Laurence Klotz, MD, FRCSC

Laurence Klotz, MD, FRCSC

Sunnybrook Health Sciences Centre

Toronto, Ontario, Canada

Laurence Klotz, MD, is the former Chief of Urology at Sunnybrook Health Sciences Centre and former President of the Urological Research Society and the Canadian Urological Association. He currently serves as Professor of Surgery at the University of Toronto and holds the Sunnybrook Chair of Prostate Cancer Research. Dr. Klotz was the Founding Editor-in-Chief of both the Canadian Journal of Urology and the Canadian Urology Association Journal, and is now Editor Emeritus of the CUAJ. He is the Founder and Chairman of the Canadian Urology Research Consortium (CURC), and is also the Chair of the Global GU Oncology Group. Dr. Klotz obtained his medical degree from the University of Toronto and completed his residency at the University of Toronto Gallie Program in Surgery. He was a fellow at Memorial Sloan Kettering Cancer Center in New York in uro-oncology. Dr. Klotz is a widely published uro-oncologist with over 350 publications and several books. His main research interest has been prostate cancer. He has served on the boards of many medical/scientific organizations and journals, including the SUO, Prostate Cancer Canada, the journals Prostate Cancer and Prostatic Diseases, Brazilian Journal of Urology, Italian Journal of Urology, and World Journal of Urology. Dr. Klotz was awarded the Queen’s Jubilee Medal for meritorious public service in 2012, and the University of Toronto Department of Surgery Lister Prize and the Society of Urologic Oncology Medal in 2013. He received the Harold Warwick Award from the Canadian Cancer Society for ‘outstanding contributions to cancer control’ in 2014. He received the Order of Canada in 2015, and the Richard Williams Award from the AUA in 2016. He received the Dean’s Lifetime Achievement Award from the University of Toronto in 2017.

Disclosures:

Chief Medical Officer - miR Scientific
Research Funding - Exact Imaging
Research Funding - Profound Imaging

Talks by Laurence Klotz, MD, FRCSC

MRI-guided Transurethral Ultrasound Ablation (TULSA) for Prostate Cancer

Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, discusses the technology, procedure, outcomes, and regulatory environment surrounding MRI-guided transurethral ultrasound ablation (TULSA) treatment for patients with prostate cancer. He begins by displaying a chart of multiple minimally invasive treatment options for prostate cancer. Dr. Klotz lists prospective studies of focal therapy that found relatively few adverse quality-of-life (QOL) effects. He goes on to compare five ultrasound-based technologies in terms of biopsy and prostate-specific antigen (PSA) outcome, concluding that data demonstrates these therapies work. Dr. Klotz emphasizes that there is not currently a way to differentiate the oncological efficacy of these treatments, citing the number of variables and reiterating that they all are reasonably effective. Dr. Klotz then turns the discussion to MRI-guided transurethral ultrasound ablation (TULSA), explaining the function of the technology and the system components involved, explaining that the energy delivered is controlled by a closed-loop control system. He outlines the key features of the TULSA system, explaining that it delivers transurethral directional ultrasound ablation which is incision and radiation free, and there is no energy coming through the rectum and there is no volume limitation. Further, real-time MRI thermal dosimetry and ablation control means temperature is measured in real time and the system adjusts the amount of energy delivered to the tissue, providing precision, actively compensating for tissue and blood flow changes during the treatment. Finally, the system offers thermal protection of important anatomy (i.e., urethra and rectum cooling). Dr. Klotz then outlines the evolution of the TULSA technology, including technical studies, canine studies, first-in-man treatment, and feasibility studies. He describes the TULSA-PRO Ablation Clinical Trial (TACT), which involved 115 patients across 13 institutions in five countries, with safety (frequency/severity of adverse events) and efficacy (PSA reduction ≥75 percent in >50 percent of patients) being the primary endpoints at 12 months. Ninety-six percent of patients had a PSA reduction ≥75 percent at 12 months and at the 12-month MRI the median prostate volume had decreased from 41 to 4 cc (a decrease of 90 percent). Further, the treatment preserved continence and erectile function. In a three-year follow-up among men who underwent the treatment, just 11 percent needed salvage treatment. Dr. Klotz explains the challenges involved in demonstrating level-one evidence for the benefit of new technologies since benefits tend to be incremental and gradual. He cites the da Vinci robot as an important example and explains that the U.S. Food and Drug Administration (FDA) has acknowledged this in its approval of high intensity focused ultrasound (HIFU) and TULSA (for tissue ablation). Dr. Klotz concludes with a summary of the TULSA technology, procedure, outcomes, and regulatory considerations, explaining that this new technology is being offered in the US and Europe and is pending in Canada.

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Active Surveillance or Focal Therapy as Primary Management

Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, addresses when it is appropriate to use focal therapy versus active surveillance (AS) for prostate cancer. He observes that focal therapy for prostate cancer is controversial, with some doubting its efficacy entirely, and gives the disclaimer that he approaches the subject as an advocate for focal therapy in certain cases. Dr. Klotz then discusses the goals of AS, explaining that for de novo Gleason grade 1 patients, the purpose is to identify higher grade cancer, and for Gleason grade 2-3, the goal is identification of clinical progression while the disease is still curable. He notes that with AS, historically the risk of ‘progression’ to higher grade cancer has been 40%, while with focal therapy, the risk of failure is 35-40%, meaning that the risk of unrecognized/persistent GG ≥ 2 is similar for both. Dr. Klotz then considers the uses and appeal of focal therapy, emphasizing the benefits of a treatment that preserves the prostate and also allows time to intervene if the cancer returns. He also mentions some of the misuses and risks of focal therapy, arguing that it can be difficult to use in cases of tumor multifocality and heterogeneity and that the significant limitations of imaging and targeting, especially for Gleason grade 2 disease, can be challenging. Additionally, Dr. Klotz highlights the lack of level 1 evidence supporting focal therapy. He goes on to discuss what makes good candidates for partial gland ablation, describing patients with a Gleason grade 2 solitary unilateral lesion as being in the ‘sweet spot’ for focal therapy, while patients with more widespread or slightly higher grade disease may be candidates, but not necessarily. Dr. Klotz would not advise partial gland ablation to young patients with high-volume Gleason grade 1 unilateral disease who have a clear target on MRI, or to patients with Gleason grade 4 disease who have a small solitary lesion on biopsy and MRI. He then discusses the current management protocols for both AS and focal therapy in detail before concluding with a look at the future of focal therapy. Dr. Klotz argues that, despite the controversies, patients will increasingly demand focal therapy and therefore the urology field has a mandate to confirm its oncologic effectiveness and safety, and to determine which of the many methods of focal therapy is best.

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Active Surveillance: Who Qualifies, Who Does Not and How Should it be Monitored

Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, outlines recent progress in active surveillance (AS), highlighting molecular genetics of Gleason Grade (GG) 1 vs. higher grade cancers, patient selection, germline testing, imaging, biomarkers, predictive nomograms, modeling, long-term outcomes, follow-up strategies, the tumor microenvironment, and dietary modifications. Dr. Klotz explains that AS is now the standard of care for GG1 prostate cancer, supported by professional organizations internationally. He displays data on the diverse genetic landscape of clinically low-risk prostate cancer, pointing out that just two percent of patients with GG1 cancer are in the highest quartile in terms of their genetic aberrancy and aggressivity. Dr. Klotz cites a study involving nearly 6,000 patients on AS that examined genetic factors associated with prostate cancer conversion from AS to treatment, explaining that 18 variants were found to be associated with conversion, 15 of which were not previously associated with prostate cancer risk. Dr. Klotz cites research involving nearly 10,0000 patients that studied metastasis and mortality in men with low- and intermediate-risk prostate cancer on AS; prostate cancer–specific mortality at 10 years was 1.1 percent in patients with GG1 cancer, 3.7 percent in patients with GG2, and then 12 percent in patients with GG3 disease. He displays a risk nomogram, the Canary PASS Biopsy Risk Calculator, pointing out that ordinary parameters such as age, body mass index (BMI), prostate-specific antigen (PSA) volume, time since diagnosis, and maximal core ratio can be powerful predictors of the likelihood of higher-grade cancer. Dr. Klotz addresses MRI, explaining it does not reliably indicate disease progression; he cites a study that showed 31 percent of men on AS with stable MRI upgraded to ≥GG2. He cites another study that emphasizes systematic biopsy must be performed whether MRI is positive or negative and explains a systematic review of 15 studies of patients on AS that indicated MRI sensitivity is just ~60 percent—a rate Dr. Klotz characterizes as unreliable. Dr. Klotz then addresses high-resolution micro-ultrasound as a complementary tool, before turning to simple heart- and prostate-healthy advice for patients on AS: stop smoking; make dietary modifications to reduce obesity, and get regular exercise. He cites a study on obesity and the tumor immune microenvironment and explains that in obese men, the tumor cells become acquisitive of free fatty acids and essentially the immune cells are deprived of free fatty acids. This leads to altered fatty acid partitioning, impairing CD8+ T cell infiltration and function. He surmises that this altered tumor microenvironment causes obese men to have worse outcomes. Dr. Klotz concludes with a summary of current AS follow-up strategy and explains that an emerging strategy is dynamic risk profiling with accurate biomarkers that will replace most serial biopsies.

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Active Surveillance 2022: Who Qualifies, Who Does Not and How Should it be Monitored

In this 12-minute presentation, Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, outlines recent progress in active surveillance (AS), highlighting molecular genetics of GG1 vs. higher grade cancers, patient selection, germline testing, imaging, biomarkers, predictive nomograms, modeling, long-term outcomes, follow-up strategies, the tumor microenvironment, and dietary modifications. Dr. Klotz summarizes current AS follow-up strategy and explains that an emerging strategy is dynamic risk profiling with accurate biomarkers that will replace most serial biopsies.

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The Sentinel Prostate Cancer Platform: Validation Studies

Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, discusses the Sentinel PCC4 assay for prostate cancer in detail and reviews data on its performance characteristics. He gives an overview of the Sentinel Prostate Disease Management Platform, explaining that it is based on an analysis of a large number of urinary exosomal small non-coding (snc)RNAs that have been found to be predictive of cancer and cancer stage. Dr. Klotz shows an electron microscopy of urinary microvesicles and overviews research that looked at the independent predictive value of around 10,000 different microRNA sequences and ranked them according to the likelihood of being associated with cancer being present or not. 442 of the sequences were selected for further analysis and are used as part of the Sentinel PCC4 assay. He then discusses initial Sentinel Assay data published in the Journal of Urology showing 98% specificity for detecting the presence or absence of cancer and 96% specificity for differentiating low-grade vs. high-grade cancer. This data raised the question of how Sentinel could predict the results of biopsy so well when biopsy does not correlate as closely with the extent and grade of cancer present. Dr. Klotz reviews a summary of the key validation data to date that reveals a specificity rate of 66%, with a 34% rate of false positives, and found that 52% of positive Sentinel assays for any cancer were followed by a negative biopsy. He suggests that this liquid biomarker test is superior to others and that the data is compelling. Dr. Klotz concludes that the Sentinel PCC4 sncRNA assay has high specificity and sensitivity, relatively speaking, and that further validation studies are ongoing.

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