SCS AUA 2024: Active Surveillance for Low Volume Gleason Grade Group 2 Disease: Con

(UroToday.com) The 2024 South Central AUA annual meeting included a session on prostate cancer, featuring a presentation by Dr. Aaron Laviana discussing the con approach for active surveillance among patients with low volume Gleason Grade Group 2 disease. Dr. Laviana started his presentation by highlighting that the NCCN defines favorable intermediate-risk prostate cancer as having all of the following criteria:

  • 1 intermediate risk feature
  • Grade Group 1 or 2 disease
  • <50% of the biopsy cores positive for prostate cancer (ie. <6 of 12 cores)

Treatment options for favorable intermediate-risk prostate cancer based on the NCCN guidelines suggest that for men with a life expectancy > 10 years, active surveillance, radiotherapy, or radical prostatectomy +/- pelvic lymph node dissection may all be reasonable treatment options. Across the board, entrance criteria for active surveillance is quite heterogeneous. The criteria for Johns Hopkins, UCSF, University of Toronto, and Canary PASS are as follows:

Moreover, ASCO suggests that active surveillance is an option for patients with low risk, favorable intermediate risk with low proportion of pattern 4 disease, or anyone older than 75 years of age. The NCCN suggests patients with very low-risk, low-risk, or favorable intermediate-risk disease may be candidates for active surveillance.

 The SPCG-4 trial randomized men with localized prostate cancer to surgery or observation, noting with 18-year follow-up no overall difference in relative risk reduction for death, prostate cancer-specific mortality, or metastasis.1 However, when assessed by risk group, the benefit of surgery with respect to death from prostate cancer was largest in men younger than 65 years of age and in those with intermediate-risk prostate cancer:
Dr. Laviana notes that in the SPCG-4 trial, for intermediate-risk patients, we do not know the percentage of Gleason Grade Group 2 or 3.

The PIVOT trial2 randomized 731 men with localized prostate cancer (>50% with non palpable disease) to prostatectomy versus observation, and with long-term follow-up there was a benefit favoring surgery for improved local and systemic disease progression. Additionally, the data highlights for all-cause mortality from PIVOT are as follows:

  • All patients: HR 0.88 (95% CI 0.71 – 1.08), p = 0.22
  • Low risk: HR 1.15 (95% CI 0.80 – 1.66), p = 0.45
  • Intermediate risk: HR 0.69 (95% CI 0.49 – 0.98), p = 0.04
  • PSA < 10 ng/mL: HR 1.03 (95% CI 0.79 – 1.35), p = 0.82
  • PSA > 10 ng/mL: HR 0.67 (95% CI 0.48 – 0.94), p = 0.02

Dr. Laviana notes that the authors from PIVOT concluded that the results did not significantly vary by patient or tumor characteristics, although differences were larger favoring surgery among men <65 years of age, those of white race, better health status, fewer comorbidities, 34% positive prostate biopsy cores, and intermediate-risk disease.

Dr. Laviana then discussed the ProtecT trial,3 which randomized 1,643 men with localized prostate cancer to active monitoring, radiotherapy, or surgery. He noted that although there were few mortalities at 10 years of follow-up (active monitoring: 8; surgery: 5; radiotherapy: 4), there were more patients with metastases in the active monitoring group (n = 33), compared to surgery (n = 13), or radiotherapy (n = 16) groups. Of note, among the eight patients in the active monitoring group that died, 5/8 had Gleason Score 7 disease at the time of diagnosis.

In the UCSF active surveillance cohort, Cooperberg et al.4 assessed 466 patients (377 low risk; 90 intermediate risk) over a median follow-up of 4 years, of which 32% had intermediate-risk disease. Notably, intermediate-risk disease (50%) vs low-risk disease (28%) was suggestive of pT3 pathology at the time of radical prostatectomy:466 patients (377 low risk; 90 intermediate risk) over a median follow-up of 4 years, of which 32% had intermediate risk disease. Notably, intermediate risk disease (50%) vs low risk disease (28%) was suggestive of pT3 pathology at the time of radical prostatectomy
In 2016, Musunuru et al.5 published outcomes of the Sunnybrook Toronto experience of active surveillance among intermediate-risk prostate cancer patients. They found that the risk of metastasis-free survival (HR 3.14, 95% CI 1.51 to 6.53) and prostate cancer-specific survival were worse for patients with intermediate-risk disease undergoing active surveillance compared to those with low-risk disease. This appeared to be driven by tumor grade, rather than PSA: 15-year metastasis-free survival was 94% in men with Gleason score 6 + PSA less than 10 ng/mL, 94% in men with Gleason score 6 + PSA 10 to 20 ng/mL, 84% in men with Gleason score 7 (3+4) + PSA less than 20 ng/mL, and 63% in men with Gleason score 7 (4+3) + PSA less than 20 ng/mL. Thus, the authors concluded that they believe that active surveillance cannot be advocated for Gleason 7 prostate cancer outside of a research protocol.

Dr. Laviana also highlighted the Memorial Sloan Kettering Cancer Center's experience with active surveillance among men with Gleason Grade Group 2.6 Among 219 intermediate-risk patients, the treatment-free survival was 61% at 5 years and 49% at 10 years:Among 219 intermediate risk patients, the treatment free survival was 61% at 5 years and 49% at 10 years
Overall, there were 3 patients with biochemical recurrence, no distant metastasis, and no prostate cancer deaths over a median follow-up of 3.1 years (IQR 1.9 – 4.9).

Finally, the Canary PASS cohort has also evaluated outcomes of active surveillance in Gleason Grade Group 2 prostate cancer.7 In this analysis, 1,557 men were enrolled by February 2019 with at least one biopsy after diagnosis, including 1,426 with Gleason Grade Group 1 and 131 with Gleason Grade Group 2. Patients with Gleason Grade Group 2 disease had more percent positive cores (17% vs 10%) and had more T2a disease (18% vs 11%):
Canary PASS cohort
Interestingly, there was no difference in time to reclassification stratified by Gleason Grade Group at the time of diagnosis (p = 0.11):there was no difference in time to reclassification stratified by Gleason Grade Group at the time of diagnosis (p = 0.11)
However, more patients with Gleason Grade Group 2 were treated at 5 years (58% vs 34%, p <0.001) compared to Gleason Grade Group 1:more patients with Gleason Grade Group 2 were treated at 5 years (58% vs 34%, p <0.001) compared to Gleason Grade Group 1
Risk of adverse pathology at the time of surgery for Gleason Grade Group 2 was higher compared to Gleason Grade Group 1 (HR 1.37, 95% CI 0.72 – 2.35), however, there was no difference in recurrence at 3 years after treatment (5% vs 9%, p = 0.50).

Based on the Johns Hopkins, UCSF, University of Toronto, and Canary PASS experience, Dr. Laviana notes that arguably the most important factors for predicting progression and treatment rates are PSA doubling time and number of positive biopsy cores:the most important factors for predicting progression and treatment rates are PSA doubling time and number of positive biopsy cores
An important note is that cribriform architecture outperforms Gleason pattern 4 percentage and tertiary Gleason pattern 5 in predicting the outcome of Grade Group 2 prostate cancer patients.8 Among 472 radical prostatectomy specimens with Grade Group 1, cribriform architecture was associated with higher percentage of pattern 4 (> 25%), and presence of tertiary pattern 5. Further, in a multivariable model, cribriform architecture independently predicted biochemical recurrence:
architecture was associated with higher percentage of pattern 4 (> 25%), and presence of tertiary pattern 5. Further, in a multivariable model, cribriform architecture independently predicted biochemical recurrence
Dr. Laviana concluded his presentation discussing the con approach for active surveillance among patients with low volume Gleason Grade Group 2 disease with the following take-home points:

  • Favorable intermediate-risk prostate cancer patients may be candidates for active surveillance with comparable outcomes to low-risk disease in limited studies
    • But, Gleason Grade Group 2 is more likely to undergo treatment, even without reclassification or progression
  • We need to consider other important clinical and pathological factors, such as percentage of pattern 4 disease, the presence of cribriform patterns, PSA density, and number of positive cores.
  • We must be careful with active surveillance for Gleason Grade Group 2, particularly for young patients with an abnormal PSA density.

Presented by: Aaron Laviana, MD, MBA, Urologist, Assistant Professor, Dell Seton Medical Center, The University of Texas at Austin, Austin, TX

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 South Central American Urological Association (AUA) Annual Meeting, Colorado Springs, CO, Wed, Oct 30 – Sat, Nov 2, 2024.

References:

  1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med 2014;370(10):932-942. 
  2. Wilt TJ, Jones KM, Barry MJ, et al. Follow-up of prostatectomy versus observation for early prostate cancer. N Engl J Med 2017;377(2):132-142.
  3. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med 2016;375(15):1415-1424.
  4. Cooperberg MR, Cowan JE, Hilton JF, et al. Outcomes of active surveillance for men with intermediate-risk prostate cancer. J Clin Oncol. 2011 Jan 10;29(2):228-234.
  5. Musunuru HB, Yamamoto T, Klotz L, et al. Active surveillance for intermediate-risk prostate cancer: Survival outcomes in the Sunnybrook experience. J Urol. 2016 Dec;196(6):1651-1658.
  6. Carlsson S, Benfante N, Alvim R, et al. Risk of metastasis in men with Grade Group 2 prostate cancer managed with active surveillance at a tertiary cancer center. J Urol. 2020 Jun;203(6):1117-1121.
  7. Waisman Malaret AJ, Chang P, Zhu K, et al. Evaluating the outcomes of active surveillance in Grade Group 2 Prostate Cancer: Prospective Results from the Canary Pass Cohort. J Urol. 2022 Apr;207(4):805-813.
  8. Sayrek N, Hollemans E, Osanto S, et al. Cribriform architecture outperforms Gleason pattern 4 percentage and tertiary Gleason pattern 5 in predicting the outcome of Grade Group 2 prostate cancer patients. Histopathology. 2022 Feb;80(3):558-565.