Laurence Klotz, MD, FRCSC

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

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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Treatment for Prostate Cancer with MRI-Guided Transurethral Ultrasound

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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Updates in ADT: Managing Adverse Effects

Laurence Klotz, MD, FRCSC, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research at Sunnybrook Health Sciences Centre, reviews simple interventions physicians can use to improve quality of life and survival as well as to ameliorate unwanted side effects in prostate cancer patients undergoing androgen deprivation therapy (ADT). He explains that there are many commonly known and relatively manageable adverse effects to ADT, but that many family practitioners may not be aware of or interested in dealing with them. The responsibility therefore falls to urologists. Dr. Klotz then discusses the available and developing interventions, as well as the mechanisms of action that underlie them. First, he looks at how statins reduce the adverse effects of metabolic syndrome related to ADT by inhibiting cellular uptake of androstenediol and therefore reducing the substrate available for testosterone synthesis in the castrate environment. Dr. Klotz then considers the benefits of bisphosphonates and monoclonal antibodies like denosumab in helping with osteoporosis, another common side effect of ADT. He also looks at metformin, an inexpensive drug that appears to reduce weight gain in men on ADT, and notes that exercise is an effective way to delay progression of prostate cancer. Dr. Klotz then presents evidence supporting the use of GnRH antagonists to reduce cardiovascular events in men on ADT and discusses new research regarding the role of FSH in obesity.

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Review of Sentinel Assay for Prostate Cancer Diagnosis

Laurence Klotz, MD, FRCSC, Professor of Surgery at the University of Toronto and the Sunnybrook Chair of Prostate Cancer Research, reviews the Sentinel Assay, a urine-based assay for detecting prostate cancer currently awaiting FDA approval. He notes that there are several significant needs in the pre-biopsy setting, including the need to increase the probability of a positive biopsy, and the need to reduce overdetection and the number of unnecessary biopsies. Dr. Klotz observes that there are several commercially-available biomarker assays that seek to help with this, all of which appear to work fairly well, although perhaps not quite as well as miR Scientific’s Sentinel Assay appears to. He explains that the Sentinel Assay is based on analysis of 442 urinary exosome microRNA sequences, and that it can identify small high-grade tumors that may be missed by imaging or biopsy. Dr. Klotz then summarizes the results of the one paper published on the Sentinel Assay so far, observing that its findings that the Sentinel prostate cancer test demonstrates a sensitivity of 94% and specificity of 92% are almost too good to be true. He presents as-yet-unpublished data that supports these findings, showing a 93% concordance between the Sentinel Assay and pathology. Dr. Klotz concludes that while validation is still needed, the Sentinel Assay appears to be an extremely accurate urine-based assay that will be easy to ship and use.

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