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Originally published as JCO Early Release 10.1200/JCO.2010.32.8112 on April 4 2011

Journal of Clinical Oncology, Vol 29, No 16 (June 1), 2011: pp. 2185-2190
© 2011 American Society of Clinical Oncology.

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Active Surveillance Program for Prostate Cancer: An Update of the Johns Hopkins Experience

Jeffrey J. Tosoian, Bruce J. Trock, Patricia Landis, Zhaoyong Feng, Jonathan I. Epstein, Alan W. Partin, Patrick C. Walsh, H. Ballentine Carter

From the Johns Hopkins University School of Medicine, The James Buchanan Brady Urological Institute, and Johns Hopkins Hospital, Baltimore, MD.

Corresponding author: H. Ballentine Carter, MD, Department of Urology, Marburg 145, Johns Hopkins Hospital, 600 N. Wolfe St, Baltimore, MD 21287-2101; e-mail: hcarter{at}jhmi.edu.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose We assessed outcomes of men with prostate cancer enrolled in active surveillance.

Patients and Methods Since 1995, a total of 769 men diagnosed with prostate cancer have been followed prospectively (median follow-up, 2.7 years; range, 0.01 to 15.0 years) on active surveillance. Enrollment criteria were for very-low-risk cancers, defined by clinical stage (T1c), prostate-specific antigen density < 0.15 ng/mL, and prostate biopsy findings (Gleason score ≤ 6, two or fewer cores with cancer, and ≤ 50% cancer involvement of any core). Curative intervention was recommended on disease reclassification on the basis of biopsy criteria. The primary outcome was survival free of intervention, and secondary outcomes were rates of disease reclassification and exit from the program. Outcomes were compared between men who did and did not meet very-low-risk criteria.

Results The median survival free of intervention was 6.5 years (range, 0.0 to 15.0 years) after diagnosis, and the proportions of men remaining free of intervention after 2, 5, and 10 years of follow-up were 81%, 59%, and 41%, respectively. Overall, 255 men (33.2%) underwent intervention at a median of 2.2 years (range, 0.6 to 10.2 years) after diagnosis; 188 men (73.7%) underwent intervention on the basis of disease reclassification on biopsy. The proportions of men who underwent curative intervention (P = .026) or had biopsy reclassification (P < .001) were significantly lower in men who met enrollment criteria than in those who did not. There were no prostate cancer deaths.

Conclusion For carefully selected men, active surveillance with curative intent appears to be a safe alternative to immediate intervention. Limiting surveillance to very-low-risk patients may reduce the frequency of adverse outcomes.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
There is concern that prostate cancer screening has led to the diagnosis and treatment of many cancers that would not have become life-threatening during a man's lifetime.1 Recent studies have shown that the prevention of one death from prostate cancer may require active treatment of up to 48 men at a median follow-up of 9 years2 and 12 men at a median follow-up of 14 years.3 These findings emphasize the prevalence of overdiagnosis and overtreatment of prostate cancer.4

Today, the majority of men diagnosed with prostate cancer are older than age 65 years and have low- to intermediate-risk disease.5 More than 90% of these patients will undergo active treatment that is unlikely to extend their life span, in contrast to younger patients or those with higher-risk disease.5,6 Thus, unnecessary treatment of nonthreatening disease appears to be most common in older men.

Active surveillance with curative intent is an alternative to immediate intervention that may reduce overtreatment. Men with cancers thought to pose minimal risk to life are monitored, and curative treatment is recommended if higher-risk features are detected during follow-up. In the short term, results from active surveillance studies have demonstrated a low risk of prostate cancer–specific mortality.712 Nonetheless, a prevailing concern is that surveillance may lead to a delay in treatment and may sacrifice the window of opportunity for cure.13 Additional follow-up is necessary to more definitively address this issue.

Since 1995, we have offered active surveillance as an alternative to immediate curative intervention in older men with presumed very-low-risk disease.14 The purpose of this study was to update the Johns Hopkins experience with active surveillance for prostate cancer.


    PATIENTS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Cohort Enrollment and Follow-Up
Since January 1995, older men presenting to our institution with very-low-risk prostate cancer (described in Patients and Methods) have been counseled that active surveillance is an acceptable alternative to immediate treatment.14 Surveillance is primarily directed toward older patients, but men not meeting some criteria may elect to enroll because of comorbidities or for personal reasons if they have a Gleason score of ≤ 6. This observational cohort study has been approved by the institutional review board at the Johns Hopkins Medical Institutions, and all patients provided informed consent before enrollment. Since 2005, 54.1% of men who were counseled that surveillance would be a reasonable option elected to enroll in the program.

As previously described by Epstein et al,15 and now endorsed by the National Comprehensive Cancer Network,16 enrollment criteria aim to identify very-low-risk prostate cancer and include clinical stage T1c disease, prostate-specific antigen (PSA) density less than 0.15 ng/mL, Gleason score ≤ 6, two or fewer biopsy cores with cancer, and a maximum of 50% involvement of any core with cancer.15 Men meeting all criteria at diagnostic biopsy were classified as having very-low-risk disease. Our surveillance protocol includes semiannual PSA measurements (total and free) with digital rectal examination and annual 12- to 14-core surveillance biopsy (transition zone biopsies obtained routinely since 2009). Curative therapy was recommended on disease reclassification, which was defined by a surveillance biopsy in which biopsy enrollment criteria were no longer met (ie, upgrade to Gleason score > 6, or > two cores with cancer, or > 50% cancer involvement of any core). Serum PSA concentration and PSA kinetics were not used as triggers for curative intervention. Notably, some patients chose to undergo curative intervention for personal reasons in the absence of disease reclassification.

Statistical Analysis
Study group characteristics at diagnosis (age, PSA, percent free PSA, PSA density [PSAD], the number of cores positive for cancer, the maximum percentage involvement of any core with cancer, and the year of diagnosis) were compared between treated and untreated men by using the t test in cases of equal variance and the Cochran t test in cases of unequal variance, with P < .05 considered statistically significant.

We calculated the crude proportion of men who experienced specific outcomes during surveillance, including curative intervention, biopsy reclassification, exit from the program, and death from all causes. Time on surveillance was defined from the time of diagnosis to an outcome, or to last clinical examination for those who did not reach a specified outcome. The proportion of patients experiencing each outcome was compared between men who met and did not meet all very-low-risk criteria by using Fisher's exact test. Additionally, the incidence rates of each outcome were calculated for all men in the study database and expressed as rates per 100 person-years of follow-up.

The Kaplan-Meier method was used to estimate time on surveillance free of biopsy reclassification and time on surveillance free of curative intervention. Time zero was defined as the time of diagnosis, and time on surveillance was defined as the time from diagnosis to an outcome. Patients who withdrew or were lost to follow-up were censored at the time of their last visit, and those who died were censored at time of death. Active patients were censored at the time of their last surveillance visit.

For men who underwent curative intervention, freedom from biochemical recurrence after treatment was estimated by using the Kaplan-Meier method. For this analysis, time zero was defined as the time of curative intervention, and patients not experiencing biochemical recurrence were censored at the time of their last PSA measurement. Recurrence was defined as PSA more than 0.2 ng/mL in men who underwent surgery and PSA of 2.0 ng/mL or more above the nadir in men who underwent radiation.17 Men with less than 1 year of follow-up after treatment were not included in the analysis. In men who selected surgery or radiation therapy, freedom from biochemical recurrence was compared using the log-rank test. The level of significance was set at 0.05 in all analyses. All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
As of March 2010, 769 men (median age, 66 years; range, 45 to 92 years) had enrolled in the active surveillance program. Most participants were white (90.4%), although 6.2% were African American, and 3.4% were of other ethnic backgrounds. Even though the majority (78.4%) of men met all criteria for very-low-risk prostate cancer, 136 (17.7%) did not meet PSAD criteria, and 30 (3.9%) failed to meet another very-low-risk disease criterion. Specifically, 16 men (2.1%) had more than two cores positive for cancer, eight men (1.0%) had more than 50% involvement of a biopsy core, and six men (0.8%) had disease not classified as stage T1c or lower. All men met the criterion for a Gleason score ≤ 6 and, thus, no patient in this program had Gleason score ≥ 7 on the diagnostic biopsy.

Overall, patients were followed for a median of 2.7 years (range, 0.01 to 15.0 years). As of March 2010, 418 men (54.4%) were active (no curative intervention or exit from the program), 255 (33.2%) underwent curative intervention, 82 (10.7%) withdrew or were lost to follow-up, and 14 (1.8%) died of causes other than prostate cancer (Fig 1). In total, 235 men (30.6%) demonstrated biopsy reclassification. Of these, 106 (45.1%) were reclassified on the basis of Gleason score upgrading (13.8% of entire cohort), and 129 (54.9%) were reclassified on the basis of number of biopsy cores or maximum core involvement with cancer (16.8% of entire cohort). Treatment was recommended for all men with Gleason score upgrading. Of the 129 men reclassified on the basis of disease volume, 38 elected to defer treatment for personal reasons or for comorbidities and thus continued on active surveillance.


Figure 1
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Fig 1. Johns Hopkins Active Surveillance Program. Eighty-two men withdrew or were lost to follow-up; 14 men died of causes not related to prostate cancer. (*) Treatment is recommended to all men with Gleason score (GS) upgrading. ({dagger}) Three of these men underwent treatment shortly after analysis. Data on treatment were unavailable for the remaining six men.

 
At the time of diagnosis, study group characteristics (PSA, percent free PSA, PSAD, and year of diagnosis) were significantly different in men who eventually underwent treatment compared with those who did not (Table 1). Earlier year of diagnosis was likely significant because in earlier years, there may have been undersampling of cancer with a six-core biopsy, whereas in later years, the standard was a 12-core biopsy or more.


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Table 1. Study Group Demographics

 
After enrollment, the mean time until the first surveillance biopsy was 1.3 years (standard deviation, 0.6) and time between subsequent surveillance biopsies was 1.1 year (standard deviation, 0.5). Compliance with annual surveillance biopsies (defined as undergoing biopsy within 0.5 years of designated biopsy date) was 92% for the first biopsy and 91% for the second biopsy. Over 12 years of follow-up, the total compliance with annual biopsies was 89% (range of annual compliance 79% to 100%). The median time on surveillance free of curative intervention was 6.5 years (range, 0 to 15.0 years; Fig 2). The probability of a patient remaining on active surveillance at 2, 5, and 10 years after diagnosis was 81%, 59%, and 41%, respectively. Of the 255 men who underwent curative intervention, 67 (26.3%) elected treatment in the absence of biopsy reclassification, and 188 (73.7%) underwent treatment on the basis of biopsy reclassification. Since 2009, 198 men underwent transition zone sampling as part of the surveillance biopsy, and cancer was detected in 46 (23.2%) of the transition zone biopsies.


Figure 2
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Fig 2. Kaplan-Meier estimates of survival free of treatment, survival free of biopsy reclassification (all causes, ie, Gleason score ≥ 7, or > two cores with cancer, and/or > 50% involvement of any core with cancer), and survival free of biopsy reclassification (upgrading to Gleason score ≥ 7). Time zero was defined as the time of diagnosis. Some men chose to undergo intervention in the absence of Gleason score ≥ 7, and others chose to undergo intervention in the absence of disease reclassification by any cause.

 
The crude numbers and proportions of men who experienced specified outcomes during surveillance are summarized in Table 2. Curative intervention (P = .026) and biopsy reclassification (all causes, ie, Gleason score > 6, or > two cores with cancer, or > 50% cancer involvement of any core; P < .001) were observed in a significantly higher proportion of men who did not meet very-low-risk entry criteria when compared with those who did. On postoperative pathology, two men who did not meet very-low-risk criteria were found to have lymph node–positive disease, although lymph node positivity was not observed in any men who met all criteria. In the entire cohort, the incidence rate of curative intervention was 9.7 per 100 person-years. The rate of biopsy reclassification (all causes) was 8.9 per 100 person-years, and the rate of biopsy reclassification due to Gleason score upgrading was 4.0 per 100 person-years of follow-up.


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Table 2. Outcomes Among Men on Active Surveillance

 
Of patients who underwent delayed curative intervention, 192 (75.3%) had sufficient post-treatment follow-up (≥ 1 year after treatment) for analysis of biochemical recurrence. Disease characteristics on diagnostic biopsy were not different when comparing the men included and those excluded from this analysis because of insufficient follow-up. However, men excluded because of insufficient follow-up were significantly older (mean age, 66 v 65 years; P = .032) and were more recently diagnosed (mean year of diagnosis, 2003 v 2002; P = .003) compared with those who were included.

Of the 192 treated men with sufficient follow-up after treatment, 96 (50%) underwent radical prostatectomy (median age, 63 years; range, 45 to 71 years), and 96 underwent radiation therapy (median age, 67 years; range, 54 to 80 years; Fig 1). The median time from diagnosis to treatment was 2.0 years (range, 0.7 to 8.0 years) in patients who underwent surgery and 2.3 years (range, 0.8 to 10.2 years) in those who underwent radiation therapy. At the time of enrollment, men who eventually underwent surgery were significantly younger than those who underwent radiation (median age, 63 v 67 years; P < .001), but the groups did not differ with respect to PSA, % of PSA, PSAD, number of positive biopsy cores, or maximum percentage of core involvement on diagnostic biopsy (data not shown). At the time of the final biopsy before treatment, men who underwent surgery had a significantly lower median PSA (5.6 v 6.9; P = .026) when compared with those who underwent radiotherapy. However, the proportion of patients with Gleason score ≥ 7 did not differ by treatment group (33.3% v 35.4%; P = .761).

Median follow-up after treatment was 2.0 years for men who underwent surgery and 2.8 years for men who underwent radiation. In total, 18 (9.4%) of 192 men experienced biochemical recurrence after delayed treatment, including four (4.2%) of 96 men who underwent surgery and 14 (14.6%) of 96 men who underwent radiation therapy. On Kaplan-Meier analysis, survival free of biochemical recurrence was significantly higher for men who underwent surgery compared with those who underwent radiation therapy (P = .004; Fig 3). Considering the entire cohort, no men have developed distant metastatic disease (M+) or died as a result of prostate cancer.


Figure 3
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Fig 3. Kaplan-Meier estimates of recurrence-free survival after surgery and radiation therapy. Time zero was defined as the time of intervention.

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Detection of prostate cancer with PSA testing followed by effective treatment results in a reduction in prostate cancer mortality.2,3,18 However, a risk associated with PSA testing is the overdiagnosis and overtreatment of prostate cancers that would not have been diagnosed during life in the absence of screening.1 Given the morbidity associated with prostate cancer treatment, it is prudent to explore alternatives aimed at preventing unnecessary intervention.

Active surveillance is an alternative to immediate intervention that involves careful follow-up with the option of delayed treatment at a time when intervention will prevent harm from disease.14,19 In men with favorable-risk disease, this approach has been associated with a prostate cancer–specific mortality of less than 3% at 10 years and is therefore considered a reasonable option for some men.12

Our approach to surveillance differs somewhat from other programs in both the selection of candidates and the criteria for intervention.20 We have used the selection criteria for very-low-risk disease originally described by Epstein et al15 and endorsed by the National Comprehensive Cancer Network,16 and we have used surveillance biopsy findings as the trigger for intervention. In total, one in three men in our program underwent curative intervention, a rate consistent with other surveillance programs.12,21 The reasons that patients eventually undergo intervention, however, differ between our program and others. Although 73.4% of men in our program underwent intervention because of biopsy reclassification, other programs cite PSA kinetics as a common trigger for intervention.12,22,23 For example, PSA doubling time triggered intervention in more than one in three men in the Prostate Cancer Research International: Active Surveillance (PRIAS) study24 and nearly one in two men in the Toronto experience.12 As previously described, PSA kinetics are not used as a trigger for intervention in our program.

We believe that high-grade cancers missed at the initial biopsy pose the greatest risk to active surveillance patients in terms of a lost opportunity for cure. For this reason, men with a Gleason score of ≥ 7 are not enrolled in our surveillance program, regardless of other disease characteristics. Furthermore, we now include transition zone sampling in our follow-up biopsy protocol because of the risk of missing a significant cancer in this undersampled region.25 We have observed that measures such as PSA kinetics and prostate cancer gene 3 (PCA3) genetic testing are not reliable for predicting the presence of high-grade cancer on an individual basis.2628 Thus, if the goal of surveillance is to identify and treat higher-risk cancers, we believe that annual biopsies may be necessary to ensure patient safety. Promisingly, our data reveal that the great majority of men on surveillance were compliant with our follow-up biopsy regimen. In the future, advances in technology such as magnetic resonance imaging could potentially reduce the need for biopsy during active surveillance through identification of high-grade cancer.29

Unlike men who have high-grade cancer on a biopsy, we have considered all men with low-grade cancer (Gleason score ≤ 6) for surveillance at their request. Inclusion of these patients has allowed for the comparison of men with Gleason scores of ≤ 6 who did and did not meet the other criteria for very-low-risk cancer. In comparing risk groups, patients who met very-low-risk criteria were significantly less likely to be reclassified on a surveillance biopsy or to undergo curative intervention during follow-up when compared with those who did not. However, there was no difference in the rate of Gleason score upgrading on surveillance biopsy when comparing those who did and did not meet entry criteria. Thus, we cannot be sure that men meeting the criteria for very-low-risk prostate cancer will have more favorable outcomes when compared with those who did not.

In men who are treated following a period on active surveillance, biochemical recurrence has been evaluated as a proxy for long-term outcomes.12,24 At this point, our crude proportion of men with biochemical recurrence after treatment is lower than that of van den Bergh et al24 and Klotz et al.12 This may be the case because of previously described differences in entry criteria specific to each program and may further support our belief that active surveillance is safest for those with very-low-risk disease. With regard to our study, it is important to emphasize that although recurrence-free survival was higher in men who underwent surgery, there were important differences between the treatment groups that may account for this difference, and our study was not designed to evaluate the effectiveness of one treatment modality versus another. Instead, we have included these data so they may be discussed, when appropriate, in the context of other surveillance programs with different criteria.

Recent analysis from Van den Bergh et al24 demonstrated that there were no differences in biochemical recurrence-free survival after immediate or delayed surgery in men eligible for surveillance. Furthermore, aggregate data from published surveillance cohorts have demonstrated prostate cancer–specific survival greater than 99% at a median follow-up of 43 months.12 Nonetheless, it has been shown that even 10 years is not an adequate time frame for the evaluation of prostate cancer–specific survival,3 and additional follow-up is therefore necessary to evaluate the safety of active surveillance for patients with a greater life expectancy. Because follow-up is limited in active surveillance programs, we believe that metastatic disease-free survival may be a meaningful end point for analysis.

There are several limitations of this study that deserve mention. First, given the lengthy natural history of low-grade prostate cancer, our follow-up interval may not be sufficient to rule out adverse outcomes in some patients after additional follow-up. Second, because of limited follow-up, we used biochemical recurrence after treatment as a proxy for long-term outcomes, although this is not a surrogate for cancer-specific survival. Thus, caution must be used in drawing conclusions on the basis of this end point. Third, our patient population was interested in alternatives to active treatment and was therefore highly motivated to return for follow-up examinations. This cohort may not be representative of other active surveillance populations that may have less stringent selection and follow-up criteria.

In conclusion, recognizing the limitations of predicting outcomes in men diagnosed with prostate cancer today, active surveillance with curative intent appears to be a reasonable alternative to immediate intervention for carefully selected older men. Limiting surveillance to patients with the lowest risk category of disease may reduce the incidence of adverse outcomes. Nonetheless, patients considering surveillance should be counseled on the possibility that delayed intervention may compromise the opportunity for cure in some cases.


    AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
The author(s) indicated no potential conflicts of interest.


    AUTHOR CONTRIBUTIONS
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Conception and design: H. Ballentine Carter

Financial support: H. Ballentine Carter

Administrative support: H. Ballentine Carter

Provision of study materials or patients: Alan W. Partin,H. Ballentine Carter

Collection and assembly of data: Jeffrey J. Tosoian, Patricia Landis, Alan W. Partin, H. Ballentine Carter

Data analysis and interpretation: Jeffrey J. Tosoian, Bruce J. Trock, Zhaoyong Feng, Jonathan I. Epstein, Patrick C. Walsh,H. Ballentine Carter

Manuscript writing: All authors

Final approval of manuscript: All authors


    NOTES
 
Supported by The Patrick C. Walsh Prostate Cancer Research Fund and the Prostate Cancer Foundation.

Presented in part at the 105th Annual Meeting of the American Urological Association, May 31, 2010, San Francisco, CA.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Draisma G, Boer R, Otto SJ, et al: Lead times and overdetection due to prostate-specific antigen screening: Estimates from the European Randomized Study of Screening for Prostate Cancer. J Natl Cancer Inst 95:868–878, 2003.[Abstract/Free Full Text]

2. Schröder FH, Hugosson J, Roobol MJ, et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360:1320–1328, 2009.[CrossRef][Medline]

3. Hugosson J, Carlsson S, Aus G, et al: Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725–732, 2010.[CrossRef][Medline]

4. Welch HG, Black WC: Overdiagnosis in cancer. J Natl Cancer Inst 102:605–613, 2010.[Abstract/Free Full Text]

5. Cooperberg MR, Moul JW, Carroll PR: The changing face of prostate cancer. J Clin Oncol 23:8146–8151, 2005.[Abstract/Free Full Text]

6. Holmberg L, Bill-Axelson A, Garmo H, et al: Prognostic markers under watchful waiting and radical prostatectomy. Hematol Oncol Clin North Am 20:845–855, 2006.[CrossRef][Medline]

7. Carter HB, Kettermann A, Warlick C, et al: Expectant management of prostate cancer with curative intent: An update of the Johns Hopkins experience. J Urol 178:2359–2364, 2007 discussion 2364-2365.[CrossRef][Medline]

8. Khatami A, Ali K, Aus G, et al: 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, 2007.[CrossRef][Medline]

9. Soloway MS, Soloway CT, Williams S, et al: Active surveillance; a reasonable management alternative for patients with prostate cancer: The Miami experience. BJU Int 101:165–169, 2008.[Medline]

10. van As NJ, Norman AR, Thomas K, et al: Predicting the probability of deferred radical treatment for localised prostate cancer managed by active surveillance. Eur Urol 54:1297–1305, 2008.[CrossRef][Medline]

11. van den Bergh RC, Roemeling S, Roobol MJ, et al: Outcomes of men with screen-detected prostate cancer eligible for active surveillance who were managed expectantly. Eur Urol 55:1–8, 2009.[CrossRef][Medline]

12. 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 28:126–131, 2010.[Abstract/Free Full Text]

13. Harlan SR, Cooperberg MR, Elkin EP, et al: Time trends and characteristics of men choosing watchful waiting for initial treatment of localized prostate cancer: Results from CaPSURE. J Urol 170:1804–1807, 2003.[CrossRef][Medline]

14. Carter HB, Walsh PC, Landis P, et al: Expectant management of nonpalpable prostate cancer with curative intent: Preliminary results. J Urol 167:1231–1234, 2002.[CrossRef][Medline]

15. Epstein JI, Walsh PC, Carmichael M, et al: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 271:368–374, 1994.[Abstract/Free Full Text]

16. Mohler J, Bahnson RR, Boston B, et al: NCCN clinical practice guidelines in oncology: Prostate cancer. J Natl Compr Canc Netw 8:162–200, 2010.[Abstract/Free Full Text]

17. Roach M 3rd, Hanks G, Thames H Jr, et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 65:965–974, 2006.[CrossRef][Medline]

18. Chu KC, Tarone RE, Freeman HP: Trends in prostate cancer mortality among black men and white men in the United States. Cancer 97:1507–1516, 2003.[CrossRef][Medline]

19. 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 167:1664–1669, 2002.[CrossRef][Medline]

20. Klotz L: Active surveillance for prostate cancer: A review. Curr Urol Rep 11:165–171, 2010.[CrossRef][Medline]

21. van den Bergh RC, Steyerberg EW, Khatami A, et al: Is delayed radical prostatectomy in men with low-risk screen-detected prostate cancer associated with a higher risk of unfavorable outcomes? Cancer 116:1281–1290, 2010.[CrossRef][Medline]

22. Eggener SE, Mueller A, Berglund RK, et al: A multi-institutional evaluation of active surveillance for low risk prostate cancer. J Urol 181:1635–1641, 2009.[CrossRef][Medline]

23. Dall'Era MA, Konety BR, Cowan JE, et al: Active surveillance for the management of prostate cancer in a contemporary cohort. Cancer 112:2664–2670, 2008.[CrossRef][Medline]

24. van den Bergh RC, Vasarainen H, van der Poel HG, et al: Short-term outcomes of the prospective multicentre ‘Prostate Cancer Research International: Active Surveillance' study. BJU Int 105:956–962, 2010.[CrossRef][Medline]

25. Duffield AS, Lee TK, Miyamoto H, et al: Radical prostatectomy findings in patients in whom active surveillance of prostate cancer fails. J Urol 182:2274–2278, 2009.[CrossRef][Medline]

26. Tseng KS, Landis P, Epstein JI, et al: Risk stratification of men choosing surveillance for low risk prostate cancer. J Urol 183:1779–1785, 2010.[CrossRef][Medline]

27. Ross AE, Loeb S, Landis P, et al: Prostate-specific antigen kinetics during follow-up are an unreliable trigger for intervention in a prostate cancer surveillance program. J Clin Oncol 28:2810–2816, 2010.[Abstract/Free Full Text]

28. Tosoian JJ, Loeb S, Kettermann A, et al: Accuracy of PCA3 measurement in predicting short-term biopsy progression in an active surveillance program. J Urol 183:534–538, 2010.[CrossRef][Medline]

29. Fradet V, Kurhanewicz J, Cowan JE, et al: Prostate cancer managed with active surveillance: Role of anatomic MR imaging and MR spectroscopic imaging. Radiology 256:176–183, 2010.[Abstract/Free Full Text]

Submitted September 30, 2010; accepted January 20, 2011.


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