Review

Continuing Medical EducationNature Clinical Practice Urology (2005) 2, 136-142
doi:10.1038/ncpuro0124  
Received 22 November 2004 | Accepted 15 February 2005

Active surveillance with selective delayed intervention is the way to manage 'good-risk' prostate cancer

Laurence Klotz  About the author

Correspondence Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Avenue # MG 408, Toronto, Ontario M4N 3M5, Canada

Email Laurence.klotz@sw.ca

Summary

This review summarizes the case for active surveillance of 'good-risk' prostate cancer, with selective delayed intervention for rapid biochemical progression, assessed by rising prostate-specific antigen (PSA) levels or grade progression. The results of a large phase II trial using this approach are also reviewed. A prospective phase II study of active surveillance with selective delayed intervention was initiated in 1995. Patients were managed initially with surveillance; those who had a PSA doubling time (PSADT) of less than or equal to2 years, or grade progression on repeat biopsy, were offered radical intervention. The remaining patients were closely monitored. The cohort now consists of 299 patients with good-risk—or, in men over 70 years of age, intermediate-risk—prostate cancer. The median PSADT was 7 years, 42% had a PSADT >10 years. The majority of patients remain on surveillance. At 8 years, overall actuarial survival was 85%, and disease-specific survival was 99%.To date, this study has shown that most men with 'good-risk' prostate cancer will die of unrelated causes. The approach of active surveillance with selective delayed intervention based on PSADT represents a practical compromise between radical therapy for all patients, which results in overtreatment for patients with indolent disease, and watchful waiting with palliative therapy only, which results in undertreatment for those with aggressive disease. The results at 8 years were favorable. Longer follow-up will be required if the study is to confirm the safety of this approach in men with a long life expectancy (>15 years).

Review criteria

PubMed and MEDLINE were searched for articles published between January 1990 and November 2004 containing the terms "watchful waiting", "surveillance", and "prostate cancer". Earlier publications were identified from monographs on the natural history of localized prostate cancer. Of the citations identified by the searches, only papers restricted to localized prostate cancer were selected. Only papers published in English have been cited in this review.

Keywords:

good risk, prostate cancer, surveillance, watchful waiting

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Introduction

Evidence indicates that a strategy of prostate cancer screening, based on prostate biopsy for men with elevated levels of prostate-specific antigen (PSA) or abnormal digital rectal examination, results in a positive diagnosis of prostate cancer in many men for whom the disease does not pose a threat to their life. The prevalence of histological prostate cancer in men over 50 years of age is 30–40%.1, 2 A large proportion of this histological, or latent, prostate cancer is never destined to progress or affect the lifespan of the patient. Since the introduction of PSA screening, the lifetime risk of being diagnosed with prostate cancer has almost doubled, from around 10% in the pre-PSA era, to 17% at the present time.3, 4

A subgroup analysis was conducted on the placebo arm (men that did not receive finasteride) of the prostate cancer prevention trial (PCPT).5 A strategy of routine systematic biopsies of the prostate in all men, regardless of PSA level, resulted in 24% of the patients in the placebo arm being diagnosed with prostate cancer over a 7-year period.5 Meanwhile, the lifetime risk of dying from prostate cancer remains at approximately 3%.4 As the lifetime risk of being diagnosed approaches the known rate of histological (mostly insignificant) prostate cancer, there is a greater risk of overtreatment. At least two studies have attempted to model the overdiagnosis rate, suggesting that it ranges from 30% to 84%.6, 7 Factors contributing to this are the increasing use of PSA screening and more extensive biopsy strategies employing 8 to 13 cores.8 Additionally, biopsies are often repeated until a cancer diagnosis is made.9 The majority of newly-diagnosed patients have stage T1c prostate cancer, which is classed as good risk. The central challenge in these patients is to identify the minority of men with aggressive prostate cancer and to offer them curative treatment, whilst sparing the remaining patients the morbidity associated with unnecessary treatment.

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Rationale for active surveillance

Prostate cancer is typically slow growing. Work by Sakr and colleagues1, 10 has indicated that, in a typical patient, the disease develops when a man is in his thirties, and takes 20 years to become clinically detectable. A study by Pound et al.11 showed that a median of 16 years elapses from surgery until death in patients that go on to die of prostate cancer following disease recurrence after radical prostatectomy. Watchful-waiting studies, most of which accrued patients from the pre-PSA era, also show that disease-related mortality in populations of prostate cancer patients only becomes substantial after 10 years. The lead time afforded by PSA screening is likely to increase this to 15 years in screened populations. In addition, it is evident that low-grade prostate cancer is associated with low progression rates and high survival rates in the intermediate term.

Widespread use of PSA testing has also resulted in a profound stage migration.12 Most patients that are newly diagnosed with prostate cancer have clinically impalpable stage T1c disease. Additionally, these patients typically have a mildly elevated PSA level (<10 ng/ml). These patients usually have slowly growing cancer with a long window of curability. This is supported by the data from Albertson et al. (Table 1).13

Table 1 Prostate cancer mortality in an active surveillance cohort according to grade.
Table 1 - Prostate cancer mortality in an active surveillance cohort according to grade.
Full tableFigures & Tables indexDownload PowerPoint slide (244K)

A meta-analysis of six surveillance series comprising 828 patients indicated that at 10 years, disease-specific survival was 87% for both well and moderately-differentiated cancers, whereas metastasis-free survival was 81% and 58% respectively.14 The studies incorporated an 'either/or' approach (either radical treatment or surveillance; surveillance offered no opportunity for delayed radical local therapy), and reflected a pre-stage migration population. Thus, many patients with favorable prognostic factors, diagnosed considerably earlier in disease development than the average patient in this nonsurveillance population, are likely to have prostate cancer with a long natural history.

D'Amico and colleagues reported that a rise in PSA of >2 ng/ml/year prior to surgery was a predictor for a poor outcome.15 A rise in PSA level of >2 ng/ml/year identified a group of patients who had a prostate cancer mortality rate of 15% at 7 years. No patients with a PSA rise of <2 ng/ml/year prior to surgery died of the disease. Clearly, therefore, a rise in PSA of >2 ng/ml/year, which corresponds roughly to a PSA DOUBLING TIME (PSADT) of 3 years or less in a patient with a PSA of 6 ng/ml, identifies a group at risk. However, 85% of these patients were still alive at the end of the test period, implying that aggressive attempts to cure these men are still warranted.15

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Watchful waiting

The watchful-waiting studies in the published literature are summarized in Table 2. Some important observations can be made from these studies. Mortality from other causes is common in all cohorts, reflecting the high average age of patients at entry. Cause-specific survival varies substantially, from 30–80% at 15 years,16, 17 which reflects patient selection at study entry. In contrast to the range of outcomes, there are some important similarities between the studies. All reflect the natural history of prostate cancer from the pre-PSA era. The stage migration phenomenon of the last decade had not occurred when these studies were carried out and none of them offered salvage radical therapy for local progression. Watchful waiting in these series consisted of no active treatment until symptomatic metastases developed, at which point androgen ablation was offered. Additionally, these series are characterized by problems of selection bias, to varying degrees. Confounding issues include the use of aspiration cytology for diagnosis, elderly cohorts, exclusion of higher-risk patients, and inclusion of patients with stage T1a tumors.


One striking feature of these studies stands out: every series contains a large subset of long-term survivors. This is especially true of the groups with favorable clinical parameters. This is a critical observation. In the absence of treatment a substantial subset of patients with prostate cancer is not destined to die of the disease. The challenge, of course, is to identify that subset accurately.

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Active surveillance

Because the prediction of clinically insignificant disease is problematic and inaccurate, an alternative strategy has been developed that allows patient entry into an expectant management protocol with rigorous monitoring and the option of curative salvage therapy, should signs of progression develop. This is referred to as active surveillance.18, 19

Choo and coauthors were the first 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.20, 21 The eligibility criteria for this included patients with stage T1c or T2a prostate cancer, who had a Gleason score less than or equal to6 and PSA less than or equal to10 ng/ml. For patients over 70 years of age, these were relaxed to include Gleason score less than or equal to7 (Gleason grade 3 + 4) and/or PSA less than or equal to15 ng/ml.20 The cohort from this study currently comprises 299 patients, 80% of whom fulfilled the criteria for favorable disease (PSA <10 ng/ml, Gleason score less than or equal to6, stage less than or equal toT2a). The median age was 70 years with an age range of 49 to 84 years. 80% of patients had a Gleason score less than or equal to6, and the same proportion had a PSA of <10 ng/ml (median 6.5 ng/ml). The median PSADT, calculated by logarithmic regression, was 7 years. A PSADT of <3 years was seen in 22% of patients, and 42% had a PSADT of >10 years, suggesting an indolent course of disease in these patients.

With a median follow-up of 64 months, 101 patients (34%) came off surveillance, while 198 have remained on surveillance. Patients came off surveillance for a variety of reasons. 15% had a rapid biochemical progression, 3% had clinical progression, 4% had histological progression, and 12% elected treatment based on patient preference only (the criteria for assessing progression in this study are outlined in Table 3). Patients were offered a repeat biopsy 1.5–2 years after being placed on the surveillance protocol, and then at 3-year intervals. Of the 243 patients who had been on surveillance for more than 2 years, approximately 75% attended for repeat biopsy. A standard 10-core technique was used in most patients. Gleason score remained stable in 92% of patients, while 8% demonstrated a significant rise in Gleason score, classed as an increase of greater than or equal to2. It is not known whether this represents true grade progression or initial undersampling; however, it is consistent with other similar series, showing a 4% rate of grade progression over 2–3 years.22

Table 3 Criteria for progression on active surveillance as indicated by Choo et al.20
Table 3 - Criteria for progression on active surveillance as indicated by Choo et al.
Full tableFigures & Tables indexDownload PowerPoint slide (269K)

From the total cohort, 24 (8%) of patients had a radical prostatectomy for a PSADT of <2 years; all had a Gleason score of 5–6, PSA <10 ng/ml, and tumor stage pT1–2 at study entry. The final pathology was stage pT2 in 10 patients (42%), pT3a–c in 14 (58%), and N1 in 2 (8%). For a group of patients with favorable clinical characteristics, this is a high rate of locally advanced disease.

At 8 years, overall survival was 85% and disease-specific survival was 99%. Only 2 out of 299 patients had died of prostate cancer at the time of writing this review. Both of these patients had a PSADT of <2 years and both deaths occurred around 5 years after diagnosis, suggesting that these patients had occult metastases at the time of diagnosis, and that their outcome would not have been altered by earlier treatment. While the median follow-up of this study is 5.3 years—too short a time to draw firm conclusions about the effectiveness of this approach—the results represent a remarkably high prostate cancer survival rate.

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Defining 'insignificant' prostate cancer

In an attempt to define insignificant prostate cancer, Stamey et al. studied prostate glands obtained from 139 consecutively sampled men and found that 55 (40%) of the radical cystoprostatectomy specimens were positive for prostate cancer.2 Given that the clinical prevalence of prostate cancer in the general male population at the time of the study was 8%, the authors concluded that the tumor volumes in the top 92nd percentile (0.5–6.1 ml) were clinically significant. The assumption was that the clinically significant cancer rate was 8%. The arbitrariness of this is of concern. If the clinically significant cancer rate was set at 4%, then the clinically significant cancer volume would be closer to 1 ml; conversely, if it were set at 12%, then the clinically significant cancer volume would be 0.2 ml.2 Additionally, the median age of the patients in the study was 65 years, which means that the applicability of this volume cut-off point to patients much older or much younger than 65 years is limited.

Epstein et al.23 utilized the data from Stamey et al.2 with historical radical prostatectomy cohorts from Johns Hopkins School of Medicine24, 25 to define insignificant cancers as those having clinical stage T1c, tumor volume <0.2 ml, no Gleason pattern of 4 or 5, organ confined disease, and no evidence of seminal vesicle or lymph node invasion. Tumors between 0.2 and 0.5 ml were identified as having a minimal risk of progression. Since this classification was developed, other authors have merged these two categories into one, despite the propensity of some of the 0.2–0.5 ml tumors to display capsular invasion.25, 26, 27, 28 Using this definition, many groups have reported on the incidence of insignificant disease. The incidence varies widely, from up to 30% in T1c patients, as reported by the Johns Hopkins group,23, 26 to as low as 9–12% in other series.27, 29

Contemporary radical prostatectomy series report insignificant prostate cancer in 6–26% of specimens.2, 29, 30 Crucially, the designation of 'insignificant' disease is based on histological volume, not natural history. The definition of insignificant cancer as <0.5 ml of low-grade disease has never been validated in a trial with a clinical end point. Based on substantial data, including the PCPT trial (where a positive biopsy occurred in 25% of normal men, regardless of PSA),5 and the ratio between the current lifetime likelihood of diagnosis (about 1 in 6) and death (1 in 40), this definition understates the proportion of patients who have prostate cancer that is not destined to pose a threat to their life (about 6 in 7).

Augustin et al.29 reported that in the last 2 years of their series, the insignificant cancer rate rose to around 10%. This might not be coincidental. As PSA screening becomes established, the initial rise in incidence, referred to as the 'incidence bump', is falling to a new baseline. The initial increased incidence may have included a number of significant cancers diagnosed earlier due to the added lead-time effect of PSA sampling, as well as many insignificant cancers. Entrance into this new era of post-incidence bump PSA-initiated diagnosis, coupled with more extensive biopsy strategies, will result in insignificant cancers comprising a larger proportion of all the prostate cancers diagnosed. This is strongly supported by Stamey et al.,31 who have shown that the correlation between prostate cancer volume and PSA has fallen from 0.68 at the beginning of the PSA era, to 0.12 at the present time.

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Monitoring and follow-up

PSA doubling time

A study by Schmid et al. was one of the first to correlate shortening of PSADT with increasing cancer volume and stage.32 Since then, others have demonstrated its utility as a prognostic factor for cancer progression after initial therapy.33 D'Amico has validated PSADT as a surrogate marker for death when measured after PSA recurrence, regardless of previous therapy.34 Choo et al. arbitrarily chose a PSADT of <2 years as one of the criteria for intervention in their active surveillance cohort.20 McLaren et al. examined PSADT in a watchful-waiting cohort and found that a PSADT of <3 years was associated with clinical progression (defined as palpable enlargement in the size of the tumor nodule or a progression in T stage) in over 80% of patients by 18 months from diagnosis.35 Egawa et al. examined PSADT before radical prostatectomy and found that a doubling time of less than or equal to3 years was more common with pT3 disease than organ confined disease determined at radical prostatectomy.36 The primary concern with using PSADT as a trigger for curative intervention is that it may act as a marker of aggressive disease that has already progressed and is no longer localized. Other authors have suggested that prostate cancer cell doubling time might be underestimated when the calculation is based on serial PSA changes.37, 38 Furthermore, PSADT calculations are subject to the vagaries of the biological variation of PSA.39, 40 The optimal method for calculating PSADT is uncertain.

McLaren et al. showed that there was no difference between using the first and last available values compared to using regression analysis.35 The relatively high proportion of pT3 disease seen in the patients who had a radical prostatectomy for a PSADT <2 years supports the view that a short PSADT is associated with an aggressive tumor cell phenotype. A PSADT of less than 2 years, in patients with otherwise favorable clinical features, portends a high likelihood of developing locally advanced disease. This also suggests that, insofar as curing patients with early rapid biochemical progression is a goal, the optimal PSADT threshold for intervention should be over 2 years. The appropriate threshold is likely to be around 3 years. In this series, patients with a PSADT of less than or equal to3 years would have constituted 22% of the cohort. This cut-off point for intervention remains empirical and speculative; however, the 20–25% of patients with a 3-year doubling time represents a rough approximation of the proportion of patients classed as 'good-risk' that are at risk of disease progression.35 For patients with a PSA in the 6–10 ng/ml range, it also approximates an annual rise of 2 ng/ml, an adverse predictor of outcome as described by D'Amico.15

PSA velocity and amplitude

A novel way of analyzing serial PSA measurements was described by Vollmer and colleagues.41 Their analysis suggested that relative PSA velocity and PSA amplitude can be combined to have a more powerful predictive ability for patients at risk of progression in an active surveillance group than PSADT alone. Other options include the subtracted PSADT, which is calculated by subtracting baseline PSA (thought to be due to benign prostatic hyperplasia) from subsequent PSA values, and rolling PSADT, where the PSADT is recalculated every 2 years. The use of PSADT to predict which patients have tumors that are destined to progress and which do not is promising, but remains investigational. Further work needs to be done to evaluate a safe cut-off value and the best method with which to calculate it.

Free PSA (fPSA)

A study by Do et al. focused on the rate of change of PERCENTAGE FREE PSA (%fPSA) in the University of Toronto active surveillance cohort.42 They found that the slope of the change in %fPSA was negatively correlated with the PSADT and initial T stage. Using the rate of change of %fPSA to predict for aggressive cancers is a concept that has promise and needs further investigation.

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Psychological impact

The psychological effects of living for many years with untreated cancer are uncertain. The most definitive data addressing this question are derived from quality-of-life analysis in the Swedish trial that compared watchful waiting to radical prostatectomy.43 In this trial, worry, anxiety, and depression had a slightly lower prevalence among men assigned to radical prostatectomy than among those assigned to watchful waiting, but none of these differences reached statistical significance. Low or moderate psychological wellbeing was reported by 35% of men assigned to radical prostatectomy and 36% of men assigned to watchful waiting. The values for low or moderate subjective quality of life were 40% in the radical-prostatectomy group and 45% in the watchful-waiting group.

Living with a cancer diagnosis is clearly stressful for many men, and patients with prostate cancer, whether treated or not, are often concerned about the risk of progression. Concern about 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 prostate cancers could avoid much of this anxiety. Further quality-of-life studies focused on this issue are clearly warranted.

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Conclusion

Watchful waiting, with palliative intent only, is clearly appropriate for patients who are elderly, have significant comorbidity, and have favorable clinical parameters. The use of comorbidity indices facilitates the identification of patients whose life expectancy is diminished relative to the natural history of their prostate cancer. The likelihood of a prostate cancer death in these patients is low.

Many good-risk, young, healthy patients, however, fall into a grey zone where there might be benefits of curative treatment, particularly if they have more biologically aggressive disease than suspected by their clinical parameters. In these patients, a policy of close monitoring with selective intervention for those whose cancers are progressing rapidly is appealing. This approach is currently the focus of several clinical trials, and preliminary analysis of these has shown that it is feasible. Most patients 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 followed carefully, with early intervention for evidence of progression, it is likely that the majority of men with indolent disease will not suffer from it, and the minority with aggressive disease will still be amenable to cure. Thus, the proportion of patients who die of disease is not likely to be different to the proportion dying, in spite of aggressive treatment of all good-risk patients at the time of diagnosis.

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Competing interests

The author declared no competing interests.

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Subject areas under which this article appears: Prostate cancer