The need for active surveillance for low risk prostate cancer

KEYWORDS:

• Prostate cancer
• active surveillance
• low risk
• PSA
• screening
• MRI
• overdiagnosis
• overtreatment
• adverse effects

1. Introduction

Prostate cancer is the most common cancer in men worldwide [1], with up to 67% of newly diagnosed cases considered to be low risk [2]. Pure Gleason grade ≤6 prostate cancer has negligible potential to metastasize and patients considered to have localized low-grade prostate cancer have minimal risk of dying of prostate cancer [3,4]. The introduction and continuous use of the prostate-specific antigen (PSA)-test followed by random transrectal ultrasound (TRUS)-guided biopsies above a certain threshold leads to a significant decrease in prostate cancer mortality but unfortunately also to a considerable increase in the detection of low risk cancers [5]. The traditional treatment options for all prostate cancers are invasive and often coincide with harmful side effects. The adverse effects of PSA-testing followed by a prostate biopsy can be reduced by avoiding the diagnosis of low risk prostate cancer, or postponing or averting the invasive treatment of clinically insignificant disease.

2. The continuous struggle between harms and benefits of early prostate cancer diagnosis

Our insight into overdiagnosis and overtreatment of low risk prostate cancer is largely based on the results of two randomized prostate cancer screening trials. The Prostate, Lung, Colorectal, and Ovarian cancer screening trial in the United States showed an increase in prostate cancer incidence, with 39–46% being low risk prostate cancer. Due to a high contamination rate of PSA-testing in the ‘non-screening’ control arm, no benefit in terms of a reduction in cancer-specific mortality for PSA-screening was observed [6]. The European Randomised study of Screening for Prostate Cancer also showed an increase in the detection of mainly low risk prostate cancer (67%). However, as the contamination rate of PSA-testing was very low, this trial did find a PSA-screening effect on prostate cancer mortality (a 21% decrease) [7], resulting in a less unfavorable benefit to harm ratio of PSA-based screening.

In 2012 the US Preventive Services Task Force (USPSTF) recommended against screening. However, as the incidence of advanced disease in the United States has declined with 70% since PSA-testing was widely adopted [8] and death rates have been falling on average 3.5% each year over 2004–2013 (SEER data) it appears that (opportunistic) PSA-based screening does affect prostate cancer mortality. Adding to these findings, a recent microsimulation model of prostate cancer incidence and mortality shows that PSA-screening can also be cost-effective, if used conservatively and in combination with conservative management [9]. Therefore it is no more than logical that PSA screening, although decreased after the USPSTF recommendation in the United States, stays common practice [10].

3. Improving the balance

The harms associated with PSA-based screening and random TRUS-guided biopsy are widely acknowledged and tremendous efforts are ongoing with the goal to diminish these harms. The focus lies on investigating and developing blood- and urine markers, genomic and proteomic assays, various imaging techniques, and pre- and post-biopsy risk calculators to better risk stratify men. Although these efforts have resulted in more accurate diagnostic approaches with less false-positive results it is, at least for now, unlikely that we will be able to completely prevent the diagnoses of low risk prostate cancer. It is for this reason that active surveillance emerged and remains a necessary primary management strategy for men with low risk prostate cancer.

4. Why active surveillance?

Since the first publication on active surveillance by the University of Toronto in 2002, the use of active surveillance has markedly increased worldwide. However, many patients with low risk prostate cancer, in and outside the United States and Europe, are still managed with initial invasive therapy [11]. Offering active surveillance instead of initial invasive therapy to patients with low risk prostate cancer aims at safely postponing or even averting invasive treatment, thereby at least for a part, compensating for the drawbacks of overdiagnosis. Contemporary active surveillance protocols allow patients with low Gleason grade (≤6), low clinical stage (≤T2), and low PSA values (≤10) to commence with active surveillance. Patients with a higher risk prostate cancer might also be eligible if competing risks (e.g. comorbidities, life expectancy shorter than 10 years) favor active surveillance in their individual benefit–harm assessment. As strict inclusion criteria more accurately select men with lower-risk disease but imply excluding potential candidates, no consensus exists on the most optimal inclusion criteria. Because patients can be misclassified at time of diagnosis and the fact that prostate cancer might progress over time, regular confirmatory risk assessments are needed during follow-up. Reclassification to a higher risk prostate cancer prompts a delayed treatment with curative intent. Reclassification rates per risk assessment are demonstrated to be in the range of 22–33% [12].

The outcomes of an active surveillance strategy should be measured against the outcomes of initial radical treatment. The ProtecT (Prostate testing for cancer and Treatment) trial demonstrated a 98.8% prostate-cancer-specific survival after 10 years of follow-up with no significant difference between their surgery-, radiotherapy- and active monitoring group. However, more metastases occurred in the active monitoring group compared to the surgery- and radiotherapy group (in 6.1% versus 2.4% and 2.9% of patients, respectively) [13]. The results of the active monitoring group, however, are not entirely representative for contemporary active surveillance protocols. The active monitoring group comprised 22% intermediate to high risk (Gleason grade 7–10) prostate cancer patients, and in addition, did not follow a strict surveillance protocol with regular risk assessments using biopsies. Longer follow-up, with more detailed information on the outcomes in the different prostate cancer risk groups, is needed to be able to compare the different treatment approaches appropriately.

Comparable to ProtecT’s active monitoring group, the University of Toronto (with the most mature active surveillance cohort in the world) initially also selected 21% of patients with intermediate risk prostate cancer. However, the Toronto cohort was monitored by a strict surveillance protocol. The 10- and 15-year actuarial prostate cancer-specific survival rates were 98.1% and 94.3%, respectively, and 2.8% of patients developed metastatic disease [14].

These trials have taught us that an active surveillance strategy is feasible and has similar survival outcomes as initial radical treatment at 10–15 years of follow-up, even without the strict inclusion criteria and new risk assessment methods of contemporary practice.

Hence, the major difference between direct radical treatment and active surveillance lies foremost in their associated adverse effects. Patients treated with radical prostatectomy or radiotherapy experience a substantial decrease in their quality of life due to erectile dysfunction and urinary- and bowel symptoms. In contrast, the adverse effects of active surveillance involve the burden of repeated risk assessments and anxiety due to living with untreated prostate cancer. However, active surveillance is associated with good quality of life and patients do not appear to suffer major negative psychological effects [15].

With current outcomes of the different treatment strategies, it is estimated that an almost fourfold increase in net benefit of prostate cancer screening could result from an increased use of active surveillance for low-risk disease and pre-biopsy risk stratification [16]. In addition, cost-effectiveness modeling studies showed considerable savings (up to $500 million for the American health system) when the use of active surveillance instead of radical treatment increased from 10% to 50% [17]. More importantly, active surveillance safely postpones or averts radical treatment for 5 years for 48–75% of patients and 10 years for 27–63.5% of patients [12,14].

5. Expectations in the nearby future

Individualized risk stratification methods can increase the accurate selection of low risk cancer patients and the detection of progression to higher risk cancer during follow-up, as shown by Venderbos et al. [18] and Ankerst et al. [19]. Further optimizing these methods would potentially increase the use and safety of the active surveillance strategy. The noninvasive manner in which multi-parametric MRI can identify suspicious lesions of clinically relevant prostate cancer makes it an appealing test for initial and especially repeated assessments. Contemporary data about the accuracy of MRI for detecting clinically significant prostate cancer in men with an elevated PSA show a sensitivity of 93% and a negative predictive value of 89% [20]. In patients initially diagnosed with low risk prostate cancer, reclassification after a positive MRI occurred in 39%, compared with 17% after a negative MRI [21]. Although thorough validation is warranted, MRI-guided biopsy appears to detect at least the same amount of clinically significant but less insignificant prostate cancer, with a reduced amount of biopsy procedures and biopsy cores per procedure than random systematic TRUS-guided biopsy. An active surveillance strategy in which an MRI and MRI-guided biopsies would be performed on the basis of individualized risk models would limit the costs and decrease the burden of the unnecessary risk assessments without compromising the safety of active surveillance.

6. Conclusion

PSA-testing and random TRUS-guided biopsy have shown to reduce prostate cancer mortality and remain common practices despite the coinciding overdiagnosis and potential overtreatment of low risk prostate cancer. Active surveillance has become a necessity to offset the harms associated with PSA-testing by postponing or averting the morbidity associated with otherwise applied invasive treatment. Further improvement of risk assessment methods is mandatory to improve the harm to benefit ratio of active surveillance and PSA-testing.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.