ASCO 2018: Active Surveillance in the Real World: What Have ProtecT and Other Prospective Trials Taught Us?

Chicago, IL (UroToday.com) Freddie Hamdy, MD, started the Precision Active Surveillance in Prostate Cancer session by discussing the role and impact of ProtecT and other prospective trials on how active surveillance is disseminated in the real world. 

Dr. Hamdy notes that young men worried about prostate cancer want to know several items, which is essentially a summary of a shared-decision making process between physician and patient:

  • Whether he needs to be further tested for prostate cancer
  • How he should be optimally tested and how accurate the tests are
  • If he has prostate cancer, knowing the grade, PSA, clinical stage and the prognostic significance of the information
  • The best treatment – to prevent suffering and death from the disease
  • Advantages and disadvantages of the treatments, including the level of the physician’s expertise
  • The balance of risks when making management decisions
Active surveillance involves identifying prostate cancer with slow progression and low risk, where competing causes of mortality and slow evaluation of the disease will prevent the disease from causing significant harm. This involves monitoring the disease with efficient means to identify, in a timely manner, men who are progressing, while keeping them in a window of curability so that they can receive curative treatment when necessary. However, our stratification of tumors is poor and tumor heterogeneity is our Achilles heel. Watchful waiting is to diagnose the disease in men with high levels of comorbidity and competing causes for mortality and keeping them without active treatment, intervening only in the presence of advancing, symptomatic disease with no intent of cure.

Two trials have assessed the appropriate treatment of localized, early prostate cancer. The SPCG-4 randomized controlled trial randomly assigned 695 men with early prostate cancer to watchful waiting or radical prostatectomy between 1989 and 1999, who were followed through the end of 2012 [1]. During 23.2 years of follow-up, there were 63 deaths in the surgery group and 99 in the watchful-waiting group due to prostate cancer (RR 0.56 95%CI 0.41-0.77). The number needed to treat to prevent one death was 8. In the US equivalent, long-term follow-up of the PIVOT trial (19.5 years), death attributed to prostate cancer or treatment occurred in 7.4% assigned to surgery and 11.4% assigned to observation (HR 0.63, 95%CI 0.39-1.02) [2]. Dr. Hamdy notes several items missing from SPCG-4 and PIVOT: (i) these were non-screen detected cases, (ii) cohorts are no longer contemporary, (iii) observation was ‘watchful waiting’, (iv) radiotherapy was not evaluated against other options, (v) competing morbidity was high, and randomization was low (PIVOT), (vi) genomic diversity was unknown, and there was poor stratification of patient risk, and (vii) ‘trade-off’ was insufficiently considered between oncological outcomes, mortality, and patient-reported outcomes. 

Several centers have published their long-term outcomes of AS cohorts, demonstrating safety and feasibility for properly selected patients. The Toronto series with Dr. Klotz over a time frame of 15 years with a median 6.4 years of follow-up from first biopsy (range, 0.2-19.8 years) found 149 (15%) of 993 patients died, with 15 deaths (1.5%) from prostate cancer [3]. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases or have died of other causes. At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance, respectively. Long-term outcomes from the Hopkins AS cohort found that with a median follow-up of 5 years (range 0.01-18.00) overall, cancer-specific, and metastasis-free survival rates were 93%, 99.9%, and 99.4%, respectively, at 10 years and 69%, 99.9%, and 99.4%, respectively, at 15 years [4]. The cumulative incidence of curative intervention was 50% at 10 years and was 57% at 15 years, whereas the median treatment-free survival was 8.5 years (range 0.01-18). Summarizing the large AS cohorts:

  • Metastasis: 0.12-6.06%
  • Prostate cancer death: 0-1.51%
  • Switch to active treatment: 27-53%
Dr. Hamdy then discussed the trial he oversaw since 1999, the highly publicized ProtecT trial [5].  Between 1999 and 2009, 82,429 men 50 to 69 years of age received a PSA test and 2664 received a diagnosis of localized prostate cancer. From these men, 1643 agreed to undergo randomization to active monitoring (n=545), surgery (n=553), or radiotherapy (n=545) with a primary outcome of prostate-cancer mortality at a median of 10 years of follow-up. Overall, there were 17 prostate-cancer-specific deaths, including 8 in the active-monitoring group, 5 in the surgery group, and 4 in the radiotherapy group, with no difference among the groups (p=0.48). However, metastases developed in more men in the active-monitoring group (n=33) than in the surgery group (n=13) or the radiotherapy group (n=16 men; p=0.004). Dr. Hamdy highlights several points he feels we have learned from the initial results:

  • The risk of death from prostate cancer over an average of 10 years of follow-up is very low (1%)
  • Surgery and radiotherapy can reduce the risk of cancer progression, but are associated with bothersome urinary, sexual and bowel symptoms. 
  • Staying on active monitoring avoids treatment side-effects, but there is an increased risk of cancer progression and spread
  • Longer-term follow-up (additional 10-20 years) is essential to provide data about the trade-off between shorter-term effects of radical treatment and risks of disease progression, and if there are any long-term benefits in cancer cure and survival. 
Finally, Dr. Hamdy discussed the recently published CAP study to evaluate the effect of a single PSA screening test and standardized diagnostic pathway on prostate cancer-specific mortality [6]. This was a clustered randomized trial in the UK of 419 582 men aged 50 to 69 years conducted at 573 primary care practices. These men were invited to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. Among randomized men, there were 189,386 in the intervention group and 219,439 in the control group. In the intervention group, 75,707 (40%) attended the PSA testing clinic and 67,313 (36%) underwent PSA testing of which 11% had a PSA level between 3 ng/mL and 19.9 ng/mL; 5.850 (85%) men then had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (RR 0.96, 95%CI 0.85-1.08, p = .50). Dr. Hamdy notes several take-home messages from the CAP trial:

  • A low-intensity screening intervention with a single PSA test had no discernable effect on prostate cancer-specific mortality at 10 years
  • In the intervention arm, a single PSA test increased detection of early-stage, low-grade prostate cancer, however, it did miss some lethal prostate cancers
  • The current diagnostic pathway of PSA-testing and TRUS-guided biopsies is inappropriate, no longer suitable, and must evolve to targeting and diagnosing clinically important prostate cancer 
Final concluding remarks from Dr. Hamdy included:

  •  AS is a by-product of irrational and inappropriate diagnosis of prostate cancer in men who will never suffer consequences from their disease if left untreated
  • AS should be replaced by a reduced detection of insignificant prostate cancer using innovative diagnostic pathways including pre-biopsy MRI, liquid biopsies and risk calculations prior to diagnosis
  • Monitoring methods need to improve in order to keep men in a genuine ‘window of curability’ and intervene when necessary
References:
  1. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med2014;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 Med2017;377(2):132-142.
  3. Klotz L, Vesprini D, Sethukavalan P, et al. Long-term follow-up of a large active surveillance cohort of patients with prostate cancer. J Clin Oncol2015;33(3):272-277.
  4. Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and longer-term outcomes from a prospective active-surveillance program for favorable-risk prostate cancer. J Clin Oncol2015;33(30):3379-3385.
  5. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer. N Engl J Med2016;375(15):1415-1424.
  6. Martin RM, Donovan JL, Turner EL, et al. Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: The CAP Randomized Clinical Trial. JAMA2018;319(9):883-895.
Presented by: Freddie Hamdy, MD, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, UK


Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, Twitter: @zklaassen_md at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
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