Prostate cancer is the most common malignancy affecting men. There has been a nearly 70% increase in new prostate cancer cases, mostly classified as low risk, that have been diagnosed in early stages as a consequence of prostate-specific antigen (PSA) screening. Data regarding the natural history of this disease confirm the clinical insignificance of low-grade prostate cancer, which is associated with scant or no metastatic dissemination. Active surveillance is a conservative management approach, conducted for those patients with “low-risk” or “favorable-risk” disease, which avoids long-term adverse effects on the patient’s quality of life. It is characterized by a routine protocol of close monitoring with digital rectal examination, periodic biopsy, and serial PSA testing. As defined by D’Amico, active surveillance is broadly appropriate for men with a Gleason score of 6 or less and a PSA level of less than 10 ng/mL. Typically, Gleason pattern 3 disease lacks the common genetic aberrancies of a true cancer. An essential element of the active surveillance approach is early recognition of higher-risk disease, which is diagnosed by systematic biopsy in 30% of patients who initiate active surveillance with low-risk disease. Also, a small group of patients have molecular alterations that can cause progression to more aggressive disease; these men can be switched to immediate treatment if such progression is detected. Oncologic outcomes for active surveillance cohorts have shown the long-term safety of this approach, with a cancer-specific mortality rate of 3% at 10 to 15 years. In this review of active surveillance for favorable-risk prostate cancer, we will discuss the rationality of this approach, the biological evidence for employing active surveillance in Gleason pattern 3 and 4 prostate cancer, patient selection for active surveillance, clinical trial data on active surveillance, and the role of prostate cancer biomarkers and imaging studies (MRI) for clinical decision making in patients with low-risk disease.
According to the American Cancer Society, in 2016 an estimated 180,890 new cases of prostate cancer were diagnosed in the United States, making this disease the most common solid tumor in men. Despite the high incidence, only 26,120 men are estimated to have died of prostate cancer in 2016; the 10-year and 15-year relative survival rates for prostate cancer are 98% and 95%, respectively. Since the 1980s, widespread screening with serum prostate-specific antigen (PSA) levels and digital rectal examination (DRE) have facilitated early detection, and the incidence of prostate cancer has increased dramatically. Almost 80% of cases are detected at clinically localized stage III, and more than half are expected to be low-risk tumors. Such tumors are an infrequent cause of death, and the men affected are more likely to die of other causes. The initial dilemma in the management of clinically localized prostate cancer stems from prostate cancer’s heterogeneity, as evidenced by its natural history. Radical prostatectomy and radiation therapy, the standard treatments for prostate cancer, both frequently result in significant adverse events, including urinary and erectile dysfunction. Many men who receive active treatment do not derive any clinical benefit from their treatment, due to the slow progression of early-stage, low-risk cancer.
Active surveillance is an approach whose intention is to diminish the morbidities of immediate active treatment for men with low-risk prostate cancer who likely will never develop cancer-related symptoms. It was first described in 2002 in a report of 206 patients managed with periodic prostate biopsies and serial PSA testing, with radical intervention recommended for patients reclassified as higher risk. The active surveillance strategy aimed to diagnose, observe, and act with the intention to cure only when essential. After 20 years of experience with this approach, active surveillance has become widely adopted around the world.
Background and Rationale
Prostate cancer screening using serum PSA levels was first reported by Catalona in 1991. The rapid adoption of PSA screening in North America and Europe dramatically increased the incidence of prostate cancer that was identified, much of which was microfocal low-grade disease. This epidemiologic phenomenon resulted in the overdetection and overtreatment of insignificant disease, raising the risk of unnecessary morbidity and impairment of men’s health-related quality of life. Over the following 10 years, more than 90% of patients with low-risk prostate cancer were managed with radical therapies (radical prostatectomy or radiation). Overdetection trends were sustained until 2012, when the United States Preventive Services Task Force (USPSTF) assigned a grade of “D” to the use of PSA-based screening for prostate cancer (meaning that they recommended against the practice) for men of all ages (the USPSTF had already recommended against PSA-based screening in men aged ≥ 75 years in 2008). Subsequent to this recommendation, rates of PSA screening decreased by 3% to 10% in all age groups, followed by a shift toward detection of tumors of higher grade and stage. Furthermore, solid evidence regarding the biology of low-grade prostate cancer established the indolent nature of the disease. This knowledge resulted in a reexamination of the role of radical intervention for low-risk cancer.
Active surveillance has emerged as a conservative approach that can mitigate overtreatment. Current practice protocols combine clinical T stage, PSA value, PSA density, Gleason score, number of cores involved (based on 12-core biopsies), and amount of malignancy per core in order to select patients for active surveillance and predict the risk of occult coexistent higher-grade cancer. Data from the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry demonstrates the increase in the use of active surveillance for patients with low-risk prostate cancer—from a low of 6.7% in the years from 1990 to 2009, to 40.4% in the period 2010 to 2013. Active surveillance has emerged as a conservative approach that can mitigate overtreatment (Figure).
Natural History and Genetic Features of Low-Grade Prostate Cancer
The chief dilemma in managing clinically localized prostate cancer stems from the heterogeneity of the disease. Prostate cancer arises from genetically altered prostate epithelium and slowly progresses over several decades. Given its features of multifocality and tumor heterogeneity, the course of prostate cancer is difficult to predict. Men may live their entire natural life without having any symptoms from prostate cancer. Zlotta et al confirmed this hypothesis when they prospectively compared tissue obtained during autopsy from prostate glands in both a Caucasian and an Asian population. Prostate cancer was found in a similar proportion (35%) of men in both groups. Also, more than 50% of the cancers in the Asian group had a Gleason score of 7 or greater. The natural history of this disease, which is characterized by slow progression, makes it possible for active surveillance to be an effective management strategy.
Gleason patterns 3 and 4 are dramatically different genetically. The hallmarks of cancer include six biological capabilities that are typically acquired by human tumors during their development: 1) sustained proliferative signaling, 2) activation of local invasion and metastasis, 3) induction of angiogenesis, 4) evasion of growth suppressors, 5) resistance to cell death, and 6) unlimited replicative potential. Ahmed et al applied these oncologic principles in a review that described the different features of Gleason patterns 3 and 4, and concluded that most small Gleason pattern ≤ 3 lesions could be considered nonmalignant. Examples of the differences between Gleason 3 and Gleason 4 lesions include the findings that translocation of TMPRSS2-ERG, PTEN deletion, sustained vascular endothelial growth factor–induced angiogenesis, and resistance to apoptosis resulting from strong DAD1 expression are most common in Gleason pattern 4 lesions, and are absent or present only at low levels (10%) in Gleason pattern 3 lesions. Clearly, solid molecular evidence suggests that Gleason pattern 3 (or Gleason 3+3=6) disease lacks the hallmarks of cancer, as defined in terms of gene expression abnormalities—and as backed up by clinical experience. The molecular and histologic patterns of Gleason 3 lesions are likely predetermined to remain stable or even involute. In contrast, Gleason pattern 4 lesions exhibit most of the molecular characteristics of cancer.
A number of large surgical series have reported a rate of metastasis that approximates zero in surgically confirmed Gleason 6 prostate cancer. In order to understand the natural history of surgically treated Gleason 6 prostate cancer, Eggener et al conducted a multicenter study of 24,000 men with long-term follow-up. Of those men, 12,000 had confirmed Gleason 6 disease. The 15-year prostate cancer–specific mortality rate for pathologic Gleason 6 disease was 0.2%. Only 1 patient in the cohort died of prostate cancer; a pathology review reported Gleason 4+3 disease in this man instead of what was initially thought to be Gleason 3+3=6 disease. An additional series from the Hopkins pathology group examined cases with a Gleason score of ≤ 6 from radical prostatectomy databases from four large academic centers. A total of 14,123 cases were identified, which altogether showed 22 lymph node metastases. A new histopathology review of those 22 lymph nodes reported not a single case of a tumor with a Gleason score of ≤ 6 that was associated with lymph node metastasis.
The key point here is that most Gleason 6 cancers have innocent genetic features and no risk of metastasis. Thus, in the absence of higher-grade cancer, there is little indication for treatment in most patients.
Outcomes of Active Surveillance
Multiple groups worldwide have reported the results of prospective cohorts that provide data about the clinical course of patients managed with active surveillance. Data and outcomes from those groups (summarized in Table 1) consistently show a low rate of progression to metastatic disease or death from prostate cancer. The first study of active surveillance was started by researchers at the University of Toronto in 1996. This single-arm cohort study included 993 men, 740 with low-risk disease (Gleason score ≤ 6 and serum PSA level ≤ 10 ng/mL) and 253 with intermediate-risk disease (serum PSA ≤ 15 ng/mL or a Gleason score of 7 [3+4]) who had significant comorbidity or a life expectancy of less than 10 years. Among the 819 survivors, the median follow-up was 6.4 years. Altogether, 2.8% of the patients developed metastatic disease, and 1.5% died of prostate cancer. In the group with low-risk disease, the metastasis-free survival rate at 10 and 15 years was 96% and 95%, respectively. In the group with intermediate-risk disease, the metastasis-free survival rate was 91% and 82% at 10 and 15 years, respectively. Importantly, the presence of Gleason pattern 4 disease at diagnosis increased the rate of metastasis by 3.75, despite close monitoring and treatment for progression.
By comparison, researchers at Johns Hopkins have limited surveillance strictly to patients who fulfilled the Epstein criteria (≤ 2 positive cores, < 50% core involvement, and PSA density < 0.15 ng/mL/cm3). A total of 1,298 men were included in this cohort; the median follow-up was 5 years. Overall survival, cancer-specific survival, and metastasis-free survival rates were 94%, 99.9%, and 99.4%, respectively, at 10 years; these rates were 69%, 99.9%, and 99.4%, respectively, at 15 years. Not surprisingly, the 15-year prostate cancer–specific mortality rate was only 0.4%. These excellent results are explained by the more rigorous active surveillance eligibility criteria used by this group.
Recently, the Prostate Cancer Research International Active Surveillance (PRIAS) study reported data after 10 years of follow-up. This multicenter international cohort included 5,302 patients with low-risk prostate cancer managed with active surveillance. At 5 and 10 years of follow-up, 52% and 73%, respectively, had discontinued active surveillance. Of those men who discontinued active surveillance, 62% were reclassified as higher risk. A third of men had subsequent surgical intervention (radical prostatectomy) and were found, despite the decision to intervene, to have favorable pathologic tumor features (Gleason 3+3 and pT2). Gleason upgrading (to Gleason score > 7) or clinical T3 disease was the only protocol-based indication for active treatment.
Three trials have been published that investigated the effectiveness of immediate treatment (radical prostatectomy) vs active surveillance for patients with localized prostate cancer detected by PSA screening. The Prostate Cancer Intervention vs Observation Trial (PIVOT) randomly assigned 731 men with prostate cancer to radical prostatectomy or observation. During the median follow-up of 12 years, the group treated by surgical intervention (47%) did not exhibit a significantly reduced all-cause or prostate cancer–specific mortality rate, as compared with the observation group (49%). The second of these large studies was the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) randomized clinical trial. This prospective study compared radical prostatectomy vs watchful waiting in early prostate cancer. After 18 years of follow-up, overall mortality and prostate cancer–specific mortality rates were higher in patients managed with watchful waiting than in those who received immediate treatment. Unfortunately, neither PIVOT nor SPCG-4 used an active surveillance approach: patients received treatment if there was evidence of progression to metastatic disease. In contrast, men on active surveillance are closely followed, rebiopsied, and treated if there is evidence of grade progression or risk reclassification—in order to prevent metastatic progression.
Lastly, the Prostate Testing for Cancer and Treatment (ProtecT) trial compared three modalities of management—active monitoring, radical prostatectomy, and external-beam radiotherapy—in patients with localized prostate cancer. Patients randomized to active monitoring had their PSA level measured every 3 months during the first year and every 6 to 12 months thereafter. Among the 2,664 patients with a diagnosis of prostate cancer, there were 17 prostate cancer–specific deaths overall (8, 5, and 4 in the active monitoring, surgery, and radiotherapy groups, respectively), demonstrating there was no significant difference in the 10-year cancer-specific survival rate or the overall survival rate. There was a difference in the metastasis rate favoring radical treatment. This likely reflects the fact that 25% of the cohort had intermediate- or high-risk disease, for which conservative management is clearly associated with an increased risk of progression. Further, “active monitoring,” while more intensive than “watchful waiting,” did not include serial biopsies or predefined indications for intervention.
1. American Cancer Society. Cancer facts & figures 2016. http://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html. Accessed April 27, 2017.
2. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med. 1991;324:1156-61.
3. Han M, Partin AW, Piantadosi S, et al. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol. 2001;166:416-9.
4. Choo R, Klotz L, Danjoux C, et al. Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate specific antigen, histological and/or clinical progression. J Urol. 2002;167:1664-9.
5. Wei JT, Dunn RL, Sandler HM, et al. Comprehensive comparison of health-related quality of life after contemporary therapies in localized prostate cancer. J Clin Oncol. 2002;20:557-66.
6. Lin K, Croswell JM, Koenig H, et al. Prostate-specific antigen-based screening for prostate cancer: an evidence update for the U.S. Preventive Services Task Force. Rockville (MD): Agency for Healthcare Research and Quality. 2011 Oct. Report No.:12-05160-EF-1.
7. Fleshner K, Carlsoon SV, Roobol MJ. The effect of the USPSTF PSA screening recommendation on prostate cancer incidence patterns in the USA. Nat Rev Urol. 2017;14:26-37.
8. Tosoian JJ, Carter HB, Lepor A, Loeb S. Active surveillance for prostate cancer: current evidence and contemporary state of practice. Nat Rev Urol. 2016;13:205-15.
9. Ritmaster RS. 5 α–reductase inhibitors in benign prostatic hyperplasia and prostate cancer risk reduction. Best Pract Res Clin Endocrinol Metab. 2008;22:389-402.
10. Zlotta AR, Egawa S, Pushkar D, et al. Prevalence of prostate cancer on autopsy: cross-sectional study on unscreened Caucasian and Asian men. J Natl Cancer Inst. 2013;105:1050-8.
11. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.
12. Ahmed H, Arya M, Emberton M, et al. Do low-grade and low-volume prostate cancers bear the hallmarks of malignancy? Lancet Oncol. 2012;13:e509-e517.
13. Berg KD, Vainer B, Thomsen FB, et al. ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer. Eur Urol. 2014;66:851-60.
14. Lotan TL, Carvalho FL, Peskoe SB, et al. PTEN loss is associated with upgrading of prostate cancer from biopsy to radical prostatectomy. Mod Pathol. 2015;28:128-37.
15. West AF, O’Donnell M, Charlton RG, et al. Correlation of vascular endothelial growth factor expression with fibroblast growth factor-8 expression and clinico-pathologic parameters in human prostate cancer. Br J Cancer. 2001;85:576-83.
16. Guo Y, Sklar GN, Borkowski A, et al. Loss of the cyclin-dependent kinase inhibitor p27 (Kip1) protein in human prostate cancer correlates with tumor grade. Clin Cancer Res. 1997;3:2269-74.
17. Eggener SE, Scardino PT, Walsh PC, et al. Predicting 15-year prostate cancer specific mortality after radical prostatectomy. J Urol. 2011;185:869-75.
18. Ross HM, Kryvenko ON, Cowan JE, et al. Do adenocarcinomas of the prostate with Gleason score <6 have the potential to metastasize to lymph nodes? Am J Surg Pathol. 2012;36:1346-52.
19. 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 Oncol. 2015;33:272-7.
20. Tosoian JJ, Mamawala M, Epstein JI, et al. Intermediate and longer-term outcomes from prospective active surveillance program for favorable-risk prostate cancer. J Clin Oncol. 2015;33:3379-85.
21. Bokhorst LP, Valdagni R, Rannikko A, et al. A decade of active surveillance in the PRIAS Study: an update and evaluation of the criteria used to recommend a switch to active treatment. Eur Urol. 2016;70:954-60.
22. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367:203-13.
23. Bill-Axelson A, Holmberg L, Garmo H, et al. Radical prostatectomy or watchful waiting in early prostate cancer. N Engl J Med. 2014;370:932-42.
24. 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;375:1415-24.
25. Lee SE, Kim DS, Lee WK, et al. Application of the Epstein criteria for prediction of clinically insignificant prostate cancer in Korean men. BJU Int. 2010;105:1526-30.
26. Klotz L, Zhang L, Lam A, et al. Clinical results of long-term follow-up of a large, active surveillance cohort with localized prostate cancer. J Clin Oncol. 2010;28:126-31.
27. Morash C, Tey R, Agbassi C, et al. Active surveillance for the management of localized prostate cancer. Can Urol Assoc J. 2015;9:171-8.
28. Chen RC, Rumble RB, Loblaw DA, et al. Active surveillance for the management of localized prostate cancer (Cancer Care Ontario guideline): American Society of Clinical Oncology clinical practice guideline endorsement. J Clin Oncol. 2016;34:2182-90.
29. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Prostate cancer. Version 2.2017. https://www.nccn.org/professionals/physician_gls/PDF/prostate.pdf. Accessed April 17, 2017.
30. National Institute for Health and Care Excellence. Prostate cancer: protocol for active surveillance. https://www.nice.org.uk/guidance/cg175/resources/protocol-for-active-surveillance-19674477. Accessed April 17, 2017.
31. Welty CJ, Cowan JE, Nguyen H, et al. Extended follow-up and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer. J Urol. 2015;193:807-11.
32. Sundi D, Ross AE, Humphreys EB, et al. African American men with very low risk prostate cancer exhibit adverse oncologic outcomes after radical prostatectomy: should active surveillance still be an option for them? J Clin Oncol. 2013;31:2991-7.
33. Sundi D, Faisal FA, Trock BJ, et al. Reclassification rates are higher among African American men than Caucasians on active surveillance. Urology. 2015;85:155-60.
34. Jalloh M, Myers F, Cowan JE, et al. Racial variation in prostate cancer upgrading and upstaging among men with low-risk clinical characteristics. Eur Urol. 2015;67:451-7.
35. Leapman MS, Freedland SJ, Aronson WJ, et al. Pathological and biochemical outcomes among African-American and Caucasian men with low risk prostate cancer in the SEARCH database: implications for active surveillance candidacy. J Urol. 2016;196:1408-14.
36. Sakr WA, Grignon DJ, Crissman JD, et al. High grade prostatic intraepithelial neoplasia (HGPIN) and prostatic adenocarcinoma between the ages of 20-69: an autopsy study of 249 cases. In Vivo. 1994;8:439-43.
37. Inoue LY, Trock BJ, Partin AW, et al. Modeling grade progression in an active surveillance study. Stat Med. 2014;33:930-9.
38. Leapman MS, Cowan JE, Nguyen HG, et al. Active surveillance in younger men with prostate cancer. J Clin Oncol. 2017 Mar 27. [Epub ahead of print]
39. van den Bergh RC, Ahmed HU, Bangma CH, et al. Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. Eur Urol. 2014;65:1023-31.
40. Steyn JH, Smith FW. Nuclear magnetic resonance (NMR) imaging of the prostate. Br J Urol. 1982;54:679-81.
41. Pessoa RR, Viana PC, Mattedi RL, et al. Value of 3-Tesla multiparametric magnetic resonance imaging and targeted biopsy for improved risk stratification in patients considered for active surveillance. BJU Int. 2016;119:535-42.
42. Schoots IG, Petrides N, Giganti F, et al. Magnetic resonance imaging in active surveillance of prostate cancer: a systematic review. Eur Urol. 2015;67:627-36.
43. Klein EA, Haddad Z, Yousefi K, et al. Decipher genomic classifier measured on prostate biopsy predicts metastasis risk. Urology. 2016;90:148-52.
44. Nguyen PL, Martin NE, Choeurng V, et al. Utilization of biopsy-based genomic classifier to predict distant metastasis after definitive radiation and short-course ADT for intermediate and high-risk prostate cancer. Prostate Cancer Prostatic Dis. 2017 Jan 24. [Epub ahead of print]
45. Cullen J, Rosner IL, Brand TC, et al. A biopsy-based 17-gene genomic prostate score predicts recurrence after radical prostatectomy and adverse surgical pathology in a racially diverse population of men with clinically low- and intermediate-risk prostate cancer. Eur Urol. 2015;68:123-31.
46. Brand TC, Zhang N, Crager MR, et al. Patient-specific meta-analysis of 2 clinical validation studies to predict pathologic outcomes in prostate cancer using the 17-gene genomic prostate score. Urology. 2016;89:69-75.
47. Cuzick J, Berney DM, Fisher G, et al. Prognostic value of a cell cycle progression signature for prostate cancer death in a conservatively managed needle biopsy cohort. Br J Cancer. 2012;106:1095-9.
48. Cuzick J, Stone S, Fisher G, et al. Validation of an RNA cell cycle progression score for predicting death from prostate cancer in a conservatively managed needle biopsy cohort. Br J Cancer. 2015;113:382-9.
49. Newcomb LF, Thompson IM Jr, Boyer HD, et al; Canary PASS Investigators. Outcomes of active surveillance for clinically localized prostate cancer in the prospective, multi-institutional Canary PASS Cohort. J Urol. 2016;195:313-20.