- Email: [email protected]
What Percentage of Patients With Newly Diagnosed Carcinoma of the Prostate are Candidates for Surveillance? An Analysis of the CaPSURE™ Database
What Percentage of Patients With Newly Diagnosed Carcinoma of the Prostate are Candidates for Surveillance? An Analysis of the CaPSURE™ Database Daniel A. Barocas,* Janet E. Cowan,† Joseph A. Smith, Jr.,* Peter R. Carroll‡,§ and the CaPSURE Investigators From the Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee (DAB, JAS), and the Department of Urology, Program in Urologic Oncology, Urologic Outcomes Research Group, UCSF/Mt. Zion Comprehensive Cancer Center, University of California San Francisco, San Francisco, California (JEC, PRC)
Purpose: Active surveillance is an option for men with clinically localized prostate cancer and may be suitable for those with very low risk disease. We determined the percentage of men in a large prostate cancer registry who met criteria predictive of latent prostate cancer. We also assessed the percentage of men meeting these criteria who chose surveillance. Materials and Methods: We conducted an observational study of 1,886 men diagnosed with clinically localized prostate cancer between 1999 and 2004 from the CaPSURE database. Outcomes were percent of men meeting Epstein surveillance criteria (prostate specific antigen less than 10 ng/ml, clinical T1 or T2a, prostate specific antigen density less than 0.15, fewer than 1 of 3 biopsy cores positive, and absence of Gleason pattern 4 and 5 on biopsy) and percent selecting surveillance stratified by risk group. Results: Of 1,886 men with all 5 criteria documented 16.4% (310 of 1,886) met all 5 surveillance criteria and 9.0% (28 of 310) of men in this very low risk category actually chose surveillance compared with 4.3% (68 of 1,576) of patients in other risk groups (p ⬍0.01). On multivariable analysis of the entire cohort older age was the only demographic predictor of surveillance. Being in the very low risk group was also a predictor of surveillance. Conclusions: Of men presenting with localized prostate cancer 16% met the criteria for very low risk disease. However, only a small subset of eligible men chose active surveillance, suggesting that it may be underused in the management of very low risk prostate cancer. Key Words: prostatic neoplasms, risk assessment, disease management
pproximately 219,000 new cases of prostate cancer are diagnosed annually in the United States.1 Early detection efforts have resulted in an increased incidence of disease and a migration toward lower stage disease. This has yielded a reduction in prostate cancer deaths and rate of metastatic disease but concerns have been raised about over diagnosis and over treatment. Up to 29% of screening detected prostate cancer is indolent at pathological examination after surgery based on characteristics that predict a low likelihood of progression.2,3 Criteria for identifying indolent disease based on clinical characteristics have been developed.2 Although surveillance of prostate cancer
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Submitted for publication January 7, 2008. The CaPSURE database is supported by the Department of Urology at the University of California, San Francisco. The founding sponsor of CaPSURE is TAP Pharmaceutical Products, Inc. * Nothing to disclose. † Financial interest and/or other relationship with TAP Pharmaceutical Products Inc. ‡ Financial interest and/or other relationship with the National Cancer Institute, the Department of Defense, TAP Pharmaceutical Products Inc. and Informedical. § Correspondence: University of California, San Francisco, 1600 Divisadero St., Room A-610, UCSF Box 1695, San Francisco, California 94115 (telephone: 415-353-7098; FAX: 415-353-9932; e-mail: [email protected]).
See Editorial on page 1217.
0022-5347/08/1804-1330/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
is controversial there is evidence that initial surveillance with delayed intervention is appropriate for some patients.4 Patients who are predicted to harbor indolent disease may be candidates for surveillance and inclusion criteria for surveillance protocols are devised accordingly.5 However, it is unclear how many men presenting with prostate cancer meet criteria predictive of indolent disease and would be eligible for surveillance. Furthermore, it is unclear how many men in this very low risk group elect to undergo surveillance. Therefore, we determined the percent of patients with newly diagnosed prostate cancer who would be candidates for surveillance by these criteria. In addition, we studied the factors associated with the patient decision to opt for surveillance and we quantified the percent of patients who choose surveillance. MATERIALS AND METHODS The Disease Registry The CaPSURE disease registry is an observational, longitudinal disease registry of men with prostate cancer. Patients are Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1578 and 1579.
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Vol. 180, 1330-1335, October 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.06.019
PROSTATE CANCER SURVEILLANCE
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recruited from 41 community based and academic urology practices across the United States. Informed consent is obtained from each patient under local institutional review board supervision. There is no treatment protocol in CaPSURE, rather patients are treated according to the usual practice of their physicians allowing for an overview of practice trends in the United States. Clinical data are reported by participating urologists. Patients report health related quality of life, health resource use and demographic information via study questionnaires. Patients are followed until time of death or study withdrawal. Additional details of the project methodology have been reported previously.6 Definitions and Inclusion Criteria Patients eligible for surveillance were those meeting the Epstein criteria for prediction of indolent prostate cancer.2 Specifically the criteria were PSA less than 10 ng/ml at diagnosis, clinical stage (American Joint Committee on Cancer 2002) cT1 or cT2a, PSA density less than 0.15, fewer than 1 of 3 cores positive on biopsy, and absence of Gleason pattern 4 and 5 on biopsy. The database does not include percent or length of each core involved so these criteria were not included. Patients who met all 5 criteria were deemed very low risk. The remaining patients were stratified into low (PSA 10 ng/ml or less, Gleason sum less than 7 without pattern 4 or 5, and clinical stage T1 or T2a), intermediate (PSA 10.1 to 20 ng/ml, or Gleason sum 7 or secondary Gleason pattern 4 to 5, or clinical stage T2b to T2c) or high risk (PSA more than 20 ng/ml, or Gleason sum 8 to 10 or primary pattern 4 or 5, or clinical stage T3 or higher) based on a modification of the D’Amico criteria that has been used in previous CaPSURE studies.7,8 The primary treatment was reported by the physician and culled from the database. Patients were included if they underwent RP, RT (including brachytherapy and/or, external beam), primary ADT or AS. AS was defined as no treatment within 6 months after diagnosis. Patients choosing alternative therapies such as cryotherapy (7.9%) were excluded from analysis because the majority of these patients were treated with cryotherapy at a single site as part of a study. Study Population Although the registry extends back to 1989 only data collected after 1995 were prospectively collected and there were few patients enrolled before 1999 who had all eligibility criteria documented. Therefore, we focused on men diagnosed between 1999 and 2004. There were 7,193 men registered with a new diagnosis of prostate cancer between 1999 and 2004, representing approximately 90% to 95% of those invited to participate at each practice site (see figure). Of these men 6,571 (91.4%) had localized disease, including 6,052 (92.1%) who chose RP, RT, primary ADT or AS. Clinical characteristics including PSA, biopsy Gleason grade and T stage were available for 5,569 patients (92.0%). We assumed that the rate of missing data for these 3 elements was random across CaPSURE patients. PSA density and the percent of cores positive for cancer were documented in 1,886 (33.9%). These latter data points depended on the availability of ultrasound determined prostate volume and number of positive and total biopsy cores, which were missing in a substantial number of cases. Therefore, the charac-
Patients included in study. Dx, diagnosis. Bx, biopsy
teristics of these 1,886 patients were compared with those of the excluded group of 3,683 patients to assess the possibility of selection bias. This study focuses on the cohort of 1,886 patients with complete documentation of very low risk criteria. Statistical Analysis We determined the percent of the cohort that met all 5 very low risk criteria and, therefore, were eligible for surveillance. Chi-square analyses were used to compare demographic characteristics among those meeting criteria for surveillance with those in higher risk strata. Chi-square analysis was also used to compare treatment choices among those with very low risk disease and the rest of the cohort. A multivariable logistic regression analysis was performed to identify clinical and demographic characteristics associated with the use of active surveillance. All variables that were significantly different between groups in univariate analysis were included in the regression model. Preliminary frequencies were used to determine whether category sizes for each possible covariate were sufficient (minimum 20 per category). Ultimately the model included a yes/no indicator of very low risk disease, age at diagnosis (74 years or younger, or older than 74 years based on median age of patients on AS in this cohort) and level of education (also used as a proxy for income). Statistical analyses were performed using SAS® for Windows, version 9.1. The figure was generated using Microsoft Office Professional Edition, 2003. RESULTS Of the 1,886 patients in our cohort 16.4% (310 of 1,886) met all 5 criteria for very low risk disease. Thus, 83.6% (1,576 of 1,886) of patients were in higher risk strata with 22% low risk, 35% moderate risk and 27% high risk. Men in the very low risk category were more likely to be younger (p ⬍0.01), and have more education (p ⬍0.01), higher income (p ⬍0.01) and private insurance (p ⬍0.01) (table 1). Mean age of pa-
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PROSTATE CANCER SURVEILLANCE TABLE 1. Sociodemographic characteristics
TABLE 3. Comparison of patient age and clinical characteristics
No. (%) Baseline Characteristics Age at diagnosis: Younger than 55 55–64 65–74 75 or Older Race: White Other Education: Less than high school High school graduate Some college College graduate Income: $30,000 or Less $30,001–$50,000 $50,001–$75,000 Greater than $75,000 Relationship status: In relationship Single Insurance status: Medicare supplement Medicare Private Veterans affairs Body mass index at diagnosis: Normal Overweight Obese Comorbidities: None 1–2 3 or Greater
Higher Risk Categories (1,576)
Very Low Risk Category (310)
Chi-Square p Value
146 (9) 466 (30) 621 (39) 343 (22)
39 (13) 114 (37) 126 (41) 31 (10)
⬍0.01
1,382 (88) 189 (12)
284 (92) 25 (8)
0.05
201 (17)
21 (9)
⬍0.01
337 (28)
63 (27)
203 (17) 444 (37)
42 (18) 110 (47)
349 (33) 238 (23) 207 (20) 260 (25)
41 (19) 57 (27) 46 (22) 68 (32)
⬍0.01
1,049 (89) 126 (11)
206 (88) 28 (12)
0.58
488 (34)
97 (33)
⬍0.01
291 (20) 627 (44) 34 (2)
32 (11) 161 (54) 6 (2)
326 (28) 571 (49) 277 (24)
54 (23) 120 (52) 57 (25)
0.39
184 (16) 654 (55) 345 (29)
35 (15) 135 (58) 62 (27)
0.70
tients eligible for surveillance was 64.4 years (SD 7.7) while it was 67.0 (SD 9.1) for the remaining patients (p ⬍0.01). Of the men who met all criteria for very low risk disease 9% (28 of 310) actually chose surveillance compared to 4% (68 of 1,576) of those in other risk categories (p ⬍0.01). Table 2 shows the primary treatment by group. Treatment options were unevenly distributed among groups with higher percentages of men in the lower risk groups choosing surgery and surveillance compared with men in higher risk categories. Clinical and demographic characteristics were compared between the final sample of 1,886 patients and the 3,683 patients who were excluded from analysis due to missing PSA density data (table 3). Although the sample of 1,886 patients was slightly older (mean age 66.5 [SD 8.89] vs 65.0
Characteristics at Diagnosis Age: Younger than 55 55–64 65–74 75 or Older PSA less than 10 ng/ml: No Yes No Gleason 4/5 pattern: No Yes Pos biopsy less than 33%: No Yes T1 or T2A: No Yes PSA density less than 0.15: No Yes Met first 4 criteria: No Yes Met all available criteria: No Yes Chose AS: No Yes
No. Pts With Complete Data (%)
No. Pts With Incomplete Data (%)
Chi-Square p Value
185 (10) 580 (31) 747 (40) 374 (20)
460 (12) 1,305 (35) 1,342 (36) 576 (16)
⬍0.01
490 (26) 1,396 (74)
669 (18) 3,014 (82)
⬍0.01
808 (43) 1,078 (57)
1,147 (31) 2,536 (69)
⬍0.01
952 (50) 934 (50)
1,430 (39) 2,253 (61)
⬍0.01
557 (30) 1,329 (70)
696 (19) 2,987 (81)
⬍0.01
1,173 (62) 713 (38)
Not available Not available
1,360 (72) 526 (28)
2,255 (61) 1,428 (39)
⬍0.01
1,576 (84) 310 (16)
2,255 (61) 1,428 (39)
⬍0.01
1,790 (95) 96 (5)
3,473 (94) 210 (6)
0.34
[SD 8.94] years, t test p ⬍0.01) and higher risk, the percentage who chose surveillance was the same. Thus, the subset of 1,886 patients is a fair although imperfect representation of CaPSURE patients with localized disease. By studying a slightly higher risk subset of the CaPSURE database we would expect to underestimate the percentage of patients in the very low risk group. Multivariable logistic regression analysis identified age and very low risk criteria as independent predictors of active surveillance among all patients in the cohort (table 4). The odds of surveillance in patients 74 years or older were more than 7 times higher than in those younger than 74 years (OR 7.3, 95% CI 4.4 –12.2). Patients who met all 5 low risk criteria had more than 3 times higher odds of choosing surveillance compared to higher risk patients (OR 3.4, 95% CI 1.9 – 6.0). Education was not independently associated with choosing surveillance. This multivariate analysis was repeated for the excluded group of 3,683 patients and results were similar. The odds of choosing surveillance were almost 3 times higher in patients who met all 4 available low risk criteria (OR 2.7, 95% CI 1.9 –3.8). DISCUSSION
TABLE 2. Primary treatment of patients by risk category No. (%)
RP* RT ADT AS
Very Low Risk (310)
Low Risk (411)
Intermediate Risk (373)
High Risk (792)
188 (61) 71 (23) 23 (7) 28 (9)
226 (55) 120 (29) 36 (9) 29 (7)
185 (50) 117 (31) 59 (16) 12 (3)
313 (40) 254 (32) 198 (25) 27 (3)
* Chi-square p ⬍0.01.
The challenge in managing localized prostate cancer is to identify patients with potentially aggressive disease and treat them aggressively while sparing those with indolent disease from over treatment. The over treatment burden on men with indolent prostate cancer may be a large public health problem because of its high prevalence. Incidental prostate cancer is found in 23% to 45% of men undergoing cystoprostatectomy for bladder cancer9 –11 and at least 35% of American men at autopsy.12,13 Many of these are low volume, low grade, organ confined cancers. In radical
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TABLE 4. Multivariate logistic regression of initial surveillance covarying for age at diagnosis, education and risk group Odds Ratio Estimates Effect
Active Surveillance (72)
Other Treatment (1,349)
Odds Ratio
95% CI
Age at diagnosis older than 74 yrs Age at diagnosis 74 yrs or younger (reference group) Education high school or less Education some or more college (reference group) Very low risk group (met all 5 criteria) Higher risk groups (reference group)
41 31 35 37 21 51
244 1,105 587 762 215 1,134
7.30 1.00 0.86 1.00 3.40 1.00
4.39–12.21
prostatectomy series up to 29% of patients have small, low grade tumors, suggesting that intensified screening efforts may have led to over detection and over treatment of indolent cancers.3 Radical prostatectomy has been shown to improve survival compared to watchful waiting in a mixed population of patients with prostate cancer.14 Furthermore, competing risk analyses demonstrate that up to 30% of patients die of prostate cancer when treated with observation and conservative therapy alone.15 Taken together these studies suggest that definitive therapy benefits some patients but perhaps not all. Bill-Axelson14 and Albertsen15 et al show that definitive therapy is most likely to benefit younger patients. Thus, older patients and those with significant medical comorbidities may be suited to surveillance. Patients in the lowest risk strata may also be candidates for surveillance. In the study that defined the inclusion criteria we have used here, Epstein et al demonstrated that 79% of men meeting these criteria had indolent tumors at radical prostatectomy.2 A recent cohort study based on these criteria demonstrated that a period of initial surveillance did not adversely affect pathological outcomes in patients going on to delayed surgery.16 The 38 patients who underwent surgery after a mean of 26.5 months were compared with 150 matched patients undergoing immediate surgery (within 3 months). There was no difference in the likelihood of noncurable disease at final pathological evaluation (RR 1.08, 95% CI 0.55–2.12, p ⫽ 0.82). Our aim in this study was to estimate the percentage of men who may eligible for surveillance by applying these surveillance criteria to the CaPSURE database. A handful of investigators have made similar efforts to quantify the population eligible for surveillance. A study from Europe evaluated 1,014 men diagnosed with prostate cancer in the screening arm of the European Randomized study of Screening for Prostate Cancer in The Netherlands between 1993 and 1999.17 Using more inclusive criteria than we used (PSA 15 ng/ml or less and PSA density 0.2 ng/ml/cc or less) the authors found that 28.9% of men were low risk and 21.8% of low risk patients chose surveillance. A study from the United States evaluated nearly 100,000 men with prostate cancer from the SEER registries, most of whom were diagnosed between 2000 and 2002.18 The investigators defined low risk disease as biopsy Gleason sum 2– 4 for men of any age and biopsy Gleason sum 2 to 7 for men older than 70 years without regard to percentage of cores positive, PSA, PSA density or clinical stage. They found that 34.7% met their criteria for low risk disease. Approximately 45% of these men chose hormonal therapy or surveillance, which are grouped together in SEER. In the present study 16.4% of patients with clinically localized prostate cancer diagnosed between 1999 and 2004
0.53–1.41 1.91–6.04
met criteria for very low risk disease. This is, as expected, lower than the approximately 30% of patients meeting broader definitions of low risk disease in prior studies. We chose to look at the very low risk group because the criteria are predictive of indolent disease, and there is greater consensus and justification for observing these men. Only 9% of patients in the very low risk category and even fewer patients in higher risk strata chose surveillance. This is lower than previously reported and may reflect differences in practice patterns over time or between Europe and the United States. It also may be due to the lumping of patients on hormonal therapy with those on surveillance in some studies and/or the inclusion of older men with more aggressive disease. However, the fact that only 9% of men considered eligible for surveillance actually elect to be observed suggests that AS may be underused in this population. We found that very low risk disease was associated with higher levels of education, higher income, private insurance and younger age. These findings parallel previous findings in the CaPSURE database and other publications, and may reflect disparities in access to care.19,20 However, the only demographic predictor of surveillance was older age, which makes sense since older men are least likely to benefit from treatment.14 Other predictors of surveillance were clinical parameters indicating low risk disease. Because CaPSURE tracks patterns from community and academic sites around the United States, it provides a gauge of national practice patterns. Clearly it is has limitations (sites are not randomly selected, it is not a comprehensive registry of all patients with prostate cancer in the country, not all patients invited to participate do so and the patients refusing may not match our cohort in risk or likelihood of choosing surveillance). The subset of CaPSURE patients we analyzed was higher risk than those with incomplete data, suggesting that our estimate of the percentage of men eligible for surveillance may be low. On the other hand the inability to use the complete Epstein criteria may have resulted in an overestimate. In addition, we recognize that the absence of treatment is not the same as active surveillance (characterized by frequent examination and PSA as well as repeat biopsy every 18 to 24 months with a plan to intervene for disease progression). Lastly, the Epstein criteria, while providing a point of departure based on clinical disease characteristics, do not take into account other significant factors in the decision to observe prostate cancer such as age (which was significant in our analysis), comorbidities and life expectancy. Despite these caveats this analysis of the CaPSURE database provides an additional data point in the effort to quantify the percentage of American men with newly diagnosed localized prostate cancer who are eligible for active surveillance. Compared to other studies our study has the
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PROSTATE CANCER SURVEILLANCE
advantages of addressing a recent American cohort, having nearly all of the Epstein criteria in use, and distinguishing between surveillance and hormonal therapy.
11.
12.
CONCLUSIONS Of the men in our cohort 16.4% met the criteria for very low risk disease. Only 9% of patients eligible for surveillance by these criteria actually chose to be observed. These findings raise questions about how patients make treatment decisions and the role of the physician in this process. In addition, our study helps define the extent to which surveillance may be underused in the management of very low risk prostate cancer.
13.
14.
15.
Abbreviations and Acronyms ADT ⫽ androgen deprivation therapy AS ⫽ active surveillance CaPSURE ⫽ Cancer of the Prostate Strategic Urologic Research Endeavor PSA ⫽ prostate specific antigen RP ⫽ radical prostatectomy RT ⫽ radiation therapy SEER ⫽ Surveillance, Epidemiology, and End Results
REFERENCES 1. 2.
3.
4. 5.
6.
7.
8.
9.
10.
Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43. Epstein JI, Walsh PC, Carmichael M and Brendler CB: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994; 271: 368. Carter HB, Sauvageot J, Walsh PC and Epstein JI: Prospective evaluation of men with stage T1C adenocarcinoma of the prostate. J Urol 1997; 157: 2206. Klotz L: Active surveillance for prostate cancer: for whom? J Clin Oncol 2005; 23: 8165. Carter HB, Walsh PC, Landis P and Epstein JI: Expectant management of nonpalpable prostate cancer with curative intent: preliminary results. J Urol 2002; 167: 1231. Lubeck DP, Litwin MS, Henning JM, Stier DM, Mazonson P, Fisk R et al: The CaPSURE database: a methodology for clinical practice and research in prostate cancer. CaPSURE Research Panel. Cancer of the Prostate Strategic Urologic Research Endeavor. Urology 1996; 48: 773. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969. Greene KL, Cowan JE, Cooperberg MR, Meng MV, DuChane J and Carroll PR: Who is the average patient presenting with prostate cancer? Urology 2005; 66: 76. Revelo MP, Cookson MS, Chang SS, Shook MF, Smith JA Jr and Shappell SB: Incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. J Urol 2004; 171: 646. Moutzouris G, Barbatis C, Plastiras D, Mertziotis N, Katsifotis C, Presvelos V et al: Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder. Scand J Urol Nephrol 1999; 33: 27.
16.
17.
18.
19.
20.
Abbas F, Hochberg D, Civantos F and Soloway M: Incidental prostatic adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder cancer. Eur Urol 1996; 30: 322. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ 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. Guileyardo JM, Johnson WD, Welsh RA, Akazaki K and Correa P: Prevalence of latent prostate carcinoma in two U.S. populations. J Natl Cancer Inst 1980; 65: 311. Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Bratell S et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352: 1977. Albertsen PC, Hanley JA and Fine J: 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005; 293: 2095. Warlick C, Trock BJ, Landis P, Epstein JI and Carter HB: Delayed versus immediate surgical intervention and prostate cancer outcome. J Natl Cancer Inst 2006; 98: 355. Roemeling S, Roobol MJ, Postma R, Gosselaar C, van der Kwast TH, Bangma CH et al: Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance. Eur Urol 2006; 50: 475. Miller DC, Gruber SB, Hollenbeck BK, Montie JE and Wei JT: Incidence of initial local therapy among men with lowerrisk prostate cancer in the United States. J Natl Cancer Inst 2006; 98: 1134. Cooperberg MR, Lubeck DP, Meng MV, Mehta SS and Carroll PR: The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. J Clin Oncol 2004; 22: 2141. Harlan LC, Potosky A, Gilliland FD, Hoffman R, Albertsen PC, Hamilton AS et al: Factors associated with initial therapy for clinically localized prostate cancer: prostate cancer outcomes study. J Natl Cancer Inst 2001; 93: 1864.
EDITORIAL COMMENT The majority of patients with prostate cancer face a minimal risk of dying of the disease.1 Those with favorable clinical parameters such as those reported in this series may have a risk of prostate cancer death approaching zero and there is little evidence that aggressive treatment changes this status. Nevertheless, these authors observe a widespread therapeutic disconnect and provide further evidence that the majority undergo treatment that offers little potential benefit. Why does this clear over treatment occur? Although it is tempting to blame greed, ignorance or fear of medicolegal risk, the fact remains that there is no consensus regarding the definition of low risk or the even more meaningless category clinically insignificant. Even Epstein’s criteria as defined in this report (PSA less than 10 ng/ml, clinical T1 or T2a disease, PSA density less than 0.15, fewer than 1 of 3 cores positive and absence of Gleason pattern 4 or 5) are misunderstood and often vary from his own description. Unlike the present report listing Epstein himself currently uses 5 slightly different factors: 1) 2 or fewer positive cores, 2) no core with greater than 50% cancer, 3) no Gleason pattern 4 or 5, 4) PSA density less than 0.15 and 5) nonpalpable on digital rectal examination.2
PROSTATE CANCER SURVEILLANCE Two positive cores in a sextant biopsy suggest a much more significant tumor burden than would 2 cores on extended or saturation biopsy, so the use of 1 of 3 biopsy cores seems more reasonable, albeit unvalidated. The present report justifiably allows T2a and considers total PSA, but omits maximum percentage involvement of any core. In addition, many definitions of clinically insignificant disease use organ confined status, which seems counterintuitive since this requires advanced disease to preclude insignificance, meaning that the moment when a low grade tumor progresses across the prostatic capsule, it goes from clinically insignificant to locally advanced without an intermediate point at which treatment might have been appropriate. Thus, although all of these parameters appear consistent with very low risk disease, the lack of consensus is troubling to the physician and patient trying to determine the best approach. Until consensus is achieved it is likely that many—if not most—men will be over treated for prostate cancer. J. Stephen Jones and Eric A. Klein Glickman Urological and Kidney Institute Cleveland Clinic Foundation Cleveland, Ohio 1.
2.
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L et al: SEER Cancer Statistics Review, 1975-2000, National Cancer Institute, 2003. Available at http://seer.cancer.gov./ csr/1975_2000. Dr. Jonathan Epstein, personal communication, March 2007.
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believe that the sub-population we identified represents a very low risk group within our cohort and that patients meeting these criteria ought to be candidates for surveillance. In fact the AUA guidelines obligate urologists to consider surveillance for any patient meeting the much more inclusive D’Amico criteria for low risk disease.1,2 There is an inherent limitation in any risk stratification system and difficulty in defining a cancer that does not require treatment. The clinical criteria that we use, even the most fastidiously validated models, are merely surrogates for the biological behavior of a particular tumor. The result is that each risk stratum will contain some patients whose cancer will behave more or less aggressively than predicted. Although models such as the Epstein model help us select the correct therapy for a particular patient, we found that the majority of patients with very low risk clinical disease characteristics still select immediate treatment. Improving the predictive ability of our models and formulating evidence-based definitions of clinically insignificant, significant and treatable, and significant but already too advanced to be cured are avenues toward bridging this therapeutic disconnect. Other avenues may involve studying patient preferences, doctor-patient interactions and decision analysis tools that help match patient preferences and the clinical scenario with a management strategy.3 1.
REPLY BY AUTHORS
2.
We agree that the lack of consensus on clinical characteristics that predict indolent disease makes counseling patients with low risk prostate cancer difficult. We did make adjustments to the original Epstein criteria to accommodate the information in our database. While we acknowledge that our criteria vary slightly from the original validated criteria, we
3.
D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D and Chen MH: Cancer specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003; 21: 2163. Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagiino ED, Cookson MS et al: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106. Sommers BD, Beard CJ, D’Amico AV, Dahl D, Kaplan I, Richie JP et al: Decision analysis using individual patient preferences to determine optimal treatment for localized prostate cancer. Cancer 2007; 110: 2210.
Purpose: Active surveillance is an option for men with clinically localized prostate cancer and may be suitable for those with very low risk disease. We determined the percentage of men in a large prostate cancer registry who met criteria predictive of latent prostate cancer. We also assessed the percentage of men meeting these criteria who chose surveillance. Materials and Methods: We conducted an observational study of 1,886 men diagnosed with clinically localized prostate cancer between 1999 and 2004 from the CaPSURE database. Outcomes were percent of men meeting Epstein surveillance criteria (prostate specific antigen less than 10 ng/ml, clinical T1 or T2a, prostate specific antigen density less than 0.15, fewer than 1 of 3 biopsy cores positive, and absence of Gleason pattern 4 and 5 on biopsy) and percent selecting surveillance stratified by risk group. Results: Of 1,886 men with all 5 criteria documented 16.4% (310 of 1,886) met all 5 surveillance criteria and 9.0% (28 of 310) of men in this very low risk category actually chose surveillance compared with 4.3% (68 of 1,576) of patients in other risk groups (p ⬍0.01). On multivariable analysis of the entire cohort older age was the only demographic predictor of surveillance. Being in the very low risk group was also a predictor of surveillance. Conclusions: Of men presenting with localized prostate cancer 16% met the criteria for very low risk disease. However, only a small subset of eligible men chose active surveillance, suggesting that it may be underused in the management of very low risk prostate cancer. Key Words: prostatic neoplasms, risk assessment, disease management
pproximately 219,000 new cases of prostate cancer are diagnosed annually in the United States.1 Early detection efforts have resulted in an increased incidence of disease and a migration toward lower stage disease. This has yielded a reduction in prostate cancer deaths and rate of metastatic disease but concerns have been raised about over diagnosis and over treatment. Up to 29% of screening detected prostate cancer is indolent at pathological examination after surgery based on characteristics that predict a low likelihood of progression.2,3 Criteria for identifying indolent disease based on clinical characteristics have been developed.2 Although surveillance of prostate cancer
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Submitted for publication January 7, 2008. The CaPSURE database is supported by the Department of Urology at the University of California, San Francisco. The founding sponsor of CaPSURE is TAP Pharmaceutical Products, Inc. * Nothing to disclose. † Financial interest and/or other relationship with TAP Pharmaceutical Products Inc. ‡ Financial interest and/or other relationship with the National Cancer Institute, the Department of Defense, TAP Pharmaceutical Products Inc. and Informedical. § Correspondence: University of California, San Francisco, 1600 Divisadero St., Room A-610, UCSF Box 1695, San Francisco, California 94115 (telephone: 415-353-7098; FAX: 415-353-9932; e-mail: [email protected]).
See Editorial on page 1217.
0022-5347/08/1804-1330/0 THE JOURNAL OF UROLOGY® Copyright © 2008 by AMERICAN UROLOGICAL ASSOCIATION
is controversial there is evidence that initial surveillance with delayed intervention is appropriate for some patients.4 Patients who are predicted to harbor indolent disease may be candidates for surveillance and inclusion criteria for surveillance protocols are devised accordingly.5 However, it is unclear how many men presenting with prostate cancer meet criteria predictive of indolent disease and would be eligible for surveillance. Furthermore, it is unclear how many men in this very low risk group elect to undergo surveillance. Therefore, we determined the percent of patients with newly diagnosed prostate cancer who would be candidates for surveillance by these criteria. In addition, we studied the factors associated with the patient decision to opt for surveillance and we quantified the percent of patients who choose surveillance. MATERIALS AND METHODS The Disease Registry The CaPSURE disease registry is an observational, longitudinal disease registry of men with prostate cancer. Patients are Editor’s Note: This article is the third of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 1578 and 1579.
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Vol. 180, 1330-1335, October 2008 Printed in U.S.A. DOI:10.1016/j.juro.2008.06.019
PROSTATE CANCER SURVEILLANCE
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recruited from 41 community based and academic urology practices across the United States. Informed consent is obtained from each patient under local institutional review board supervision. There is no treatment protocol in CaPSURE, rather patients are treated according to the usual practice of their physicians allowing for an overview of practice trends in the United States. Clinical data are reported by participating urologists. Patients report health related quality of life, health resource use and demographic information via study questionnaires. Patients are followed until time of death or study withdrawal. Additional details of the project methodology have been reported previously.6 Definitions and Inclusion Criteria Patients eligible for surveillance were those meeting the Epstein criteria for prediction of indolent prostate cancer.2 Specifically the criteria were PSA less than 10 ng/ml at diagnosis, clinical stage (American Joint Committee on Cancer 2002) cT1 or cT2a, PSA density less than 0.15, fewer than 1 of 3 cores positive on biopsy, and absence of Gleason pattern 4 and 5 on biopsy. The database does not include percent or length of each core involved so these criteria were not included. Patients who met all 5 criteria were deemed very low risk. The remaining patients were stratified into low (PSA 10 ng/ml or less, Gleason sum less than 7 without pattern 4 or 5, and clinical stage T1 or T2a), intermediate (PSA 10.1 to 20 ng/ml, or Gleason sum 7 or secondary Gleason pattern 4 to 5, or clinical stage T2b to T2c) or high risk (PSA more than 20 ng/ml, or Gleason sum 8 to 10 or primary pattern 4 or 5, or clinical stage T3 or higher) based on a modification of the D’Amico criteria that has been used in previous CaPSURE studies.7,8 The primary treatment was reported by the physician and culled from the database. Patients were included if they underwent RP, RT (including brachytherapy and/or, external beam), primary ADT or AS. AS was defined as no treatment within 6 months after diagnosis. Patients choosing alternative therapies such as cryotherapy (7.9%) were excluded from analysis because the majority of these patients were treated with cryotherapy at a single site as part of a study. Study Population Although the registry extends back to 1989 only data collected after 1995 were prospectively collected and there were few patients enrolled before 1999 who had all eligibility criteria documented. Therefore, we focused on men diagnosed between 1999 and 2004. There were 7,193 men registered with a new diagnosis of prostate cancer between 1999 and 2004, representing approximately 90% to 95% of those invited to participate at each practice site (see figure). Of these men 6,571 (91.4%) had localized disease, including 6,052 (92.1%) who chose RP, RT, primary ADT or AS. Clinical characteristics including PSA, biopsy Gleason grade and T stage were available for 5,569 patients (92.0%). We assumed that the rate of missing data for these 3 elements was random across CaPSURE patients. PSA density and the percent of cores positive for cancer were documented in 1,886 (33.9%). These latter data points depended on the availability of ultrasound determined prostate volume and number of positive and total biopsy cores, which were missing in a substantial number of cases. Therefore, the charac-
Patients included in study. Dx, diagnosis. Bx, biopsy
teristics of these 1,886 patients were compared with those of the excluded group of 3,683 patients to assess the possibility of selection bias. This study focuses on the cohort of 1,886 patients with complete documentation of very low risk criteria. Statistical Analysis We determined the percent of the cohort that met all 5 very low risk criteria and, therefore, were eligible for surveillance. Chi-square analyses were used to compare demographic characteristics among those meeting criteria for surveillance with those in higher risk strata. Chi-square analysis was also used to compare treatment choices among those with very low risk disease and the rest of the cohort. A multivariable logistic regression analysis was performed to identify clinical and demographic characteristics associated with the use of active surveillance. All variables that were significantly different between groups in univariate analysis were included in the regression model. Preliminary frequencies were used to determine whether category sizes for each possible covariate were sufficient (minimum 20 per category). Ultimately the model included a yes/no indicator of very low risk disease, age at diagnosis (74 years or younger, or older than 74 years based on median age of patients on AS in this cohort) and level of education (also used as a proxy for income). Statistical analyses were performed using SAS® for Windows, version 9.1. The figure was generated using Microsoft Office Professional Edition, 2003. RESULTS Of the 1,886 patients in our cohort 16.4% (310 of 1,886) met all 5 criteria for very low risk disease. Thus, 83.6% (1,576 of 1,886) of patients were in higher risk strata with 22% low risk, 35% moderate risk and 27% high risk. Men in the very low risk category were more likely to be younger (p ⬍0.01), and have more education (p ⬍0.01), higher income (p ⬍0.01) and private insurance (p ⬍0.01) (table 1). Mean age of pa-
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PROSTATE CANCER SURVEILLANCE TABLE 1. Sociodemographic characteristics
TABLE 3. Comparison of patient age and clinical characteristics
No. (%) Baseline Characteristics Age at diagnosis: Younger than 55 55–64 65–74 75 or Older Race: White Other Education: Less than high school High school graduate Some college College graduate Income: $30,000 or Less $30,001–$50,000 $50,001–$75,000 Greater than $75,000 Relationship status: In relationship Single Insurance status: Medicare supplement Medicare Private Veterans affairs Body mass index at diagnosis: Normal Overweight Obese Comorbidities: None 1–2 3 or Greater
Higher Risk Categories (1,576)
Very Low Risk Category (310)
Chi-Square p Value
146 (9) 466 (30) 621 (39) 343 (22)
39 (13) 114 (37) 126 (41) 31 (10)
⬍0.01
1,382 (88) 189 (12)
284 (92) 25 (8)
0.05
201 (17)
21 (9)
⬍0.01
337 (28)
63 (27)
203 (17) 444 (37)
42 (18) 110 (47)
349 (33) 238 (23) 207 (20) 260 (25)
41 (19) 57 (27) 46 (22) 68 (32)
⬍0.01
1,049 (89) 126 (11)
206 (88) 28 (12)
0.58
488 (34)
97 (33)
⬍0.01
291 (20) 627 (44) 34 (2)
32 (11) 161 (54) 6 (2)
326 (28) 571 (49) 277 (24)
54 (23) 120 (52) 57 (25)
0.39
184 (16) 654 (55) 345 (29)
35 (15) 135 (58) 62 (27)
0.70
tients eligible for surveillance was 64.4 years (SD 7.7) while it was 67.0 (SD 9.1) for the remaining patients (p ⬍0.01). Of the men who met all criteria for very low risk disease 9% (28 of 310) actually chose surveillance compared to 4% (68 of 1,576) of those in other risk categories (p ⬍0.01). Table 2 shows the primary treatment by group. Treatment options were unevenly distributed among groups with higher percentages of men in the lower risk groups choosing surgery and surveillance compared with men in higher risk categories. Clinical and demographic characteristics were compared between the final sample of 1,886 patients and the 3,683 patients who were excluded from analysis due to missing PSA density data (table 3). Although the sample of 1,886 patients was slightly older (mean age 66.5 [SD 8.89] vs 65.0
Characteristics at Diagnosis Age: Younger than 55 55–64 65–74 75 or Older PSA less than 10 ng/ml: No Yes No Gleason 4/5 pattern: No Yes Pos biopsy less than 33%: No Yes T1 or T2A: No Yes PSA density less than 0.15: No Yes Met first 4 criteria: No Yes Met all available criteria: No Yes Chose AS: No Yes
No. Pts With Complete Data (%)
No. Pts With Incomplete Data (%)
Chi-Square p Value
185 (10) 580 (31) 747 (40) 374 (20)
460 (12) 1,305 (35) 1,342 (36) 576 (16)
⬍0.01
490 (26) 1,396 (74)
669 (18) 3,014 (82)
⬍0.01
808 (43) 1,078 (57)
1,147 (31) 2,536 (69)
⬍0.01
952 (50) 934 (50)
1,430 (39) 2,253 (61)
⬍0.01
557 (30) 1,329 (70)
696 (19) 2,987 (81)
⬍0.01
1,173 (62) 713 (38)
Not available Not available
1,360 (72) 526 (28)
2,255 (61) 1,428 (39)
⬍0.01
1,576 (84) 310 (16)
2,255 (61) 1,428 (39)
⬍0.01
1,790 (95) 96 (5)
3,473 (94) 210 (6)
0.34
[SD 8.94] years, t test p ⬍0.01) and higher risk, the percentage who chose surveillance was the same. Thus, the subset of 1,886 patients is a fair although imperfect representation of CaPSURE patients with localized disease. By studying a slightly higher risk subset of the CaPSURE database we would expect to underestimate the percentage of patients in the very low risk group. Multivariable logistic regression analysis identified age and very low risk criteria as independent predictors of active surveillance among all patients in the cohort (table 4). The odds of surveillance in patients 74 years or older were more than 7 times higher than in those younger than 74 years (OR 7.3, 95% CI 4.4 –12.2). Patients who met all 5 low risk criteria had more than 3 times higher odds of choosing surveillance compared to higher risk patients (OR 3.4, 95% CI 1.9 – 6.0). Education was not independently associated with choosing surveillance. This multivariate analysis was repeated for the excluded group of 3,683 patients and results were similar. The odds of choosing surveillance were almost 3 times higher in patients who met all 4 available low risk criteria (OR 2.7, 95% CI 1.9 –3.8). DISCUSSION
TABLE 2. Primary treatment of patients by risk category No. (%)
RP* RT ADT AS
Very Low Risk (310)
Low Risk (411)
Intermediate Risk (373)
High Risk (792)
188 (61) 71 (23) 23 (7) 28 (9)
226 (55) 120 (29) 36 (9) 29 (7)
185 (50) 117 (31) 59 (16) 12 (3)
313 (40) 254 (32) 198 (25) 27 (3)
* Chi-square p ⬍0.01.
The challenge in managing localized prostate cancer is to identify patients with potentially aggressive disease and treat them aggressively while sparing those with indolent disease from over treatment. The over treatment burden on men with indolent prostate cancer may be a large public health problem because of its high prevalence. Incidental prostate cancer is found in 23% to 45% of men undergoing cystoprostatectomy for bladder cancer9 –11 and at least 35% of American men at autopsy.12,13 Many of these are low volume, low grade, organ confined cancers. In radical
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TABLE 4. Multivariate logistic regression of initial surveillance covarying for age at diagnosis, education and risk group Odds Ratio Estimates Effect
Active Surveillance (72)
Other Treatment (1,349)
Odds Ratio
95% CI
Age at diagnosis older than 74 yrs Age at diagnosis 74 yrs or younger (reference group) Education high school or less Education some or more college (reference group) Very low risk group (met all 5 criteria) Higher risk groups (reference group)
41 31 35 37 21 51
244 1,105 587 762 215 1,134
7.30 1.00 0.86 1.00 3.40 1.00
4.39–12.21
prostatectomy series up to 29% of patients have small, low grade tumors, suggesting that intensified screening efforts may have led to over detection and over treatment of indolent cancers.3 Radical prostatectomy has been shown to improve survival compared to watchful waiting in a mixed population of patients with prostate cancer.14 Furthermore, competing risk analyses demonstrate that up to 30% of patients die of prostate cancer when treated with observation and conservative therapy alone.15 Taken together these studies suggest that definitive therapy benefits some patients but perhaps not all. Bill-Axelson14 and Albertsen15 et al show that definitive therapy is most likely to benefit younger patients. Thus, older patients and those with significant medical comorbidities may be suited to surveillance. Patients in the lowest risk strata may also be candidates for surveillance. In the study that defined the inclusion criteria we have used here, Epstein et al demonstrated that 79% of men meeting these criteria had indolent tumors at radical prostatectomy.2 A recent cohort study based on these criteria demonstrated that a period of initial surveillance did not adversely affect pathological outcomes in patients going on to delayed surgery.16 The 38 patients who underwent surgery after a mean of 26.5 months were compared with 150 matched patients undergoing immediate surgery (within 3 months). There was no difference in the likelihood of noncurable disease at final pathological evaluation (RR 1.08, 95% CI 0.55–2.12, p ⫽ 0.82). Our aim in this study was to estimate the percentage of men who may eligible for surveillance by applying these surveillance criteria to the CaPSURE database. A handful of investigators have made similar efforts to quantify the population eligible for surveillance. A study from Europe evaluated 1,014 men diagnosed with prostate cancer in the screening arm of the European Randomized study of Screening for Prostate Cancer in The Netherlands between 1993 and 1999.17 Using more inclusive criteria than we used (PSA 15 ng/ml or less and PSA density 0.2 ng/ml/cc or less) the authors found that 28.9% of men were low risk and 21.8% of low risk patients chose surveillance. A study from the United States evaluated nearly 100,000 men with prostate cancer from the SEER registries, most of whom were diagnosed between 2000 and 2002.18 The investigators defined low risk disease as biopsy Gleason sum 2– 4 for men of any age and biopsy Gleason sum 2 to 7 for men older than 70 years without regard to percentage of cores positive, PSA, PSA density or clinical stage. They found that 34.7% met their criteria for low risk disease. Approximately 45% of these men chose hormonal therapy or surveillance, which are grouped together in SEER. In the present study 16.4% of patients with clinically localized prostate cancer diagnosed between 1999 and 2004
0.53–1.41 1.91–6.04
met criteria for very low risk disease. This is, as expected, lower than the approximately 30% of patients meeting broader definitions of low risk disease in prior studies. We chose to look at the very low risk group because the criteria are predictive of indolent disease, and there is greater consensus and justification for observing these men. Only 9% of patients in the very low risk category and even fewer patients in higher risk strata chose surveillance. This is lower than previously reported and may reflect differences in practice patterns over time or between Europe and the United States. It also may be due to the lumping of patients on hormonal therapy with those on surveillance in some studies and/or the inclusion of older men with more aggressive disease. However, the fact that only 9% of men considered eligible for surveillance actually elect to be observed suggests that AS may be underused in this population. We found that very low risk disease was associated with higher levels of education, higher income, private insurance and younger age. These findings parallel previous findings in the CaPSURE database and other publications, and may reflect disparities in access to care.19,20 However, the only demographic predictor of surveillance was older age, which makes sense since older men are least likely to benefit from treatment.14 Other predictors of surveillance were clinical parameters indicating low risk disease. Because CaPSURE tracks patterns from community and academic sites around the United States, it provides a gauge of national practice patterns. Clearly it is has limitations (sites are not randomly selected, it is not a comprehensive registry of all patients with prostate cancer in the country, not all patients invited to participate do so and the patients refusing may not match our cohort in risk or likelihood of choosing surveillance). The subset of CaPSURE patients we analyzed was higher risk than those with incomplete data, suggesting that our estimate of the percentage of men eligible for surveillance may be low. On the other hand the inability to use the complete Epstein criteria may have resulted in an overestimate. In addition, we recognize that the absence of treatment is not the same as active surveillance (characterized by frequent examination and PSA as well as repeat biopsy every 18 to 24 months with a plan to intervene for disease progression). Lastly, the Epstein criteria, while providing a point of departure based on clinical disease characteristics, do not take into account other significant factors in the decision to observe prostate cancer such as age (which was significant in our analysis), comorbidities and life expectancy. Despite these caveats this analysis of the CaPSURE database provides an additional data point in the effort to quantify the percentage of American men with newly diagnosed localized prostate cancer who are eligible for active surveillance. Compared to other studies our study has the
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PROSTATE CANCER SURVEILLANCE
advantages of addressing a recent American cohort, having nearly all of the Epstein criteria in use, and distinguishing between surveillance and hormonal therapy.
11.
12.
CONCLUSIONS Of the men in our cohort 16.4% met the criteria for very low risk disease. Only 9% of patients eligible for surveillance by these criteria actually chose to be observed. These findings raise questions about how patients make treatment decisions and the role of the physician in this process. In addition, our study helps define the extent to which surveillance may be underused in the management of very low risk prostate cancer.
13.
14.
15.
Abbreviations and Acronyms ADT ⫽ androgen deprivation therapy AS ⫽ active surveillance CaPSURE ⫽ Cancer of the Prostate Strategic Urologic Research Endeavor PSA ⫽ prostate specific antigen RP ⫽ radical prostatectomy RT ⫽ radiation therapy SEER ⫽ Surveillance, Epidemiology, and End Results
REFERENCES 1. 2.
3.
4. 5.
6.
7.
8.
9.
10.
Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43. Epstein JI, Walsh PC, Carmichael M and Brendler CB: Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994; 271: 368. Carter HB, Sauvageot J, Walsh PC and Epstein JI: Prospective evaluation of men with stage T1C adenocarcinoma of the prostate. J Urol 1997; 157: 2206. Klotz L: Active surveillance for prostate cancer: for whom? J Clin Oncol 2005; 23: 8165. Carter HB, Walsh PC, Landis P and Epstein JI: Expectant management of nonpalpable prostate cancer with curative intent: preliminary results. J Urol 2002; 167: 1231. Lubeck DP, Litwin MS, Henning JM, Stier DM, Mazonson P, Fisk R et al: The CaPSURE database: a methodology for clinical practice and research in prostate cancer. CaPSURE Research Panel. Cancer of the Prostate Strategic Urologic Research Endeavor. Urology 1996; 48: 773. D’Amico AV, Whittington R, Malkowicz SB, Schultz D, Blank K, Broderick GA et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280: 969. Greene KL, Cowan JE, Cooperberg MR, Meng MV, DuChane J and Carroll PR: Who is the average patient presenting with prostate cancer? Urology 2005; 66: 76. Revelo MP, Cookson MS, Chang SS, Shook MF, Smith JA Jr and Shappell SB: Incidence and location of prostate and urothelial carcinoma in prostates from cystoprostatectomies: implications for possible apical sparing surgery. J Urol 2004; 171: 646. Moutzouris G, Barbatis C, Plastiras D, Mertziotis N, Katsifotis C, Presvelos V et al: Incidence and histological findings of unsuspected prostatic adenocarcinoma in radical cystoprostatectomy for transitional cell carcinoma of the bladder. Scand J Urol Nephrol 1999; 33: 27.
16.
17.
18.
19.
20.
Abbas F, Hochberg D, Civantos F and Soloway M: Incidental prostatic adenocarcinoma in patients undergoing radical cystoprostatectomy for bladder cancer. Eur Urol 1996; 30: 322. Sakr WA, Grignon DJ, Crissman JD, Heilbrun LK, Cassin BJ, Pontes JJ 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. Guileyardo JM, Johnson WD, Welsh RA, Akazaki K and Correa P: Prevalence of latent prostate carcinoma in two U.S. populations. J Natl Cancer Inst 1980; 65: 311. Bill-Axelson A, Holmberg L, Ruutu M, Haggman M, Andersson SO, Bratell S et al: Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005; 352: 1977. Albertsen PC, Hanley JA and Fine J: 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005; 293: 2095. Warlick C, Trock BJ, Landis P, Epstein JI and Carter HB: Delayed versus immediate surgical intervention and prostate cancer outcome. J Natl Cancer Inst 2006; 98: 355. Roemeling S, Roobol MJ, Postma R, Gosselaar C, van der Kwast TH, Bangma CH et al: Management and survival of screen-detected prostate cancer patients who might have been suitable for active surveillance. Eur Urol 2006; 50: 475. Miller DC, Gruber SB, Hollenbeck BK, Montie JE and Wei JT: Incidence of initial local therapy among men with lowerrisk prostate cancer in the United States. J Natl Cancer Inst 2006; 98: 1134. Cooperberg MR, Lubeck DP, Meng MV, Mehta SS and Carroll PR: The changing face of low-risk prostate cancer: trends in clinical presentation and primary management. J Clin Oncol 2004; 22: 2141. Harlan LC, Potosky A, Gilliland FD, Hoffman R, Albertsen PC, Hamilton AS et al: Factors associated with initial therapy for clinically localized prostate cancer: prostate cancer outcomes study. J Natl Cancer Inst 2001; 93: 1864.
EDITORIAL COMMENT The majority of patients with prostate cancer face a minimal risk of dying of the disease.1 Those with favorable clinical parameters such as those reported in this series may have a risk of prostate cancer death approaching zero and there is little evidence that aggressive treatment changes this status. Nevertheless, these authors observe a widespread therapeutic disconnect and provide further evidence that the majority undergo treatment that offers little potential benefit. Why does this clear over treatment occur? Although it is tempting to blame greed, ignorance or fear of medicolegal risk, the fact remains that there is no consensus regarding the definition of low risk or the even more meaningless category clinically insignificant. Even Epstein’s criteria as defined in this report (PSA less than 10 ng/ml, clinical T1 or T2a disease, PSA density less than 0.15, fewer than 1 of 3 cores positive and absence of Gleason pattern 4 or 5) are misunderstood and often vary from his own description. Unlike the present report listing Epstein himself currently uses 5 slightly different factors: 1) 2 or fewer positive cores, 2) no core with greater than 50% cancer, 3) no Gleason pattern 4 or 5, 4) PSA density less than 0.15 and 5) nonpalpable on digital rectal examination.2
PROSTATE CANCER SURVEILLANCE Two positive cores in a sextant biopsy suggest a much more significant tumor burden than would 2 cores on extended or saturation biopsy, so the use of 1 of 3 biopsy cores seems more reasonable, albeit unvalidated. The present report justifiably allows T2a and considers total PSA, but omits maximum percentage involvement of any core. In addition, many definitions of clinically insignificant disease use organ confined status, which seems counterintuitive since this requires advanced disease to preclude insignificance, meaning that the moment when a low grade tumor progresses across the prostatic capsule, it goes from clinically insignificant to locally advanced without an intermediate point at which treatment might have been appropriate. Thus, although all of these parameters appear consistent with very low risk disease, the lack of consensus is troubling to the physician and patient trying to determine the best approach. Until consensus is achieved it is likely that many—if not most—men will be over treated for prostate cancer. J. Stephen Jones and Eric A. Klein Glickman Urological and Kidney Institute Cleveland Clinic Foundation Cleveland, Ohio 1.
2.
Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg L et al: SEER Cancer Statistics Review, 1975-2000, National Cancer Institute, 2003. Available at http://seer.cancer.gov./ csr/1975_2000. Dr. Jonathan Epstein, personal communication, March 2007.
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believe that the sub-population we identified represents a very low risk group within our cohort and that patients meeting these criteria ought to be candidates for surveillance. In fact the AUA guidelines obligate urologists to consider surveillance for any patient meeting the much more inclusive D’Amico criteria for low risk disease.1,2 There is an inherent limitation in any risk stratification system and difficulty in defining a cancer that does not require treatment. The clinical criteria that we use, even the most fastidiously validated models, are merely surrogates for the biological behavior of a particular tumor. The result is that each risk stratum will contain some patients whose cancer will behave more or less aggressively than predicted. Although models such as the Epstein model help us select the correct therapy for a particular patient, we found that the majority of patients with very low risk clinical disease characteristics still select immediate treatment. Improving the predictive ability of our models and formulating evidence-based definitions of clinically insignificant, significant and treatable, and significant but already too advanced to be cured are avenues toward bridging this therapeutic disconnect. Other avenues may involve studying patient preferences, doctor-patient interactions and decision analysis tools that help match patient preferences and the clinical scenario with a management strategy.3 1.
REPLY BY AUTHORS
2.
We agree that the lack of consensus on clinical characteristics that predict indolent disease makes counseling patients with low risk prostate cancer difficult. We did make adjustments to the original Epstein criteria to accommodate the information in our database. While we acknowledge that our criteria vary slightly from the original validated criteria, we
3.
D’Amico AV, Moul J, Carroll PR, Sun L, Lubeck D and Chen MH: Cancer specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003; 21: 2163. Thompson I, Thrasher JB, Aus G, Burnett AL, Canby-Hagiino ED, Cookson MS et al: Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106. Sommers BD, Beard CJ, D’Amico AV, Dahl D, Kaplan I, Richie JP et al: Decision analysis using individual patient preferences to determine optimal treatment for localized prostate cancer. Cancer 2007; 110: 2210.