Laurence Klotz, MD

Dr. Laurence Klotz Discusses Active Surveillance at National Institutes of Health Conference

Laurence Klotz, MD, one of many distinguished speakers, is an active surveillance pioneer who conducted the very first North American research study on active surveillance. His study of active surveillance is ongoing. Dr. Klotz is Chief of Urology at Sunnybrook Health Sciences Centre and Professor of Surgery at the University of Toronto. He is also Chairman of the World Urologic Oncology Federation and the Founding Editor-in-Chief of the Canadian Journal of Urology.

Dr. Klotz’s presentation, entitled “Active Surveillance: Inclusive Approach,” addressed which men are candidates for active surveillance, summarized the outcomes for men using active surveillance in a study being conducted by his research group, and introduced new developments that may improve active surveillance management plans in the future. Dr. Klotz’s presentation is summarized below.

What is the potential threat Gleason pattern 3 may pose to men? Based on data from several studies, Gleason pattern 3 prostate cancer appears to have a very low likelihood for metastasizing and causing the death of a patient. According to Dr. Klotz, “It’s very debatable whether this Gleason 6 [3+3] is a true cancer and that’s why when I talk to patients I use words like pseudo-cancer, pseudo-disease to refer to microfocal [less than 1 mm] Gleason pattern 3 prostate cancer.” Men with Gleason score 6 [3+3] prostate cancer may therefore choose to use active surveillance to manage the disease instead of opting for radical treatment.

Occasionally, due to differences among pathologists, prostate cancer that is actually more aggressive (i.e. Gleason score 7 [3+4] or higher) can be under-graded as Gleason score 6 [3+3]. For this reason, it is important to confirm that prostate cancer is truly Gleason score 6 [3+3] before deciding on a treatment plan.

Many prostate cancers diagnosed are likely to be clinically insignificant.

Current evidence indicates that more prostate cancers can be considered clinically insignificant than previously thought. Clinically insignificant prostate cancers are those that are never likely to metastasize and cause the death of a patient. A 1993 study suggested that prostate cancers with a Gleason score of 6 or less and a volume of less than 0.5 mL are clinically insignificant. According to Dr. Klotz, “that is far too stringent by all reasonable criteria for what constitutes clinically insignificant disease based on what we know now.” A 2011 study by the ERSPC (European Randomized Study for the Screening of Prostate Cancer) group has redefined clinically insignificant prostate cancer as those cancers with a Gleason score of 6 or less and a volume of less than 1.3 mL. According to Klotz, this should be reassuring information because cancers that large are almost always found with standard biopsy or MRI. Therefore, there appears to be less of a danger of doctors missing cancers that need to be treated. Also, Klotz asserts that “many patients who we previously had thought to have significant disease based on above 0.5 mL, we can now think of as being clinically insignificant.”

Recent evidence indicating that fewer prostate cancers are actually life-threatening than previously believed has prompted Dr. Klotz’s group and others to include more men in their active surveillance programs. The current NCCN (National Comprehensive Cancer Network) guidelines for the initial therapy offered to men with prostate cancer have also been changed to include more men as candidates for active surveillance. NCCN’s recommended initial treatment for prostate cancer is based on both the severity of the cancer and the age of the patient.

NCCN recommends active surveillance as the initial treatment for men with “very low risk” prostate cancer regardless of their age. “Very low risk” prostate cancers are category T1c with a Gleason score of less than 6. Patients with “very low risk” prostate cancer also have standard PSA levels of less than 10 ng/mL and PSA density levels of less than 0.15. Upon biopsy, these patients have no more than 2 cores with cancer, and these positive cores have no more than 50% cancer cells.

NCCN also recommends active surveillance as an initial treatment for men with “low risk” prostate cancer regardless of their age. “Low risk” prostate cancers are category T1 or T2a with a Gleason score less than or equal to 6. Patients with “low risk” prostate cancer have standard PSA levels of less than 10 ng/mL. If a man with “low risk” prostate cancer is at an age at which he is expected to live less than 10 more years, NCCN recommends active surveillance as the initial treatment. If expected survival is more than 10 years for patients with “low risk” prostate cancer, NCCN recommends considering active surveillance, radiation therapy, and surgery as initial treatments.

Dr. Klotz’s group at Stonybrook Health Sciences Centre began an active surveillance study about 15 years ago. The study follows “favorable risk” patients using active surveillance to manage their prostate cancer. For this study, “favorable risk” patients are defined as patients with a Gleason score of 6 or less and a PSA level of 10 ng/mL or less. From 1995 to 1999, the study was also open to patients over 70 years of age with a PSA level up to 15 ng/mL and a Gleason score of 7 [3+4]. Although the outcome for these Gleason score 7 [3+4] patients was the same as that for patients with Gleason score 6, only “favorable risk” patients have been followed in this study since January of 2000.

Patients in this study undergo serial PSA screening (every 3 months for 2 years and then every 6 months in stable patients) and a biopsy after one year and then again every 3 to 4 years. If the patient’s cancer becomes higher risk during the course of this study, he is offered more radical treatment. A patient’s cancer is considered higher risk in this study if his PSA doubling time is less than 3 years, his biopsy reveals significant amounts of Gleason pattern 4, or he develops a nodule of the prostate than can be felt upon examination.

In the Stonybrook active surveillance study, 5 out of 453 men died of prostate cancer over a 10 year period. The observed actuarial prostate cancer mortality rate at 10 years about 3%. Overall, men in this active surveillance study were 19 times more likely to die of other causes than to die of prostate cancer over a 10 year period.

Gleason score 6 [3+3] prostate cancer does not appear to be life-threatening to most men. A problem can arise when doctors detect only Gleason score 6[3+3] prostate cancer and miss Gleason score 7 [3+4] or higher cancer that is actually present in the patient. A man may choose to treat more aggressively if he knows this higher grade cancer is present. Most standard ultrasound-guided prostate biopsies target the peripheral posterior zone of the prostate because cancer is more likely to be located in that area. The majority of patients whose prostate cancers are under-graded by doctors have cancer located in the under-examined anterior area of the prostate.

According to Dr. Klotz, “the answer here, in my opinion, is an increasing role for MRI, which finds these cancers.” Recent evidence suggests that only cancers larger than 1 mL are actually clinically significant, and MRI-guided biopsy is reliable for picking up prostate cancers of this size, even when they are located in the anterior region. In addition, MRI-guided biopsy appears to be more reliable for picking up high-grade cancers than the standard ultrasound-guided biopsy. The use of MRI-guided biopsy in men using active surveillance is being evaluated in new studies sponsored by the Ontario Institute for Cancer Research and the Canadian Urology Research Consortium.

Dr. Klotz grew up in Toronto where his father was a urologist. There were a number of healthcare practitioners in his family. Notably, his maternal grandfather was one of the first Jewish physicians to graduate from the University of Toronto in the early 1900s. Dr. Klotz received his medical degree from the University of Toronto in 1977. He later completed advanced training as a fellow at Memorial Sloan Kettering Cancer Center. During Dr. Klotz’s fellowship the Chief of Urology, Willet Whitmore, Jr., made a lasting impression. Years ahead of the watchful waiting movement, Dr. Whitmore urged prostate cancer patients over 65 years of age not to rush into surgery and recommended watchful waiting to them instead. Dr. Klotz recalled his experience with Dr. Whitmore in an interview in the British Journal of Urology: “Probably my main debt to him was that he recognized and communicated the importance of what you would call surgical humility. That is, recognizing the limits of intervention. He invoked the sense that the outcome of disease is mostly determined by biology not intervention. That’s accepted now.”

To watch video footage of this presentation and other presentations and discussions at the NIH State-of-the-Science Conference: Role of Active Surveillance in the Management of Men With Localized Prostate Cancer, visit http://videocast.nih.gov/.