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Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study
EUF-172; No. of Pages 7 EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Prostate Cancer
Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study Marco Moschini a,b, Nicola Fossati a,c, Akshay Sood d, Justin K. Lee c, Jesse Sammon d, Maxine Sun e, Dan Pucheril d, Deepansh Dalela d, Francesco Montorsi a, R. Jeffrey Karnes b, Alberto Briganti a, Quoc-Dien Trinh f, Mani Menon d, Firas Abdollah d,* a
Department of Urology, Vita Salute San Raffaele University, Milan, Italy;
b
Department of Urology, Mayo Clinic, Rochester, MN, USA; c Department of
Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; d Vattikuti Urology Institute (VUI) and VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, Detroit, MI, USA; e Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada; f Division of Urology and Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA, USA
Article info
Abstract
Article history: Accepted June 2, 2016
Background: Active surveillance (AS) is increasingly recognized as a recommended treatment option for prostate cancer (PCa) patients with clinically localized, low-risk disease; however, previous studies suggested that its utilization is uncommon in the United States. Objective: We evaluated the nationwide utilization rate of AS in the contemporary era. Design, setting, and participants: We relied on the 2010–2011 Surveillance Epidemiology and End Results (SEER) database using all 18 SEER-based registries. We identified 9049 patients that fulfilled the University of California, San Francisco AS criteria (prostate-specific antigen level <10 ng/ml, clinical T stage 2a, Gleason score 6 [no pattern 4 or 5], and percentage of positive biopsy cores <33%). Outcome measurements and statistical analysis: Logistic regression analysis tested the relationship between receiving local treatment and all available predictors. Results and limitations: Only 32% of AS candidates did not receive any active local treatment. This proportion varied widely among the SEER-based registries, ranging from 13% to 49% (p < 0.001). In multivariable analyses, clinical stage T2a (odds ratio [OR]: 1.23; p = 0.04) and percentage of positive cores (OR: 1.10 for each 2% increase; p < 0.001) were associated with a higher probability of receiving local treatment. Conversely, older age (OR: 0.89 for each 2-yr increase; p < 0.001), not being married (OR: 0.64; p < 0.001), and uninsured status (OR: 0.55; p = 0.008) were associated with a lower probability of receiving active local treatment. The study is limited by the fact that SEER does not distinguish among patients undergoing observation, AS, watchful waiting, or initial hormonal therapy. Conclusions: In the United States, a considerable proportion of patients suitable for AS receive local treatment for PCa. Proportions differ significantly among SEER registries. Patient summary: Having more extensive and palpable disease, having medical insurance, being married, and being younger are associated with an increased probability of receiving local treatment for low-risk prostate cancer. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Prostate cancer Active surveillance SEER UCSF criteria Racial disparities
* Corresponding author. Vattikuti Urology Institute (VUI) and VUI Center for Outcomes Research Analytics and Evaluation (VCORE), Henry Ford Health System, 2799W Grand Blvd., Detroit, MI 482022689, USA. Tel. +1 313 916 9923. E-mail addresses: fi[email protected], [email protected] (F. Abdollah). http://dx.doi.org/10.1016/j.euf.2016.06.001 2405-4569/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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1.
Introduction
dividing the number of positive cores by the total number of cores. Primary treatment options consisted of radical prostatectomy (RP),
The introduction of prostate-specific antigen (PSA) in clinical practice has permanently changed the face of prostate cancer (PCa) [1–3]. Indeed, 24-42% of contemporary PCa patients are diagnosed with low-risk tumors that are unlikely to compromise patient survival, even if left untreated [4–6]. Given this premise, and considering the significant morbidity associated with active local treatment [7], several investigators have proposed active surveillance (AS) as a treatment option for men with low-risk PCa [8–10]. Despite the appealing aspects of AS as an initial treatment option, its use appears to be limited in United States [8,11–13]. Reasons for this might include cancer severity, patient preference, and physician-related factors [8,14,15]. In its latest version (years 2010–2011), the Surveillance Epidemiology and End Results (SEER) database released data for the first time regarding biopsy Gleason score, total number of cores at prostate biopsy, and number of positive cores at prostate biopsy. This information allowed, for the first time, accurate identification of AS candidates at a North American population-based level. We evaluated utilization of active local treatment for AS candidates, using the SEER data. Moreover, we tried to identify the clinical and demographic variables associated with the use of active treatment for AS candidates. 2.
Materials and methods
2.1.
Study population and data source
We relied on the 2010–2011 SEER database, which includes 18 registries. The SEER database covers approximately 30% of the US population and records basic information on demographics, tumor site, histology, stage, grade, and treatments performed. Participants with histologically confirmed prostatic adenocarcinoma (International Classification of Diseases for Oncology code 61.9, histologic code 8140) were identified (n = 462 831). We included only patients suitable for AS according to the University of California, San Francisco (UCSF) criteria (n = 10 894): PSA level <10 ng/ml, clinical T stage 2a, Gleason score 6 (no pattern 4 or 5), and percentage of positive biopsy cores <33% [16]. Participants with unknown information regarding marital status (n = 1269), race (n = 223), or insurance status (n = 353) were excluded. These selection criteria yielded 9049 evaluable patients. The SEER program registries routinely collect data on patient demographics, primary tumor site, tumor morphology, tumor stage at diagnosis, first course of treatment, and follow-up for vital status. The SEER program is the only comprehensive source of population-based information in the United States that includes stage of cancer at the time of diagnosis and patient survival data [17].
2.2.
Variable definition and outcomes
All patients included in this study had complete clinical and pathologic data consisting of age at diagnosis, years at diagnosis, race (white, black, Hispanic, other), marital status (married, not married), annual family income, insurance status (insured, Medicaid coverage, uninsured), PSA (in nanograms per milliliter), clinical T stage (cT1 vs cT2a), biopsy Gleason score (2–6), year of diagnosis (2010–2011), and SEER registry. The percentage of positive cores at prostate biopsy was calculated by
external-beam radiotherapy (EBRT), brachytherapy, or observation. The treatment option was identified using the ‘‘site-specific surgery,’’ ‘‘radiation therapy,’’ and ‘‘radiation sequence with surgery’’ fields, as previously reported [18,19]. Our primary outcome was to identify the rate of active local treatment in AS candidates and the clinical and demographical characteristics associated with such a practice.
2.3.
Statistical analyses
Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges (IQRs) were reported for continuously coded variables. Chi-square and Mann-Whitney tests were used to compare the statistical significance of differences in proportions and medians, respectively. Univariate and multivariate logistic regression analysis tested the relationship between receiving local treatment and all available clinical, pathologic, and socioeconomic predictors. In regression analysis, the state with the biggest population (ie, California) was used as a reference category. Statistical analyses were performed using the R statistical package (R Foundation for Statistical Computing, Vienna, Austria) and SPSS v. 20.0 (IBM Corp., Armonk, NY, USA), considering statistical significance at p < 0.05.
3.
Results
3.1.
Baseline characteristics
Clinical and socioeconomic demographics of the cohort, stratified by treatment type (active local treatment vs no active local treatment) are reported in Table 1. Among AS candidates, 3300 patients (36.5%) received RP, 1281 (14.1%) received brachytherapy, and 1549 (17.1%) received EBRT, whereas 2919 (32.3%) did not receive any active local treatment. Median age was 63 yr (IQR: 58–68 yr), and median PSA value was 5.3 ng/ml (IQR: 4.6–6.7 ng/ml). Clinical stage was cT1c in 8459 patients (93%) and cT2a in 590 patients (7%). Median percentage of positive cores was 14% (IQR: 8–18%). When patients were stratified according to age category (Fig. 1), the highest utilization rate of active local treatment was observed in patients aged 50 yr (79.6%), whereas the lowest rate was observed in patients aged 80 yr (37.0%). Likewise, when patients were stratified according to SEER registry (Fig. 2), the highest utilization rate of active local treatment was observed in Hawaii (97.3%), whereas the lowest rate was observed in San Francisco (51.4%) (Fig. 2). Patients that underwent local treatment were younger (median: 62 vs 65 yr), were more frequently married (81% vs 74%), had lower family income (median: $59 000 vs $61 000), were more frequently covered by insurance (96% vs 95%), had a lower PSA value (median: 5.2 vs 5.4 ng/ml), had a higher clinical stage (cT2a: 6.9% vs 5.7%), and had a higher percentage of positive cores (median: 17% vs 10%) in comparison to their counterparts that received no active local treatment (all p 0.03).
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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Table 1 – Descriptive characteristics of 9049 prostate cancer patients diagnosed within the Surveillance Epidemiology and End Results database between 2010 and 2011 and deemed suitable for active surveillance by University of California, San Francisco active surveillance criteria Variables
Age, yr Mean Median (IQR) Type of treatment, n (%) Radical prostatectomy Brachitherapy EBRT No active local treatment Race, n (%) White Black Hispanic Other Marital status, n (%) Married Not married Annual family income, thousands, $ Mean Median (IQR) Insurance status, n (%) Insured Medicaid coverage Uninsured PSA, ng/ml Mean Median (IQR) Clinical stage, n (%) T1 T2a Biopsy Gleason score 2–6 Percentage of positive cores, % Mean Median (IQR) Year of diagnosis, n (%) 2010 2011 SEER registries, n (%) California New Jersey Los Angeles Greater Georgia Detroit Seattle Louisiana San Francisco Kentucky Connecticut Iowa Atlanta Utah San Jose New Mexico Hawaii Rural Georgia Alaska Natives
Overall population (n = 9049; 100%)
No active local treatment (n = 2919; 32%)
Active local treatment (n = 6130; 68%)
p value
<0.0001 63 63 (58–68)
65 65 (60–70)
62 62 (57–67)
3300 1281 1549 2919
– – – 2919 (32.3)
3300 (36.5) 1281 (14.1) 1549 (17.1) –
6603 (73) 1207 (13) 787 (9) 452 (5)
2115 (72) 380 (13) 271 (9.3) 153 (5.2)
4488 (73) 827 (13) 516 (8.4) 299 (4.9)
7116 (79) 1933 (21)
2151 (74) 768 (26)
4965 (81) 1165 (19)
60 58 (49–71)
61 60 (52–72)
59 58 (48–69)
8694 (96) 266 (3) 89 (1)
2783 (95) 99 (3.4) 37 (1.3)
5911 (96) 167 (2.7) 52 (0.8)
5.4 5.3 (4.3–6.7)
5.6 5.4 (4.4–6.9)
5.4 5.2 (4.2–6.6)
8459 (93) 590 (7)
2753 (94) 166 (5.7)
5706 (93) 424 (6.9)
9049 (100)
2919 (100)
6130 (100)
15 14 (8–18)
13 10 (8–17)
15 17 (8–20)
4676 (52) 4373 (48)
1350 (46) 1569 (54)
3326 (54) 2804 (46)
2197 (24.3) 680 (7.5) 559 (6.2) 705 (7.8) 647 (7.1) 495 (5.5) 474 (5.2) 576 (6.4) 561 (6.2) 492 (5.4) 228 (2.5) 604 (3.4) 268 (3.0) 514 (5.7) 216 (2.4) 110 (1.2) 18 (0.2) 5 (0.1)
768 (26.3) 156 (5.3) 213 (7.3) 151 (5.2) 180 (6.2) 186 (6.4) 151 (5.2) 280 (9.6) 108 (3.7) 190 (6.5) 52 (1.8) 82 (2.8) 81 (2.8) 212 (7.3) 91 (3.1) 14 (0.5) 3 (0.1) 0 (0.0)
1429 (23.3) 524 (8.5) 346 (5.6) 554 (9.0) 467 (7.6) 309 (5.0) 323 (5.3) 296 (4.8) 453 (7.4) 302 (4.9) 176 (2.9) 222 (3.6) 187 (3.1) 302 (4.9) 125 (2.0) 96 (1.6) 15 (0.2) 4 (0.1)
– (36.5) (14.1) (17.1) (32.3)
0.4
<0.0001
<0.0001
0.034
<0.0001
0.027
– <0.0001
<0.0001
<0.001
EBRT = external-beam radiotherapy; IQR = interquartile range; PSA = prostate-specific antigen; SEER = Surveillance Epidemiology and End Results.
3.2.
Logistic regression analyses
Logistic regression analyses testing the relationship between available covariates and receipt of active local treatment in AS candidates were reported in Table 2.
In multivariable analyses, stage cT2a (odds ratio [OR]: 1.23; 95% confidence interval [CI], 1.01–1.50; p = 0.04) and higher percentage of positive cores (per 2%; OR: 1.10; 95% CI, 1.08–1.11; p < 0.001) were independent predictors of a higher utilization rate of active local treatment. Conversely,
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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4.
Fig. 1 – Utilization rates of active local treatment in 9049 prostate cancer patients deemed suitable for active surveillance, diagnosed between 2010 and 2011, within the Surveillance Epidemiology and End Results Program (SEER) database. Men were stratified according to age at diagnosis.
being older (per 2 yr; OR: 0.89; 95% CI, 0.88–0.91; p < 0.001), being not married (OR: 0.64; 95% CI, 0.57–0.72; p < 0.001), and being uninsured (OR: 0.55; 95% CI, 0.35–0.85; p = 0.008) were independent predictors of a lower utilization rate of active local treatment. Finally, race, annual family income, and PSA value at diagnosis were not associated with the utilization of local active treatment in AS candidates.
Discussion
Previous studies suggested a relatively uncommon but increasing utilization of AS among PCa patients diagnosed with low-risk PCa [8,20]. In the present study, we focused on the newest release of the SEER program, which, for the first time, provided complete data regarding biopsy Gleason score, total number of biopsy cores, and number of positive biopsy cores. This allowed us to accurately identify patients deemed suitable for AS by UCSF criteria at a nationwide level. Moreover, we evaluated the utilization of active local treatment for AS candidates and factors associated with this practice. We made several findings. First, in our cohort of 9049 PCa patients deemed suitable for AS by the UCSF criteria [16], almost 68% received active local treatment. This implies that in United States, there is significant underutilization of AS with corresponding significant overtreatment of ‘‘indolent’’ PCa. Inevitably, such trends might translate into higher morbidity and higher costs for patients due to unnecessary active local treatments. In this context, the underutilization of AS can be considered an indicator of poor quality of care. Consequently, this finding should be seriously considered by surgeons, radiotherapists, and policy makers to improve the quality of PCa management across the nation. Although we were unable to identify the cause of AS underutilization in our cohort, previous reports attributed this practice to several factors, such as financial factors [8], lack of information about
Fig. 2 – Utilization rates of active local treatment in 9049 prostate cancer patients deemed suitable for active surveillance, diagnosed between 2010 and 2011, within the Surveillance Epidemiology and End Results Program (SEER) database. Men were stratified according to SEER registries.
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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Table 2 – Univariable and multivariable logistic regression analysis predicting active local treatment of the prostate in 9049 patients deemed suitable for active surveillance by University of California, San Francisco active surveillance criteria Univariable OR (95% CI) Age (per 2 yr) Race White Black Hispanic Other Marital status Married Not married Annual family income (per $10 000) Insurance status Insured Medicaid Uninsured PSA (per 2 ng/ml) Clinical stage T1 T2a Percentage of positive cores (per 2%) SEER registries California New Jersey Los Angeles Greater Georgia Detroit Seattle Louisiana San Francisco Kentucky Connecticut Iowa Atlanta Utah San Jose New Mexico Hawaii Rural Georgia Alaska Natives
Multivariable p value
OR (95% CI)
p value
0.91 (0.90-0.92)
<0.001
0.89 (0.88-0.91)
<0.001
1.00 1.03 (0.90–1.17) 0.90 (0.77–.1.05) 0.92 (0.75–1.13)
Ref 0.7 0.2 0.4
1.0 0.88 (0.76–1.02) 1.14 (0.96–1.35) 1.08 (0.86–1.36)
Ref 0.08 0.1 0.5
1.00 0.66 (0.59–0.73)
Ref <0.001
1.00 0.64 (0.57–0.72)
Ref <0.001
0.91 (0.88–0.93)
<0.001
0.98 (0.94–1.03)
0.5
1.00 0.79 (0.62–1.02) 0.66 (0.43–1.01) 0.95 (0.93–0.97)
Ref 0.07 0.06 <0.001
1.00 0.92 (0.70–1.21) 0.55 (0.35–0.85) 1.01 (0.96–1.06)
Ref 0.5 0.008 0.7
1.00 1.23 (1.02–1.48)
Ref 0.03
1.00 1.23 (1.01–1.50)
Ref 0.04
1.09 (1.07–1.10)
<0.001
1.10 (1.08–1.11)
<0.001
1.00 1.80 0.87 1.97 1.39 0.89 1.15 0.57 2.25 0.85 1.82 1.45 1.24 0.77 0.74 3.68 2.69 2.15
Ref <0.001 0.2 <0.001 0.001 0.3 0.2 <0.001 <0.001 0.1 <0.001 0.006 0.1 0.008 0.04 <0.001 0.1 0.5
1.00 1.98 0.83 2.14 1.50 0.84 1.24 0.58 2.36 0.87 1.89 1.53 1.19 0.78 0.72 3.90 3.72 2.30
Ref <0.001 0.07 <0.001 <0.001 0.1 0.07 <0.001 <0.001 0.2 <0.001 0.003 0.2 0.03 0.04 <0.001 0.04 0.5
(1.48–2.20) (0.72–1.06) (1.61–2.41) (1.15–1.69) (0.73–1.09) (0.93–1.42) (0.47–0.68) (1.80–2.83) (0.70–1.04) (1.32–2.51) (1.11–1.90) (0.94–1.63) (0.63–0.93) (0.56–0.98) (2.09–6.50) (0.78–9.31) (0.24–19.27)
(1.59–2.46) (0.68–1.01) (1.72–2.66) (1.22–1.84) (0.68–1.04) (0.98–1.56) (0.47–0.72) (1.84–3.02) (0.70–1.08) (1.35–2.65) (1.16–2.03) (0.90–1.58) (0.62–0.98) (0.53–0.98) (2.15–7.07) (1.03–13.38) (0.24–22.03)
CI = confidence interval; OR = odds ratio; PSA = prostate specific antigen; Ref = reference; SEER = Surveillance Epidemiology and End Results. Data were derived from men diagnosed with prostate cancer within the SEER database between 2010 and 2011.
treatments side effects [21], overestimated benefit of definitive therapy on survival [22], physician recommendations [21,23], and quality of the physician–patient relationship [24]. Second, despite the fact that the utilization rate of AS in contemporary patients appears to be suboptimal, our findings indicate an increasing trend in the utilization of AS over the years in United States. Third, based on geographic region (Fig. 2), there were substantial differences in the utilization rate of active local treatment in AS candidates. This implies that reports based on certain geographic areas and/or certain practices are not necessarily representative of the general practice in United States. In a recent study, for example, Womble et al [11] observed that in the state of Michigan, 49% of PCa patients with low-risk tumors were treated with AS. Based on our findings, this rate is not applicable to other states. In this context, our
cohort might be considered more generalizable; however, the SEER data capture only 26% of the US population, and many geographic regions are not included. Nonetheless, the SEER program represents the only comprehensive source of population-based information in the United States that includes stage of cancer at diagnosis and survival data [17]. These registry-based data can be used to compare practices among the different regions with the aim of improving the utilization of AS at a nationwide level. Finally, we found that age, marital status, insurance status, and tumor characteristics were also independent predictors of active local treatment of PCa in AS candidates. These findings are expected and corroborate previous reports [14,15,25–27]. Interestingly, some reports recommended against the use of AS in black patients because of the aggressiveness of PCa in these patients [28,29]. In our report, however, there were no racial differences in the
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX
utilization rate of active treatment in AS candidates. Whether or not such a practice would compromise the survival outcomes of black men has yet to be demonstrated. Our report complements previous literature addressing the utilization of AS [30–32]. Loeb et al [20], for example, analyzed the utilization of AS among men with low- and intermediate-risk PCa diagnosed within Prostate Cancer Database Sweden (PCBaSe). Likewise, Cooperberg et al [8] recorded variation in the utilization of AS over time using the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database. Despite several strengths, the present study is not devoid of limitations. First, the SEER database does not contain information on comorbidities that may represent a selection bias for treatment choice; however, SEER is the only comprehensive population-based database [17] in the United States and represents a very good source for studying current treatment choices for AS candidates. Second, SEER does not distinguish among patients undergoing observation, AS, watchful waiting, or initial hormonal therapy. This is why we had to focus on the utilization rate of active local treatment in AS candidates rather than the utilization rate of AS itself. This implies that our results might somewhat overestimate the true utilization of AS; however, it might be argued that treatment modalities such as mere observation, watchful waiting, and/or initial hormonal therapy are used infrequently in contemporary patients. Third, problems have been uncovered recently with the quality of the PSA values and PSA interpretation variables in SEER data; however, the SEER Web site states that the inaccuracy in PSA values is limited when PSA is analyzed as a categorical variable (as done in our report).
Administrative, technical, or material support: None. Supervision: Karnes, Abdollah, Menon, Montorsi. Other (specify): None. Financial disclosures: Firas Abdollah certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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5.
Conclusions
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Our findings show that the majority of PCa patients deemed suitable for AS are treated with active local treatment in the United States. This might increase the morbidity and costs associated with treating PCa without a significant survival benefit. Our report represents an initial step that aims at raising awareness regarding the magnitude of the problem. It is also noteworthy that there were important differences in AS utilization across SEER registries. Our registry-based findings can be of great value in focusing the efforts of investigators and policy makers, where they are most needed. This should help increase utilization of AS for appropriate candidates across the nation.
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Author contributions: Firas Abdollah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Moschini, Fossati, Sood, Sun. Acquisition of data: Sammon, Sood, Pucheril, Dalela. Analysis and interpretation of data: Moschini, Abdollah, Trinh, Sun. Drafting of the manuscript: Moschini, Abdollah, Fossati, Montorsi.
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Critical revision of the manuscript for important intellectual content:
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Briganti, Montorsi, Menon, Abdollah, Karnes.
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Statistical analysis: Fossati, Abdollah. Obtaining funding: None.
[17] Overview of the SEER program. National Cancer Institute Web site. http://seer.cancer.gov/about/overview.html
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available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus
Prostate Cancer
Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study Marco Moschini a,b, Nicola Fossati a,c, Akshay Sood d, Justin K. Lee c, Jesse Sammon d, Maxine Sun e, Dan Pucheril d, Deepansh Dalela d, Francesco Montorsi a, R. Jeffrey Karnes b, Alberto Briganti a, Quoc-Dien Trinh f, Mani Menon d, Firas Abdollah d,* a
Department of Urology, Vita Salute San Raffaele University, Milan, Italy;
b
Department of Urology, Mayo Clinic, Rochester, MN, USA; c Department of
Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA; d Vattikuti Urology Institute (VUI) and VUI Center for Outcomes Research Analytics and Evaluation, Henry Ford Hospital, Detroit, Detroit, MI, USA; e Cancer Prognostics and Health Outcomes Unit, University of Montreal Health Center, Montreal, Quebec, Canada; f Division of Urology and Center for Surgery and Public Health, Brigham and Women’s Hospital, Boston, MA, USA
Article info
Abstract
Article history: Accepted June 2, 2016
Background: Active surveillance (AS) is increasingly recognized as a recommended treatment option for prostate cancer (PCa) patients with clinically localized, low-risk disease; however, previous studies suggested that its utilization is uncommon in the United States. Objective: We evaluated the nationwide utilization rate of AS in the contemporary era. Design, setting, and participants: We relied on the 2010–2011 Surveillance Epidemiology and End Results (SEER) database using all 18 SEER-based registries. We identified 9049 patients that fulfilled the University of California, San Francisco AS criteria (prostate-specific antigen level <10 ng/ml, clinical T stage 2a, Gleason score 6 [no pattern 4 or 5], and percentage of positive biopsy cores <33%). Outcome measurements and statistical analysis: Logistic regression analysis tested the relationship between receiving local treatment and all available predictors. Results and limitations: Only 32% of AS candidates did not receive any active local treatment. This proportion varied widely among the SEER-based registries, ranging from 13% to 49% (p < 0.001). In multivariable analyses, clinical stage T2a (odds ratio [OR]: 1.23; p = 0.04) and percentage of positive cores (OR: 1.10 for each 2% increase; p < 0.001) were associated with a higher probability of receiving local treatment. Conversely, older age (OR: 0.89 for each 2-yr increase; p < 0.001), not being married (OR: 0.64; p < 0.001), and uninsured status (OR: 0.55; p = 0.008) were associated with a lower probability of receiving active local treatment. The study is limited by the fact that SEER does not distinguish among patients undergoing observation, AS, watchful waiting, or initial hormonal therapy. Conclusions: In the United States, a considerable proportion of patients suitable for AS receive local treatment for PCa. Proportions differ significantly among SEER registries. Patient summary: Having more extensive and palpable disease, having medical insurance, being married, and being younger are associated with an increased probability of receiving local treatment for low-risk prostate cancer. # 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: James Catto Keywords: Prostate cancer Active surveillance SEER UCSF criteria Racial disparities
* Corresponding author. Vattikuti Urology Institute (VUI) and VUI Center for Outcomes Research Analytics and Evaluation (VCORE), Henry Ford Health System, 2799W Grand Blvd., Detroit, MI 482022689, USA. Tel. +1 313 916 9923. E-mail addresses: fi[email protected], [email protected] (F. Abdollah). http://dx.doi.org/10.1016/j.euf.2016.06.001 2405-4569/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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1.
Introduction
dividing the number of positive cores by the total number of cores. Primary treatment options consisted of radical prostatectomy (RP),
The introduction of prostate-specific antigen (PSA) in clinical practice has permanently changed the face of prostate cancer (PCa) [1–3]. Indeed, 24-42% of contemporary PCa patients are diagnosed with low-risk tumors that are unlikely to compromise patient survival, even if left untreated [4–6]. Given this premise, and considering the significant morbidity associated with active local treatment [7], several investigators have proposed active surveillance (AS) as a treatment option for men with low-risk PCa [8–10]. Despite the appealing aspects of AS as an initial treatment option, its use appears to be limited in United States [8,11–13]. Reasons for this might include cancer severity, patient preference, and physician-related factors [8,14,15]. In its latest version (years 2010–2011), the Surveillance Epidemiology and End Results (SEER) database released data for the first time regarding biopsy Gleason score, total number of cores at prostate biopsy, and number of positive cores at prostate biopsy. This information allowed, for the first time, accurate identification of AS candidates at a North American population-based level. We evaluated utilization of active local treatment for AS candidates, using the SEER data. Moreover, we tried to identify the clinical and demographic variables associated with the use of active treatment for AS candidates. 2.
Materials and methods
2.1.
Study population and data source
We relied on the 2010–2011 SEER database, which includes 18 registries. The SEER database covers approximately 30% of the US population and records basic information on demographics, tumor site, histology, stage, grade, and treatments performed. Participants with histologically confirmed prostatic adenocarcinoma (International Classification of Diseases for Oncology code 61.9, histologic code 8140) were identified (n = 462 831). We included only patients suitable for AS according to the University of California, San Francisco (UCSF) criteria (n = 10 894): PSA level <10 ng/ml, clinical T stage 2a, Gleason score 6 (no pattern 4 or 5), and percentage of positive biopsy cores <33% [16]. Participants with unknown information regarding marital status (n = 1269), race (n = 223), or insurance status (n = 353) were excluded. These selection criteria yielded 9049 evaluable patients. The SEER program registries routinely collect data on patient demographics, primary tumor site, tumor morphology, tumor stage at diagnosis, first course of treatment, and follow-up for vital status. The SEER program is the only comprehensive source of population-based information in the United States that includes stage of cancer at the time of diagnosis and patient survival data [17].
2.2.
Variable definition and outcomes
All patients included in this study had complete clinical and pathologic data consisting of age at diagnosis, years at diagnosis, race (white, black, Hispanic, other), marital status (married, not married), annual family income, insurance status (insured, Medicaid coverage, uninsured), PSA (in nanograms per milliliter), clinical T stage (cT1 vs cT2a), biopsy Gleason score (2–6), year of diagnosis (2010–2011), and SEER registry. The percentage of positive cores at prostate biopsy was calculated by
external-beam radiotherapy (EBRT), brachytherapy, or observation. The treatment option was identified using the ‘‘site-specific surgery,’’ ‘‘radiation therapy,’’ and ‘‘radiation sequence with surgery’’ fields, as previously reported [18,19]. Our primary outcome was to identify the rate of active local treatment in AS candidates and the clinical and demographical characteristics associated with such a practice.
2.3.
Statistical analyses
Descriptive statistics of categorical variables focused on frequencies and proportions. Means, medians, and interquartile ranges (IQRs) were reported for continuously coded variables. Chi-square and Mann-Whitney tests were used to compare the statistical significance of differences in proportions and medians, respectively. Univariate and multivariate logistic regression analysis tested the relationship between receiving local treatment and all available clinical, pathologic, and socioeconomic predictors. In regression analysis, the state with the biggest population (ie, California) was used as a reference category. Statistical analyses were performed using the R statistical package (R Foundation for Statistical Computing, Vienna, Austria) and SPSS v. 20.0 (IBM Corp., Armonk, NY, USA), considering statistical significance at p < 0.05.
3.
Results
3.1.
Baseline characteristics
Clinical and socioeconomic demographics of the cohort, stratified by treatment type (active local treatment vs no active local treatment) are reported in Table 1. Among AS candidates, 3300 patients (36.5%) received RP, 1281 (14.1%) received brachytherapy, and 1549 (17.1%) received EBRT, whereas 2919 (32.3%) did not receive any active local treatment. Median age was 63 yr (IQR: 58–68 yr), and median PSA value was 5.3 ng/ml (IQR: 4.6–6.7 ng/ml). Clinical stage was cT1c in 8459 patients (93%) and cT2a in 590 patients (7%). Median percentage of positive cores was 14% (IQR: 8–18%). When patients were stratified according to age category (Fig. 1), the highest utilization rate of active local treatment was observed in patients aged 50 yr (79.6%), whereas the lowest rate was observed in patients aged 80 yr (37.0%). Likewise, when patients were stratified according to SEER registry (Fig. 2), the highest utilization rate of active local treatment was observed in Hawaii (97.3%), whereas the lowest rate was observed in San Francisco (51.4%) (Fig. 2). Patients that underwent local treatment were younger (median: 62 vs 65 yr), were more frequently married (81% vs 74%), had lower family income (median: $59 000 vs $61 000), were more frequently covered by insurance (96% vs 95%), had a lower PSA value (median: 5.2 vs 5.4 ng/ml), had a higher clinical stage (cT2a: 6.9% vs 5.7%), and had a higher percentage of positive cores (median: 17% vs 10%) in comparison to their counterparts that received no active local treatment (all p 0.03).
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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Table 1 – Descriptive characteristics of 9049 prostate cancer patients diagnosed within the Surveillance Epidemiology and End Results database between 2010 and 2011 and deemed suitable for active surveillance by University of California, San Francisco active surveillance criteria Variables
Age, yr Mean Median (IQR) Type of treatment, n (%) Radical prostatectomy Brachitherapy EBRT No active local treatment Race, n (%) White Black Hispanic Other Marital status, n (%) Married Not married Annual family income, thousands, $ Mean Median (IQR) Insurance status, n (%) Insured Medicaid coverage Uninsured PSA, ng/ml Mean Median (IQR) Clinical stage, n (%) T1 T2a Biopsy Gleason score 2–6 Percentage of positive cores, % Mean Median (IQR) Year of diagnosis, n (%) 2010 2011 SEER registries, n (%) California New Jersey Los Angeles Greater Georgia Detroit Seattle Louisiana San Francisco Kentucky Connecticut Iowa Atlanta Utah San Jose New Mexico Hawaii Rural Georgia Alaska Natives
Overall population (n = 9049; 100%)
No active local treatment (n = 2919; 32%)
Active local treatment (n = 6130; 68%)
p value
<0.0001 63 63 (58–68)
65 65 (60–70)
62 62 (57–67)
3300 1281 1549 2919
– – – 2919 (32.3)
3300 (36.5) 1281 (14.1) 1549 (17.1) –
6603 (73) 1207 (13) 787 (9) 452 (5)
2115 (72) 380 (13) 271 (9.3) 153 (5.2)
4488 (73) 827 (13) 516 (8.4) 299 (4.9)
7116 (79) 1933 (21)
2151 (74) 768 (26)
4965 (81) 1165 (19)
60 58 (49–71)
61 60 (52–72)
59 58 (48–69)
8694 (96) 266 (3) 89 (1)
2783 (95) 99 (3.4) 37 (1.3)
5911 (96) 167 (2.7) 52 (0.8)
5.4 5.3 (4.3–6.7)
5.6 5.4 (4.4–6.9)
5.4 5.2 (4.2–6.6)
8459 (93) 590 (7)
2753 (94) 166 (5.7)
5706 (93) 424 (6.9)
9049 (100)
2919 (100)
6130 (100)
15 14 (8–18)
13 10 (8–17)
15 17 (8–20)
4676 (52) 4373 (48)
1350 (46) 1569 (54)
3326 (54) 2804 (46)
2197 (24.3) 680 (7.5) 559 (6.2) 705 (7.8) 647 (7.1) 495 (5.5) 474 (5.2) 576 (6.4) 561 (6.2) 492 (5.4) 228 (2.5) 604 (3.4) 268 (3.0) 514 (5.7) 216 (2.4) 110 (1.2) 18 (0.2) 5 (0.1)
768 (26.3) 156 (5.3) 213 (7.3) 151 (5.2) 180 (6.2) 186 (6.4) 151 (5.2) 280 (9.6) 108 (3.7) 190 (6.5) 52 (1.8) 82 (2.8) 81 (2.8) 212 (7.3) 91 (3.1) 14 (0.5) 3 (0.1) 0 (0.0)
1429 (23.3) 524 (8.5) 346 (5.6) 554 (9.0) 467 (7.6) 309 (5.0) 323 (5.3) 296 (4.8) 453 (7.4) 302 (4.9) 176 (2.9) 222 (3.6) 187 (3.1) 302 (4.9) 125 (2.0) 96 (1.6) 15 (0.2) 4 (0.1)
– (36.5) (14.1) (17.1) (32.3)
0.4
<0.0001
<0.0001
0.034
<0.0001
0.027
– <0.0001
<0.0001
<0.001
EBRT = external-beam radiotherapy; IQR = interquartile range; PSA = prostate-specific antigen; SEER = Surveillance Epidemiology and End Results.
3.2.
Logistic regression analyses
Logistic regression analyses testing the relationship between available covariates and receipt of active local treatment in AS candidates were reported in Table 2.
In multivariable analyses, stage cT2a (odds ratio [OR]: 1.23; 95% confidence interval [CI], 1.01–1.50; p = 0.04) and higher percentage of positive cores (per 2%; OR: 1.10; 95% CI, 1.08–1.11; p < 0.001) were independent predictors of a higher utilization rate of active local treatment. Conversely,
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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4.
Fig. 1 – Utilization rates of active local treatment in 9049 prostate cancer patients deemed suitable for active surveillance, diagnosed between 2010 and 2011, within the Surveillance Epidemiology and End Results Program (SEER) database. Men were stratified according to age at diagnosis.
being older (per 2 yr; OR: 0.89; 95% CI, 0.88–0.91; p < 0.001), being not married (OR: 0.64; 95% CI, 0.57–0.72; p < 0.001), and being uninsured (OR: 0.55; 95% CI, 0.35–0.85; p = 0.008) were independent predictors of a lower utilization rate of active local treatment. Finally, race, annual family income, and PSA value at diagnosis were not associated with the utilization of local active treatment in AS candidates.
Discussion
Previous studies suggested a relatively uncommon but increasing utilization of AS among PCa patients diagnosed with low-risk PCa [8,20]. In the present study, we focused on the newest release of the SEER program, which, for the first time, provided complete data regarding biopsy Gleason score, total number of biopsy cores, and number of positive biopsy cores. This allowed us to accurately identify patients deemed suitable for AS by UCSF criteria at a nationwide level. Moreover, we evaluated the utilization of active local treatment for AS candidates and factors associated with this practice. We made several findings. First, in our cohort of 9049 PCa patients deemed suitable for AS by the UCSF criteria [16], almost 68% received active local treatment. This implies that in United States, there is significant underutilization of AS with corresponding significant overtreatment of ‘‘indolent’’ PCa. Inevitably, such trends might translate into higher morbidity and higher costs for patients due to unnecessary active local treatments. In this context, the underutilization of AS can be considered an indicator of poor quality of care. Consequently, this finding should be seriously considered by surgeons, radiotherapists, and policy makers to improve the quality of PCa management across the nation. Although we were unable to identify the cause of AS underutilization in our cohort, previous reports attributed this practice to several factors, such as financial factors [8], lack of information about
Fig. 2 – Utilization rates of active local treatment in 9049 prostate cancer patients deemed suitable for active surveillance, diagnosed between 2010 and 2011, within the Surveillance Epidemiology and End Results Program (SEER) database. Men were stratified according to SEER registries.
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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Table 2 – Univariable and multivariable logistic regression analysis predicting active local treatment of the prostate in 9049 patients deemed suitable for active surveillance by University of California, San Francisco active surveillance criteria Univariable OR (95% CI) Age (per 2 yr) Race White Black Hispanic Other Marital status Married Not married Annual family income (per $10 000) Insurance status Insured Medicaid Uninsured PSA (per 2 ng/ml) Clinical stage T1 T2a Percentage of positive cores (per 2%) SEER registries California New Jersey Los Angeles Greater Georgia Detroit Seattle Louisiana San Francisco Kentucky Connecticut Iowa Atlanta Utah San Jose New Mexico Hawaii Rural Georgia Alaska Natives
Multivariable p value
OR (95% CI)
p value
0.91 (0.90-0.92)
<0.001
0.89 (0.88-0.91)
<0.001
1.00 1.03 (0.90–1.17) 0.90 (0.77–.1.05) 0.92 (0.75–1.13)
Ref 0.7 0.2 0.4
1.0 0.88 (0.76–1.02) 1.14 (0.96–1.35) 1.08 (0.86–1.36)
Ref 0.08 0.1 0.5
1.00 0.66 (0.59–0.73)
Ref <0.001
1.00 0.64 (0.57–0.72)
Ref <0.001
0.91 (0.88–0.93)
<0.001
0.98 (0.94–1.03)
0.5
1.00 0.79 (0.62–1.02) 0.66 (0.43–1.01) 0.95 (0.93–0.97)
Ref 0.07 0.06 <0.001
1.00 0.92 (0.70–1.21) 0.55 (0.35–0.85) 1.01 (0.96–1.06)
Ref 0.5 0.008 0.7
1.00 1.23 (1.02–1.48)
Ref 0.03
1.00 1.23 (1.01–1.50)
Ref 0.04
1.09 (1.07–1.10)
<0.001
1.10 (1.08–1.11)
<0.001
1.00 1.80 0.87 1.97 1.39 0.89 1.15 0.57 2.25 0.85 1.82 1.45 1.24 0.77 0.74 3.68 2.69 2.15
Ref <0.001 0.2 <0.001 0.001 0.3 0.2 <0.001 <0.001 0.1 <0.001 0.006 0.1 0.008 0.04 <0.001 0.1 0.5
1.00 1.98 0.83 2.14 1.50 0.84 1.24 0.58 2.36 0.87 1.89 1.53 1.19 0.78 0.72 3.90 3.72 2.30
Ref <0.001 0.07 <0.001 <0.001 0.1 0.07 <0.001 <0.001 0.2 <0.001 0.003 0.2 0.03 0.04 <0.001 0.04 0.5
(1.48–2.20) (0.72–1.06) (1.61–2.41) (1.15–1.69) (0.73–1.09) (0.93–1.42) (0.47–0.68) (1.80–2.83) (0.70–1.04) (1.32–2.51) (1.11–1.90) (0.94–1.63) (0.63–0.93) (0.56–0.98) (2.09–6.50) (0.78–9.31) (0.24–19.27)
(1.59–2.46) (0.68–1.01) (1.72–2.66) (1.22–1.84) (0.68–1.04) (0.98–1.56) (0.47–0.72) (1.84–3.02) (0.70–1.08) (1.35–2.65) (1.16–2.03) (0.90–1.58) (0.62–0.98) (0.53–0.98) (2.15–7.07) (1.03–13.38) (0.24–22.03)
CI = confidence interval; OR = odds ratio; PSA = prostate specific antigen; Ref = reference; SEER = Surveillance Epidemiology and End Results. Data were derived from men diagnosed with prostate cancer within the SEER database between 2010 and 2011.
treatments side effects [21], overestimated benefit of definitive therapy on survival [22], physician recommendations [21,23], and quality of the physician–patient relationship [24]. Second, despite the fact that the utilization rate of AS in contemporary patients appears to be suboptimal, our findings indicate an increasing trend in the utilization of AS over the years in United States. Third, based on geographic region (Fig. 2), there were substantial differences in the utilization rate of active local treatment in AS candidates. This implies that reports based on certain geographic areas and/or certain practices are not necessarily representative of the general practice in United States. In a recent study, for example, Womble et al [11] observed that in the state of Michigan, 49% of PCa patients with low-risk tumors were treated with AS. Based on our findings, this rate is not applicable to other states. In this context, our
cohort might be considered more generalizable; however, the SEER data capture only 26% of the US population, and many geographic regions are not included. Nonetheless, the SEER program represents the only comprehensive source of population-based information in the United States that includes stage of cancer at diagnosis and survival data [17]. These registry-based data can be used to compare practices among the different regions with the aim of improving the utilization of AS at a nationwide level. Finally, we found that age, marital status, insurance status, and tumor characteristics were also independent predictors of active local treatment of PCa in AS candidates. These findings are expected and corroborate previous reports [14,15,25–27]. Interestingly, some reports recommended against the use of AS in black patients because of the aggressiveness of PCa in these patients [28,29]. In our report, however, there were no racial differences in the
Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001
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utilization rate of active treatment in AS candidates. Whether or not such a practice would compromise the survival outcomes of black men has yet to be demonstrated. Our report complements previous literature addressing the utilization of AS [30–32]. Loeb et al [20], for example, analyzed the utilization of AS among men with low- and intermediate-risk PCa diagnosed within Prostate Cancer Database Sweden (PCBaSe). Likewise, Cooperberg et al [8] recorded variation in the utilization of AS over time using the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database. Despite several strengths, the present study is not devoid of limitations. First, the SEER database does not contain information on comorbidities that may represent a selection bias for treatment choice; however, SEER is the only comprehensive population-based database [17] in the United States and represents a very good source for studying current treatment choices for AS candidates. Second, SEER does not distinguish among patients undergoing observation, AS, watchful waiting, or initial hormonal therapy. This is why we had to focus on the utilization rate of active local treatment in AS candidates rather than the utilization rate of AS itself. This implies that our results might somewhat overestimate the true utilization of AS; however, it might be argued that treatment modalities such as mere observation, watchful waiting, and/or initial hormonal therapy are used infrequently in contemporary patients. Third, problems have been uncovered recently with the quality of the PSA values and PSA interpretation variables in SEER data; however, the SEER Web site states that the inaccuracy in PSA values is limited when PSA is analyzed as a categorical variable (as done in our report).
Administrative, technical, or material support: None. Supervision: Karnes, Abdollah, Menon, Montorsi. Other (specify): None. Financial disclosures: Firas Abdollah certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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5.
Conclusions
[8] Cooperberg MR, Carroll PR. Trends in management for patients with localized prostate cancer, 1990-2013. JAMA 2015;314:80–2.
Our findings show that the majority of PCa patients deemed suitable for AS are treated with active local treatment in the United States. This might increase the morbidity and costs associated with treating PCa without a significant survival benefit. Our report represents an initial step that aims at raising awareness regarding the magnitude of the problem. It is also noteworthy that there were important differences in AS utilization across SEER registries. Our registry-based findings can be of great value in focusing the efforts of investigators and policy makers, where they are most needed. This should help increase utilization of AS for appropriate candidates across the nation.
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Author contributions: Firas Abdollah had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Moschini, Fossati, Sood, Sun. Acquisition of data: Sammon, Sood, Pucheril, Dalela. Analysis and interpretation of data: Moschini, Abdollah, Trinh, Sun. Drafting of the manuscript: Moschini, Abdollah, Fossati, Montorsi.
Population-based assessment of determining predictors for quality of prostate cancer surveillance. Cancer 2015;121:4150–7. [14] Mitchell JM. Urologists’ use of intensity-modulated radiation therapy for prostate cancer. N Engl J Med 2013;369:1629–37. [15] Hoffman KE, Niu J, Shen Y, et al. Physician variation in management of low-risk prostate cancer: a population-based cohort study. JAMA Intern Med 2014;174:1450–9. [16] Dall’Era MA, Konety BR, Cowan JE, et al. Active surveillance for the
Critical revision of the manuscript for important intellectual content:
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Briganti, Montorsi, Menon, Abdollah, Karnes.
2008;112:2664–70.
Statistical analysis: Fossati, Abdollah. Obtaining funding: None.
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Please cite this article in press as: Moschini M, et al. Contemporary Management of Prostate Cancer Patients Suitable for Active Surveillance: A North American Population-based Study. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.06.001