AUA 2018: Debate - Should We Offer Active Surveillance for Gleason 7 (3+4) Risk Disease? (CON)

San Francisco, CA ( Dr. Laurence Klotz presented on why we should not offer active surveillance (AS) for Gleason 7 (3+4) prostate cancer. Klotz began with a brief outline of the known data in 2018. Gleason 3 cells resemble normal cells in most cases, with a metastatic potential of zero. In contrast, for Gleason 4 cells there is a known metastatic potential.  Many Gleason 3+4 cancers are clinically insignificant but some are lethal. Therefore, the stakes are much higher and the risks are much greater. 

Patel et al. looked at pathologic findings of patients in a single center who underwent immediate radical prostatectomy (RP) in a recently published paper. [1] A total of 1264 patients with very low risk disease, 4849 with low risk disease, and 608 patients with low volume intermediate risk disease, who underwent RP were analyzed. 25% of low volume Gleason grade 2 (3+4) were upgraded to Gleason grade >=3 (4+3) at RP. To date, no criteria exist to identify true low risk in low volume intermediate risk disease.

Another study compared outcomes of favorable risk Gleason 3+4 disease and Gleason 6 (3+3) disease. A total of 8095 RPs for Gleason grade (GG) 1 and 2 were analyzed. [2] All had PSA less than 10, and a T stage of less than T2a. The results demonstrated that biochemical recurrence at 10 years was 89% for GG1 and 81% for GG2. Progression free survival at 10 years was 99% for GG1 and 96% for GG 2. 

Lastly, looking at the PROTECT trial, 77% of patients were diagnosed with Gleason 6 (3+3) on biopsy. Only 120 men in each group were diagnosed with Gleason 7 or higher disease. [3] Therefore, this study was underpowered to show a difference, and results could be misleading.

MRI and biomarkers will most likely transform this controversy, however, neither of them are perfect. With GG1 disease, the goal of monitoring should be to identify the presence of higher grade cancer. With GG2 disease, the triggers for intervention are not so obvious, and metastasis may, unfortunately, occur during observation. Practically speaking, we cannot be confident that a Gleason 3+4 lesion with a stable MRI does not metastasize. When assessing all the available published trials, MRI can rule out clinically significant cancer with an accuracy ranging between 35%-97% and with a negative predictive value ranging between 76-100%, clearly demonstrating there is still significant room for improvement.

Klotz concluded his talk stating that all studies of Gleason 7 on AS show substantially increased risk of metastasis with long term follow-up (despite offering selective delayed intervention). Although most patients do well, the risk is still substantial. The key point to remember is patient selection and looking for relevant triggers. Currently, there are many emerging therapeutic alternatives – focal therapy (HIFU, Cryo, Brachy, Electroporation, and more). Lastly, MRI and biomarkers have limitations and validation in this setting is required.

Presented by: Laurence Klotz, MD, FRCSC, Professor, Department of Surgery, University of Toronto, Chief, Division of Urology, Sunnybrook Health Sciences Center, Chair, Canadian Uro-Oncology Group, and NCIC GU Site Group, Editor in Chief (founding), Canadian Journal of Urology, Chair, Global GU Oncology Group

1. Patel HD et al. Adverse Pathologic Findings for Men Electing Immediate Radical Prostatectomy: Defining a Favorable Intermediate-Risk Group. JAMA Oncol. 2018 Jan 1;4(1):89-92. doi: 10.1001/jamaoncol.2017.1879.
2.  Gearman DJ et al. Comparison of Pathological and Oncologic Outcomes of Favorable Risk Gleason Score 3 + 4 and Low Risk Gleason Score 6 Prostate Cancer: Considerations for Active Surveillance. J Urol. 2018 May;199(5):1188-1195. doi: 10.1016/j.juro.2017.11.116. Epub 2017 Dec 7.
3.  Freddie C. Hamdy et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med 2016; 375:1415-1424, DOI: 10.1056/NEJMoa1606220

Read the Opposing Debate: Should We Offer Active Surveillance for Gleason 7 (3+4) Risk Disease? (PRO)

Written by:  Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA

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