researchers in Surgical Training (BURST) Research Collaborative: an alternative research model for carrying out large scale multi-centre urological studies

Veeru Kasivisvanathans research is funded from the National Institute for Health Research. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Taimur Shah would like to acknowledge funding from the St Peters Trust for clinical research and has received support for conference attendance and speaker fees from Astellas, Ferring and Galil Medical. Mark Emberton is a National Institute for Health Research Senior Investigator (2015-) and receives research support from the UCLH/UCL NIHR Biomedical Research Centre. This article is protected by copyright. All rights reserved.

Fokale Therapie des Prostatakarzinoms

Focal therapy is a treatment strategy for men with localized prostate cancer that may serve as an alternative option to radical therapy. A number of minimally invasive ablative technologies are available to deliver treatment, and the energies most commonly used include high-intensity focused ultrasound and cryotherapy. The benefit of a tissue-preserving approach is the limitation of damage to key structures such as the neurovascular bundles, external urinary sphincter, rectal mucosa and bladder neck. This in turn minimizes side effects typically associated with radical therapies whilst also aiming to maintain oncological control. Over 30 single-centre studies of focal therapy have been published to date reporting excellent continence rates, good potency rates and acceptable short-term oncological outcomes. However, there are a number of controversial aspects associated with focal therapy including the index lesion hypothesis, patient selection criteria, assessment of treatment effect and the lack of medium- and long-term oncological outcomes. In the process of the adoption of new technology, there is a limited window of opportunity to provide this evidence in well-designed prospective trials. Men should be allowed to benefit from the potential advantages of this novel treatment whilst under close surveillance. An English version of this article is available under dx.doi.org/10.1007/s00120-014-3734-7.