Abstract Introduction Prostate speciWc antigen (PSA) screening results in the detection of prostate cancer in many men who are not destined to die from the disease. This often results in overtreatment. One approach to reducing the overtreatment eVect is to treat selectively by observing patients with favorable risk disease, and treating only the subsets who are reclassiWed as higher risk over time, based on biochemical or pathologic progression of disease. Methods The data supporting the active surveillance concept is reviewed, including the results of several large-scale Phase 2 studies. A number needed to treat analysis was performed based on these studies and a large randomized trial of radical prostatectomy versus watchful waiting. The arguments in favor of, and opposed to, active surveillance are presented. Results The largest, most mature Phase 2 study of active surveillance has reported an 85% overall survival and 99% disease-speciWc survival with a median follow-up of 8 years (range 2–11 years). The number needed to treat analysis suggests that between 80 and 100 radical prostatectomies would be required for each prostate cancer death avoided in a favorable risk, screen detected population. Conclusion Active surveillance appears to be safe for favorable risk prostate cancer and represents an appealing alternative to radical treatment for all newly diagnosed men. Further follow-up and a randomized study design are required to conclusively demonstrate the safety of this
approach over the 15- to 20-year time frame. A large-scale randomized trial has recently been initiated internationally to address this question. Keywords Prostate cancer · Active surveillance · Review · Low-risk disease · Conservative management
Introduction PSA screening is widely supported in North America and in most of Europe, because it results in the diagnosis of potentially lethal prostate cancer (PC) at a stage when it is much more amenable to cure. Indeed, PC mortality has dropped about 25% in constituencies where PSA screening is widespread. Most experts believe this is due, at least in part, to early detection. However, early and repeated PSA testing results in many men being diagnosed with clinically insigniWcant PC that may pose little or no threat to their life if left untreated. Unfortunately, the diagnosis of cancer typically results, at least initially, in ‘cancer hysteria,’ that is, fear of an aggressive, life-threatening condition. This may lead to a quick and early decision for treatment, regardless of the risks and beneWts. In fact, the condition most of these men have is far removed from a rampaging aggressive cancer. In this article, an alternative approach, which involves using the behavior of the patient’s disease over time to determine how aggressively he will be treated, is reviewed. Scope of problem
L. Klotz (&) Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, 2075 Bayview Avenue, MG-408, Toronto, ON M4N 3M5, Canada e-mail: [email protected]
PC screening based on PSA and prostate biopsy results in diagnosing many men with PC for whom the disease does not pose a threat to their life. Welch has recently modeled
the rate of PC diagnosis. There are 2.74 million U.S. men who are 50–70 with a PSA > 2.5 ng/ml. If all American men in this age group had a PSA, and a PSA > 2.5 ng/ml is used as an indication for biopsy, 775,000 cases would be diagnosed this year in the United States alone. This is 543,000 more than the 232,000 cases diagnosed in 2005, and 25 times more than the 30,350 men expected to die of PC per year in the United States . The PSA era (1990 to the present) has been characterized by a high level of enthusiasm for radical therapy, including surgery and radiation. This has been driven by high-quality data from Phase 2 prospective databases, population databases, and randomized trials showing improved biochemical disease-free survival with aggressive treatment. However, this has come at the cost of many patients being diagnosed and treated who have nonlife-threatening cancer. At the moment, 90% of men with low-risk PC in the United States are treated radically. The current situation is that one in Wve is diagnosed (as compared to the one in thirty truly at risk from PC mortality); treatment has a frequent long-term eVect on quality of life, and the survival beneWt in most patients who are cured is modest. This is not reasonable. A strategy that would reduce unnecessary treatment is highly desirable. The fundamental approach embodied in active surveillance is to monitor aggressively (thereby detecting intermediate and high-grade cancers earlier, where treatment is more clearly of beneWt), but manage the patients with low-risk disease conservatively. The rationale for active surveillance This term is used to describe an approach to favorable risk PC characterized by initial observation, with close monitoring of PSA kinetics and serial biopsy. Over time, a minority of patients will be reclassiWed as having higher risk disease and oVered deWnitive radical treatment. The remainder will continue to be followed closely. Watchful waiting, a term coined in the pre-PSA era, referred to conservative management until metastatic disease developed, at which point patients would be treated palliatively. The key distinction is the use of selected delayed deWnitive treatment in a subset of patients based on biologic markers, prior to the development of clinical disease progression. Cancer aggressiveness can be predicted using existing clinical parameters. The ones mostly widely used are tumor grade or Gleason score, PSA, and tumor stage. Favorablerisk PC is characterized as a Gleason sum 6 or less (i.e. no Pattern 4 or 5 disease), a PSA 10 ng/ml or less, and T1c– T2a disease . As a result of stage migration due to PSA screening, the proportion of newly diagnosed patients who fall into the ‘favorable-risk’ category has increased, and it now constitutes about 40–50%. While men with these characteristics have a much more favorable natural history and
World J Urol (2008) 26:437–442
progression rate than those with a higher Gleason grade or PSA, unfortunately a few of them will still progress to advanced, incurable PC and death. Review of previous studies A large group of patients in Connecticut were treated with watchful waiting, and outcomes at 20 years have been reported . The study data conWrms the powerful predictive value of Gleason score. In that pre-PSA screening cohort, 23% of untreated Gleason 6 patients died of PC within 20 years. For Gleason 7 PC, about 65% died of PC within 20 years. In addition, there has been a shift in Gleason scoring  interpretation over the last 20 years. This is largely due to the current practice of calculating the Gleason sum based on the presence of any high-grade foci, even if these are scant. A pattern 3 + 3 cancer with 5% Gleason 4 would have been called a 6/10 20 years ago but today it would be 7. Thus, the Connecticut results likely represent a ‘worst case’ scenario for the expected mortality from untreated Gleason 6 cancer. The PC mortality of untreated nonscreen detected contemporary Gleason 6 cancer may be as low as 10% at 20 years. Lead time with PSA screening is about 10 years in men in their 60s, estimated from a variety of serum databases and modeling [5, 6]. It is plausible, therefore, that in a serially screened population, the cancer mortality of Gleason 6 cancer may be as low as 10% at 30 years. The results of a watchful waiting approach (no treatment until progression to metastatic or locally advanced disease) have been reported by many groups [7–16]. These studies all describe nonprogression in many patients. However, the results are diYcult to apply in the current era for two reasons: (1) the cohorts described are from the pre-PSA era, and constitute patients with more extensive disease at the time of diagnosis, and (2) patients were not oVered the opportunity for selective deWnitive therapy. In the era of PSA monitoring, men treated conservatively receive periodic PSA tests. EVective, albeit delayed, therapy need only be oVered to the patient subset in whom PSA progresses rapidly or the tumor grade increases [17, 18]. Klotz and Choo were the Wrst to report on a prospective active surveillance protocol incorporating selective delayed intervention for the subset with rapid PSA progression or grade progression on repeat biopsy [19, 20]. The eligibility criteria for this included patients with T1c or T2a PC, who had a Gleason · 6 and a PSA · 10 ng/ml. For patients above the age of 70 years, these were relaxed to include Gleason · 7 (3 + 4) and/or PSA · 15 ng/ml. The core prospective cohort is 331 patients, with a median follow-up of 8 years (range 2–11 years). Overall survival is 85%, and the disease-speciWc and metastasis-free survival is 99%.
World J Urol (2008) 26:437–442
Three out of 331 patients have died of PC to date. All three had PSA doubling times (PSADTs) of <2 years, and death occurred 3.0, 5.1, and 5.2 years after diagnosis. All three exhibited the same pattern of clinical progression: initial favorable prognostic factors, a rapid rise in PSA, which led to treatment in 6, 9, and 11 months after the initial diagnosis; a progressive rise in PSA and clinically apparent bone metastases within a year after treatment, leading to androgen deprivation therapy. This very rapid progression after diagnosis suggests that these patients had occult metastases at the time of initial disease presentation, and that their outcome would not have been altered by earlier treatment. Even in the Scandinavian trial , there were almost no ‘saves’ before 5 years had elapsed. The median PSADT, calculated by logarithmic regression, was 7 years. Forty-two percent had a PSADT above 10 years, suggesting an indolent course of disease in these patients. Twenty-two percent of patients had a PSADT of <3 years; however, 35% of the patients have received radical treatment. Twenty percent were treated for a PSADT < 3 years; 5% for progression to Gleason 4 + 3 or higher on repeat biopsy; and 10% because of patient preference. The remainder has not required any local or systemic therapy. A number of other groups have now reported favorable results of active surveillance. Two hundred and seventy patients diagnosed in the Swedish arm of the European screening trail have been managed with this approach. Thirty-nine percent have been treated; there are no PC deaths or metastatic progression. Twelve percent of the 70 patients treated with delayed surgery have had biochemical recurrence; none who had a PSADT > 4 years have recurred after surgery . Soloway et al. have reported on 175 patients . With a median follow-up of 4 years (range 1–12), there are no PC deaths or metastatic disease; only 8% have had delayed radical intervention. At Johns Hopkins, Carter et al. have reported on 407 patients managed with active surveillance . Median follow-up is 3.4 years (0.4–12). There have been no PC deaths. These series conWrm that this approach is associated with an extremely low rate of progression to metastatic disease and/or PC death, and that the majority of patients do not require intervention. The limitation of these studies in the context of the long natural history of this disease is the length of observation and it will require another 5–7 years before even the most mature of these studies will have a median 15 years follow-up. Nonetheless, the results are extremely encouraging to date. Modeling the risk We have used data from the Scandinavian randomized trial of surgery versus watchful waiting  and the Connecticut
watchful waiting data to estimate, for each PC death averted at 20 years, the number of patients with favorable-risk PC that would have to be treated at the time of diagnosis. The number-needed-to-treat (NNT) for each death avoided at 10 years in the Swedish trial was 20. It is likely that with additional (i.e. 20 year) follow-up, the survival beneWt in the Swedish trial, now 10 years, will increase. In those men diagnosed by PSA screening, this beneWt is likely to be balanced by the additional 10 year lead-time aVorded by screening. Thus, in a screened patient with intermediate grade and PSA similar to the Swedish cohort, the NNT at 20 years is also estimated to be around 20. The Albertsen et al. data  indicate that the mortality for intermediate-risk disease (Gleason 7) was about 2.5 times greater at 20 years than it was for favorable-risk disease. This number may be an underestimate if the shift in contemporary Gleason scoring is factored in. Even so, compared with no treatment, about 50 favorable-risk patients (Gleason 6 or less) would need to be treated for each death that will be prevented by surgery. However, if one oVers selective delayed intervention to those who progress, it can be conservatively estimated that at least 50% can be salvaged. The conclusion is that about 80–100 radical prostatectomies would be required for each PC death averted in favorable risk disease. Correcting the Connecticut data for grade migration, as referred to earlier, would increase this even further. A similar analysis has been performed by Parker et al., also conWrming that, for Gleason 6 or less, virtually no reduction in PC mortality would be expected by radical treatment of all patients . Do we have clinical tools that make active surveillance safe? The two challenges in managing patients on active surveillance are to avoid excessive delay for those who appear to be at higher risk for progression over time, and to avoid overtreating patients based on a transient change in PSA or other biomarkers. All groups have used a combination of PSA kinetics and serial biopsy. The speciWc approach varies. We have used a doubling time of 3 years or less, based on multiple determinations at 3-month intervals, calculated using a General Linear Mixed Model, which corrects for baseline PSA, grade, and age. This model is available freely at http://psakinetics.sunnybrook.ca. Others use a calculated or actual PSA velocity > 2.0 ng ml¡1 year¡1. Most groups advise serial biopsies at intervals varying from 1 to 4 years. Our group recommends a conWrmatory biopsy at 1 year to identify higher grade disease that was missed on the original biopsy; following this, biopsies are performed every 4–5 years to Wnd biological progression, a much more uncommon event. The Hopkins group performs biopsies annually or when a rise in PSA occurs .
In our Toronto series, patients with a PSADT of 3 years or less constituted 22% of the cohort. This cut point for intervention remains empirical and speculative. However, 20–25% of patients with a 3-year doubling time represents a pessimistic approximation of the proportion of good risk patients ‘at risk’ for disease progression. For those men with a PSA in the 6–10 range, it also approximates an annual rise of 2 ng/ml, an adverse predictor of outcome as described by D’Amico et al. . PSA kinetics is prone to artifact from biological variation, prostatitis, etc. There are a number of other promising biomarkers to identify patients at risk for disease progression, including PSA density, free versus total PSA ratio, and PCA3. It is also likely that genetic biomarkers, including SNP chip arrays and BRCA2 mutations, for example, will allow better prediction of patient risk within the next decade. This remains an active area of research. Prostate biopsy is also imperfect, since it is a limited sampling of the prostate. This has been addressed, in part, by serial biopsies with particular attention to the anterolateral horn, a common site for disease missed on routine biopsies. Some have advocated saturation biopsies, consisting of 50 or more cores performed under GA, for patients contemplating surveillance. This approach, which may identify some patients with higher risk disease, has not been embraced by most advocates of active surveillance, and does not appear necessary in the majority of patients . The psychological eVects of living for many years with untreated cancer are a potential concern. Does the cumulative eVect, year after year, of knowing one is living with untreated cancer lead to depression or other adverse eVects? The best data on this comes from a companion study to the Holmberg-randomized trial of surgery versus watchful waiting in Sweden. It found no signiWcant psychological diVerence between the two groups after 5 years. Worry, anxiety and depression all were equal in two arms . The absence of any adverse eVect compared to patients treated radically has been reported by others . While surveillance may be stressful for some men, the reality is that most patients with PC, whether treated or not, are concerned about the risk of progression. Anxiety regarding PSA recurrence is common amongst both treated and untreated patients. Patients who are educated to appreciate the very indolent natural history of most good risk PCs may avoid much of this anxiety. The counter argument The concept of active surveillance is not universally accepted. Criticisms are based on the uncertainty of the accuracy of clinical parameters (grade, tumor volume, and PSA kinetics) to identify patients with an indolent natural
World J Urol (2008) 26:437–442
history and the ability of delayed treatment to be curative. SpeciWcally, these criticisms focus on the following: 1. Biopsy Gleason score undergrades many cancers. Indeed, upgrading from biopsy to radical prostatectomy occurs in about 30% of patients. 2. Small volume of disease on biopsy is a poor predictor of pathologic stage. A proportion of patients with small volume low-grade disease on biopsy will have evidence of extracapsular extension, positive margins, or nodal metastases. 3. PSA kinetics is imperfect. At least one study in an unscreened population managed with watchful waiting concluded that PSA kinetics did not predict for lethal PC. 4. Focal therapy may cure the index lesion without inducing adverse quality of life eVects. The counter-counter argument Upgrading is most commonly one point increase in Gleason sum (typically from 3 + 3 to 3 + 4). Between- and intraobserver variation amongst pathologists accounts for some of this, and sampling for the remainder. The concept of stage migration suggests that a biopsy determined Gleason 6 with Wnal pathology 7 is likely to be a more favorable group than biopsy 7 conWrmed on Wnal pathology to be 7. This has been supported by clinical observations. The fact that some patients with a very small volume of disease on biopsy have more extensive, even locally advanced disease at surgery does not negate the approach of surveillance. This scenario is also less common with more extensive biopsy strategies. Further our data suggests that the patients with adverse disease biology appear to be identiWed over time by PSA kinetics and repeat biopsy, and their curability is unlikely to be adversely aVected by the delay in most cases. As regards the PSA kinetics, numerous studies in the last 5 years have documented the powerful association between a rapid rise in PSA and more aggressive PC. Most of these arguments are based on the Wnding in some favorable risk patients of surrogate markers of PC aggressiveness, particularly higher Gleason score and positive margins. The reality seems to be that most of these patients have an indolent course, and that those with a more aggressive biology can in almost all cases be identiWed and treated during a period of observation, without a signiWcant adverse eVect on survival. Focal therapy remains investigational. For favorable risk disease, which is an uncommon cause of cancer mortality, it will be many years before this is shown to alter death rates. More importantly, surveillance results in the identiWcation over time of a few patients at higher risk of progression, providing the opportunity for deWnitive radical
World J Urol (2008) 26:437–442
treatment to this subset of patients. Focal intervention may provide false reassurance, impairing the ability to oVer deWnitive eVective therapy for higher risk disease. No strategy is risk-free; however, the Wnal answer will come from long-term prospective trials of surveillance, which are currently ongoing. Clinical trials There are currently about eight prospective Phase 2 trials of active surveillance that report ongoing results. In addition, the NCI (Canada), in conjunction with four US-based cooperative oncology trials groups (SWOG, CALGB, ECOG, and RTOG) and the UK (UKCCR), have opened a trial entitled Surveillance Therapy Against Radical Treatment (START). This trial, which opened to accrual in September 2007, will randomize 2,100 patients between the active surveillance approach described before and the patient’s choice of radical treatment (surgery or radiation). The primary end point is PC survival. We estimate that this will be reached by 2025.
Conclusion Less aggressive management has been resisted in many constituencies due to concern about the inaccuracies of clinical staging and grading. The advent of widespread PSA screening has the positive eVect of identifying patients with life-threatening PC at a time when they are still more likely to be curable, and the negative eVect of identifying many patients with nonlife-threatening cancer who are susceptible to overtreatment. In a population subjected to regular screening, the latter group is far more prevalent. PSA testing will result in hundreds of thousands of patients needlessly subjected to the side eVects of therapy. A rational approach is to oVer deWnitive treatment (i.e. surgery or radiation) to the intermediate and high-risk group and little or no treatment to the low-risk group. However, some apparently favorable-risk patients harbor more aggressive disease. In these patients, there are beneWts from curative treatment. A policy of active and close monitoring with selective intervention for those whose cancers exhibit characteristics of higher risk disease over time is an appealing way to deal with this. Intervention is oVered for a PSADT < 3 years (depending on age, comorbidity, etc.), or grade progression to a predominant Gleason 4 pattern. This strategy is currently the focus of several clinical trials, and preliminary analysis of these has demonstrated that it is feasible. Most who understand the basis for this approach will remain on long-term surveillance. If patients are selected properly (i.e. good-risk and low-volume disease) and are followed carefully to enable early intervention if there is
evidence of progression, it is likely that the majority of men with indolent disease will not suVer from clinical disease progression or PC death, and the minority with aggressive disease will still be amenable to cure. We estimate that if all such patients were oVered radical prostatectomy compared to the strategy described before, the NNT would be approximately 100 for each patient who avoids a PC death. Thus, the proportion of those who die of disease is not likely to be signiWcantly diVerent from the proportion dying in spite of aggressive treatment of all good risk patients at the time of diagnosis. ConXict of interest statement
There is no conXict of interest.
References 1. Welch HG, Schwartz LM, Woloshin S (2005) Prostate-speciWc antigen levels in the United States: implications of various deWnitions for abnormal. J Natl Cancer Inst 97(15):1132–1137 2. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA, Tomaszewski JE, Renshaw AA, Kaplan I, Beard CJ, Wein A (1998) Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 280:969–974 3. Albertsen P, Hanley JA, Fine J (2005) 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 293:2095–2101 4. Albertsen PC, Hanley JA, Barrows GH, Penson DF, Kowalczyk PD, Sanders MM, Fine J (2005) Prostate cancer and the Will Rogers phenomenon. Natl Cancer Inst 97:1248–1253 5. Draisma G, Boer R, Otto SJ, van der Cruijsen IW, Damhuis RA, Schröder FH, de Koning HJ (2003) Lead times and overdetection due to PSA screening: estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 95(12):868–878 6. Tornblom M, Eriksson H, Franzén S, Gustafsson O, Lilja H, Norming U, Hugosson J (2004) Lead time associated with screening for prostate cancer. Int J Cancer 108(1):122–129 7. Hanash K, Utz DC, Cook EN, Taylor WF, Titus JL (1972) Carcinoma of the prostate: a 15-year followup. J Urol 107:450–453 8. Johansson JE, Holmberg L, Johansson S, Bergström R, Adami HO (1997) Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 277(6):467–471 9. Lerner SP, Seale-Hawkins C, Carlton CE Jr, Scardino PT (1991) The risk of dying of prostate cancer in patients with clinically localized disease. J Urol 146(4):1040–1045 10. Handley R, Carr TW, Travis D, Powell PH, Hall RR (1988) Deferred treatment for prostate cancer. Br J Urol 62(3):249–253 11. Adolfsson J, Carstensen J, Löwhagen T (1992) Deferred treatment in clinically localized prostate carcinoma. Brit J Urol 69:183–187 12. Waaler G, Stenwig AE (1993) Prognosis of localised prostatic cancer managed by “Watch and Wait” policy. Br J Urol 72:214–219 13. Whitmore W Jr, Warner JA, Thompson IM Jr (1991) Expectant management of localized prostatic cancer. Cancer 67:1091–1096 14. George N (1988) Natural history of localised prostatic cancer managed by conservative therapy alone. Lancet 1(8584):494–497 15. Aus G, Hugosson I, Norlen L (1995) Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 154:460–465 16. Sandblom G, Dufmats M, Varenhorst E (2000) Long-term survival in a Swedish population-based cohort of men with prostate cancer. Urology 56:442–447
442 17. Parker C (2004) Active surveillance: towards a new paradigm in the management of early prostate cancer. Lancet Oncol 5:101–106 18. Parker C (2003) Active surveillance: an individualized approach to early prostate cancer. BJU Int 92:2–3 19. Choo R, Klotz L, Danjoux C, Morton GC, DeBoer G, Szumacher E, Fleshner N, Bunting P, Hruby G (2002) Feasibility study: watchful waiting for localized low to intermediate grade prostate carcinoma with selective delayed intervention based on prostate speciWc antigen, histological and/or clinical progression. J Urol 167:1664–1669 20. Choo R, DeBoer G, Klotz L, Danjoux C, Morton GC, Rakovitch E, Fleshner N, Bunting P, Kapusta L, Hruby G (2001) PSA doubling time of prostate carcinoma managed with watchful observation alone. Int J Radiat Oncol Biol Phys 50:615–620 21. Bill-Axelson A, Holmberg L, Ruutu M, Häggman M, Andersson SO, Bratell S, Spångberg A, Busch C, Nordling S, Garmo H, Palmgren J, Adami HO, Norlén BJ, Johansson JE, Scandinavian Prostate Cancer Group Study No. 4 (2005) Radical prostatectomy versus watchful waiting (update). N Engl J Med 352(19):1977–1984 22. Khatami A, Aus G, Damber JE, Lilja H, Lodding P, Hugosson J (2006) PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: results from the European randomized study of screening for prostate cancer, Sweden section. Int J Cancer 120:170–174 23. Soloway MS, Soloway CT, Williams S, Ayyathurai R, Kava B, Manoharan M (2008) Active surveillance; a reasonable manage-
World J Urol (2008) 26:437–442
ment alternative for patients with prostate cancer: the Miami experience. BJU Int 101(2):165–169 Carter HB, Kettermann A, Warlick C, Metter EJ, Landis P, Walsh PC, Epstein JI (2007) Expectant management of prostate cancer with curative intent: an update of the Johns Hopkins experience. J Urol 178(6):2359–2365 Parker C, Muston D, Melia J, Moss S, Dearnaley D (2006) A model of the natural history of screen-detected prostate cancer, and the eVect of radical treatment on overall survival. Br J Cancer 94(10):1361–1368 D’Amico AV, Chen MH, Roehl KA, Catalona WJ (2004) Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med 351(2):125–135 Scattoni V, Zlotta A, Montironi R, Schulman C, Rigatti P, Montorsi F (2007) Extended and saturation prostatic biopsy in the diagnosis and characterisation of prostate cancer: a critical analysis of the literature. Eur Urol 52(5):1309–1322 Steineck G, Helgesen F, Adolfsson J, Dickman PW, Johansson JE, Norlen BJ, Holmberg L, Scandinavian Prostatic Cancer Group Study Number 4 (2002) Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 347(11):790–796 Burnet KL, Parker C, Dearnaley D, Brewin CR, Watson M (2007) Does active surveillance for men with localized prostate cancer carry psychological morbidity? BJU Int 100(3):540–543