Laurence Klotz, MD, FRCSC

University of Toronto

Toronto, Ontario, Canada

Laurence Klotz, MD, FRCSC, is a professor of surgery at the University of Toronto and 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 (CUAJ), and he is now editor emeritus of the CUAJ. Dr. Klotz obtained his medical degree and completed his residency at the University of Toronto. He was also a uro-oncology fellow at Memorial Sloan Kettering Cancer Center in New York.

Dr. Klotz has 550 peer review publications and eight books. He coined the phrase “active surveillance” and successfully championed this approach for men with favorable-risk prostate cancer against substantial resistance. He was the associate editor of the Journal of Urology, responsible for prostate cancer, for eight years. Dr. Klotz received the Queen’s Jubilee Medal for outstanding public service, the University of Toronto's Lister Prize, the Society of Urologic Oncology’s SUO Medal, the American Urological Association’s Richard Williams Award, the University of Toronto's Lifetime Achievement Award, the Canadian Urological Association Lifetime Achievement Award, and the Harold Warwick Award from the Canadian Cancer Society for “outstanding contributions to cancer control.” In 2015 he was inducted as a Member of the Order of Canada, Canada’s highest civilian award.

Disclosures:

Research Support: Sanofi-Aventis, AbbVie, Exact Imaging
Honorarium Recipient: AstraZeneca, TerSera, Sanofi-Aventis
Consultant: miR Scientific

Talks by Laurence Klotz, MD, FRCSC

Active Surveillance or Focal Therapy as Primary Management

Posted by Laurence Klotz, MD, FRCSC | Mar 2022

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.

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

Posted by Laurence Klotz, MD, FRCSC | Mar 2022

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.

The Sentinel Prostate Cancer Platform: Validation Studies

Posted by Laurence Klotz, MD, FRCSC | Feb 2022

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.

International Prostate Cancer Update 2021 Session Review: Localized Prostate Cancer, Including ADT and Radiation Oncology

Posted by Laurence Klotz, MD, FRCSC | Nov 2021

Laurence Klotz, MD, FRCSC, summarizes talks from a session he moderated on Localized PCa, Including ADT & Radiation Oncology, during IPCU 31.

Treatment for Prostate Cancer with MRI-Guided Transurethral Ultrasound

Posted by Laurence Klotz, MD, FRCSC | Oct 2021

Laurence Klotz, MD, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, discusses MRI-guided transurethral ultrasound ablation (TULSA) in patients with localized prostate cancer. He characterizes this energy-based therapy as one that meets a need for patients with intermediate-risk prostate cancer, offering a less-invasive therapy with fewer quality-of-life effects than radiation and radical prostatectomy. Dr. Klotz explains the closed-loop controlled system and lays out the TULSA-PRO system components, emphasizing the power of the real-time thermal map when using thermal energy to heat tissue to destroy it. He then outlines the MRI-guided treatment workflow before listing the key features of TULSA: since it is a transurethral directional ultrasound ablation, it is incision- and radiation-free, with no energy being delivered through the rectum (thus avoiding rectal injury) and no volume limitation; the automated, closed-loop system eliminates guesswork and allows for precision, measuring temperature in real time, adjusting the amount of energy delivered to the tissue, and actively compensating for tissue and blood flow changes during the treatment; the therapy also offers thermal protection of important anatomy, including the urethra and rectum. Dr. Klotz then reviews previous TULSA technical and canine studies and the first-in-man treat and resect study for feasibility. This research led to a phase one safety and precision study that showed a 90 percent prostate-specific antigen (PSA) reduction. Dr. Klotz then reviews the TULSA-PRO Ablation Clinical Trial (TACT), which demonstrated a median PSA reduction of 95 percent, with consistent rates of biopsy-based improvement in 75-80% of men one year after TULSA therapy; data also show that TULSA therapy is easily tolerated and that most patients recover continence and erectile function within the year after therapy. Indeed, three-year follow-up data for TACT demonstrate that PSA response has been durable over time. Dr. Klotz concludes with a summary of TULSA, emphasizing the newness of this complex technology that is safe, precise, and has low toxicity. He highlights that it has been approved by the FDA and Health Canada and is emerging as a novel alternative to conventional therapy.

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