Dr. Carroll’s first lesson is that each urologic oncologist should build their own infrastructure. At UCSF, Dr. Carroll assembled a tissue bank of >9,000 specimens of FFP, urine, and blood, as well as developed several registries including CaPSURE (a prostate cancer registry from 40 sites, >15,000 men, with 1,000 variables per patient) and the UODB-UCSF (7,000 patients and 500 variables linked to the tissue bank). These databases have produced many studies assessing, for example, outcomes and patterns and care.
The next lesson is that we can learn a lot from what we have readily available if we use it. For example, at UCSF Dr. Carroll and Dr. Matt Cooperberg have developed the CAPRA score, which is highlighted in the following table:
The CAPRA score has been shown to be associated with biochemical recurrence free survival, cancer-specific survival, and overall survival. Additionally, adding the oncotype GPS 17 gene assay to CAPRA score was found to improve accuracy for predicting favorable histology:1
As such, Dr. Carroll states that the future is in developing biomarkers, which are predictive (predict response to treatment).
The next lesson provided by Dr. Carroll is to measure your own outcomes. If one knows their outcomes, it is easy to learn from them, and to be able to counsel patients and collaborators honestly and transparently. Dr. Carroll’s fourth lesson is to know who to treat. Over Dr. Carroll’s first several thousand radical prostatectomies, he was treating mostly low-risk T1/T2, low grade patients, commonly over treating patients, and with a limited survival benefit. Presently, Dr. Carroll notes that he is mostly operating on high-risk patients (those that may benefit the most), adopting new technology (ie. robotic platform), utilizing biomarkers, and engaging a multimodal/multidisciplinary approach.
Dr. Carroll then discussed the importance of separating your beliefs and your current role as surgeon from your values. With regards to surgery for low risk prostate cancer, Dr. Carroll again quotes Dr. Whitmore “Is cure possible only when it is not necessary?” given that the majority these patients should be managed with active surveillance. Indeed, active surveillance is a response to the over-detection and treatment of prostate cancer brought about by widespread and repeated PSA screening. Its uptake by the urology community has helped pave the way for an upgraded assessment by the USPSTF on the early detection of prostate cancer. At UCSF, Dr. Carroll has developed a robust active surveillance cohort, including 2,200 enrolled patients through 2020. Among these patients, the median year of diagnosis was 2010 (IQR 2006-2013), mean age of diagnosis was 62 years (SD 7.6), median PSA at diagnosis was 5.6 ng/mL (IQR 4.2-7.5), mean duration of follow-up was 74 months, and 85% were low-risk (15% intermediate risk). The upgrade-free survival during active surveillance was 41% at 7 years (n=689 patients upgraded at a median follow-up of 25 months, IQR 13, 52). The upgrade-free survival was 40% at 7 years for men with Gleason Group 1 disease and 54% for men with Gleason Group >=2. The treatment free survival was 59% at 7 years, with 682 undergoing treatment at a median 27 months (IQR 15, 50) after diagnosis. The treatment-free survival was 60% at 7 years for men with Gleason Group 1 disease and 50% for men with Gleason Group >=2. In the overall cohort, metastasis free survival was 99%, prostate cancer specific survival was 99%, and overall survival was 96%. The main predictors of upgrading include age >=65 years (HR 1.31, 95% CI 1.12, 1.53), PSA density >= 0.15 (HR 1.69, 95% CI 1.45-1.98), biopsy GPS score >=30 (HR 1.68, 95% CI 1.32, 2.14), PI-RADS 3-5 (HR 2.20, 95% CI 1.57, 3.10), PI-RADS 4-5 (HR 1.62, 95% CI 1.22, 2.14), and negative biopsy (HR 0.21, 95% CI 0.16, 0.26). Although there has been remarkable improvement over 10 years, the current active surveillance uptake for low-risk prostate cancer according to the AQUA registry is still only 55.2% in 2018:
With regards to high-risk disease, is cure possible when it is necessary? Looking at his own data, Dr. Carroll notes that recurrence-free survival curves for high risk disease after radical prostatectomy also have many additional post-radical prostatectomy secondary treatments, many of which are curative.
The next lesson discussed by Dr. Carroll was to test assumptions and seek solutions. This is evident in how we think about lymphadenectomy for prostate cancer, which is present in all of the treatment guidelines. There has been enthusiasm for extended lymphadenectomy, but it has never been well-tested, although commonly performed and a potential source of morbidity. Among 1,543 men who underwent primary RP and pelvic lymph node dissection at UCSF, 174 (11%) had pN1 disease, and median follow-up was 34 months (IQR 15-62).2 Seven-year outcomes were similar whether less than or ≥14 lymph nodes were dissected. Among node-positive patients, 29% had undetectable PSA, 11% had undetectable PSA + adjuvant therapy, and 60% had detectable PSA, and 7-year biochemical RFS differed (75% for undetectable PSA, 90% for undetectable + adjuvant therapy, 38% for detectable PSA, p < 0.01).
Another lesson by Dr. Carroll is that better imaging may be critical for prostate cancer. The fundamentals of PSMA are that PSMA is a glycoprotein found on the cell surface of prostatic cells, and is overexpressed on prostate cancer tissue by 100-1000-fold with low expression in native prostate and health tissues. Overall, ~90% of prostate tumors express PSMA; IS-002 targets the PSMA biomarker. What we know thus far is that PSMA PET/CT is more sensitive than standard imaging, is highly specific, and commonly changes the management at diagnosis and recurrence. Importantly, 30-40% of patients with positive nodes on PSMA PET/CT have such nodes outside the standard fields for radiation or surgery.
One of the biggest challenges is that in men with high-risk prostate cancer, 15-40% will have positive margins or missed metastatic disease in lymph nodes, both of which may impact outcomes. Presenting work that is under embargo and cannot be discussed/reproduced at the present time, Dr. Carroll’s group is working on improving/combining imaging/surgical resection.
Dr. Carroll completed his Whitmore Lecture by highlighting several final thoughts from over his career:
- Seek great mentors
- Build infrastructure early and be prepared
- Seek opportunity, not convenience (be open, look around you)
- Be prepared to think and do differently (do not be defined by the outcome and not by what you do or what you have done)
- Practice (good, better, best, never let it rest…)
- Be persistent, generate knowledge and insight
- Build teams of great people, in and outside of the Urology community, since the best investment is in human capital
Presented by: Peter R. Carroll, MD, MPH, Department of Urology, UCSF Helen Diller Family Comprehensive Cancer Cetner, University of California – San Francisco, San Francisco, CA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, @zklaassen_md on Twitter during the 2021 American Urological Association, (AUA) Annual Meeting, Fri, Sep 10, 2021 – Mon, Sep 13, 2021.
- Klein EA, Cooperberg MR, Magi-Galluzzi C, et al. A 17-gene assay to predict prostate cancer aggressiveness in the context of Gleason grade heterogeneity, tumor multifocality, and biopsy undersampling. Eur Urol Sep;66(3):550-560.
- Washington 3rd SL, Cowan JE, Herlemann A, et al. Influence of pelvic lymph node dissection and node-positive disease on biochemical recurrence, secondary treatment, and survival after radical prostatectomy in men with prostate cancer. Prostate. 2021 Feb;81(2):102-108.