Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer

A Critical Appraisal Exercise

A pretty good portion of what we post on Sensible Medicine could be considered critical appraisal of the medical literature. Whether it is John Mandrola’s Study of the Week column, my “Improving Your Critical Appraisal Skills” articles, or Vinay Prasad calling out articles that contend something other than what they actually show, this is clearly an interest of ours. Understanding how to read the literature is core to understanding what medicine is sensible, and what is not. 

Thus, it was an easy decision when a group of medical students asked if we would consider posting an appraisal that came out of their journal club. We get to encourage critical appraisal in undergraduate medical education and our readers get a careful summary of a recent, important article. You also get a chance to appraise the appraisers.

Adam Cifu

Introduction

Nearly four decades into PSA-based prostate cancer screening, the debate over its efficacy remains unresolved. There have been three main randomized control trials (linked here, here, and here) that have sought to clarify whether prostate cancer screening yields net benefit or net harm. The findings of these trials can be interpreted with either a ‘glass half full’ or ‘glass half empty’ perspective. Proponents highlight the benefits of early detection, while critics emphasize overdiagnosis and the harms of therapy. Amidst this ongoing debate, active surveillance (formally called watchful waiting or expectant management) has become more sophisticated. In this context, the Canary Prostate Active Surveillance Study (PASS) sought to understand the long-term outcomes of active surveillance. 

Question

What are the long-term outcomes for patients with favorable risk prostate cancer managed with protocol-directed active surveillance?

Design/Setting/Patients

PASS is a North American multicenter, prospective cohort study that enrolled 2155 active surveillance patients with low-risk localized prostate cancer and no prior treatment. The cohort enrolled patients from 2008 to 2022. The protocol for active surveillance consisted of measuring PSA levels and obtaining biopsies at timed intervals. Measurements of PSA levels were obtained every 3 months until 2020, and in 6-month intervals after 2020. Confirmatory and surveillance biopsies were performed at 6, 12 and 24 months after diagnosis, and then every 2 years thereafter. MRI, now part of active surveillance guidelines, was not part of the protocol. 

Outcomes

Outcomes of interest were the cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies.

Funding 

This study was supported by the NIH, Institute for Prostate Cancer Research, and the Canary Foundation. 

Results

The rates of unfavorable outcomes were similar amongst those treated immediately after confirmatory biopsy and those who underwent treatment after active surveillance. Some of the important results from the data are highlighted in the table below. Specifically, there was no difference in the likelihood of adverse pathology (defined as one or more of primary Gleason pattern 4, any Gleason pattern 5, ≥pT3b, or N1), recurrence after initial treatment, or progression to metastatic disease.

Considering the entire cohort of 2155 men, the 10-year cumulative incidence of all-cause mortality, prostate-specific mortality, and metastasis were 5.1%, 0.1%, and 1.4% respectively. These results are shown graphically in the figure below. 

Author Conclusion

Protocol-directed active surveillance is an effective management strategy for patients diagnosed with favorable-risk prostate cancer which avoids overtreatment and prevents undertreatment.

Commentary

The authors conclude that “protocol-directed active surveillance offers a clear set of expectations for patients and clinicians to follow.” This is perhaps too strong a conclusion given this study’s design. The authors base this conclusion on the rates of unfavorable outcomes being similar for those treated after several years compared to those who were treated immediately after confirmatory biopsy. This may suggest that active surveillance is non-inferior (not unacceptably worse) to immediate treatment after a confirmatory biopsy. 

But are men still better off than had they not been screened at all? A close look at the mortality data from this study raises the concern of persisting overdiagnosis and overtreatment despite active surveillance. When looking at the total cohort of 2155 men, 105 patients (4.9%) died. Of those 105 men, 34 were treated for prostate cancer and only 3 died of the disease. This raises the question of whether 102 of the 105 men who died from causes besides prostate cancer were diagnosed unnecessarily and that 31 of these men were treated for prostate cancer unnecessarily. For this reason, we question whether the author's conclusion is warranted. The article is more  hypothesis-generating than conclusive. 

There were other obvious limitations to the study. This cohort was primarily made up of insured, educated, and non-Hispanic white patients. These “more privileged” patients still had a biopsy adherence rate that fell from 83% to 74% between the second and third surveillance biopsies. Uptake would likely be even lower among a wider population. 

Additionally, the authors note the lack of MRI as part of the protocol in this study, stating, “it is possible that early use of MRI will further reduce rates of recurrence and metastasis observed in this study.” Although MRI is part of current guidelines, there is no randomized evidence on the impact MRI has on prostate cancer mortality. All RCTs assessing MRI in the management of prostate cancer have used Gleason grade as the measured outcome [linked here, here, here, and here]. As a surrogate endpoint, this does not reliably predict mortality. This is discussed more here by Dr. Vinay Prasad who thoughtfully breaks down one of the RCTs on MRI.

Conclusion

This study highlights the intensive healthcare resources used in prostate cancer screening programs. Active surveillance has been recognized as a more cost effective management strategy than surgery or radiation [source]. Interestingly, the cost-effectiveness of active surveillance is greater in the early years following diagnosis and then falls behind prostatectomy and radiotherapy in later years. [source]. Not considered in these studies are the indirect costs related to missed workdays, adverse events, and other inconveniences attributed to the routine follow-up required. Importantly then, for individuals diagnosed with low-risk prostate cancer, it becomes imperative to evaluate whether the resources expended on active surveillance truly yield commensurate benefits in terms of patient outcomes and overall healthcare value. 

A positive takeaway from this study is that it may be used to inform protocol development of future RCTs. It also suggests that some men may not need to be monitored for as long and as extensively. On the other hand, it suggests that prostate cancer screening and active surveillance imposes a significant burden on men and our healthcare system. A trial to be on the lookout for beginning in 2025 is the 54 million dollar funded TRANSFORM trial. This trial will take place in the UK and will consist of two phases. The first phase, with an enrollment of around 12,500 men will evaluate invitations to different screening options compared to control who will receive no invitation. The second phase will consist of up to 300,000 men and will test the most promising options from phase one to evaluate the potential benefit and harms. Official methodology is expected in the coming months.