analysis of pathologic extent of disease for clinically localized prostate cancer after radical...

Analysis of Pathologic Extent of Disease forClinically Localized Prostate Cancer AfterRadical Prostatectomy and Subsequent Useof Adjuvant Radiation in a National CohortDavid Schreiber, MD1,2; Justin Rineer, MD3; James B. Yu, MD4; Michelle Olsheski, MD1; Emmanuel Nwokedi, MD1;

David Schwartz, MD1,2; Kwang Choi, MD1; and Marvin Rotman, MD1

BACKGROUND: The Surveillance, Epidemiology, and End Results database was analyzed to explore the pathologic

extent of disease for clinically localized prostate cancer after radical prostatectomy as well as the use of adjuvant

radiation in this population. METHODS: Identified were patients from 2004 to 2006 with clinically staged T1c-2cNx-

0M0 prostate adenocarcinoma who underwent radical prostatectomy. All patients had complete clinical and patho-

logic data. The use of postoperative radiation was recorded. Logistic regression analysis was performed to identify

unadjusted and adjusted predictors for extraprostatic disease or positive surgical margins and for adjuvant radiation

use. RESULTS: A total of 35,642 patients were identified. For those patients with Gleason 7 (4þ3) and a prostate-

specific antigen (PSA) level of �10.1 ng/mL or Gleason 8 to 10 with any PSA level, the rate of organ-confined disease

with negative surgical margins was found to be <50%. Of those with indications for adjuvant radiation, 11.1% received

the treatment. CONCLUSIONS: This large population-based study detailed the risk of extraprostatic extension and

positive surgical margins in a broad setting across multiple regions and communities, as well as the use of adjuvant

radiation for these patients. As of 2006, 11.1% of patients who had indications for adjuvant radiation received

this treatment, providing a useful baseline for future patterns of care studies. Cancer 2010;116:5757–66. VC 2010 American

Cancer Society.

KEYWORDS: prostate cancer, radical prostatectomy, radiation, Surveillance, Epidemiology, and End Results program,

adjuvant radiation.

Many series have demonstrated excellent outcomes with organ-confined prostate cancer (CaP) after radical prostatec-tomy. However, those patients who were found, pathologically, to have more advanced disease are more likely todevelop biochemical recurrences.1 Biochemical disease recurrence after radical prostatectomy has been shown to increaseCaP-specific mortality.2 Therefore, both the preoperative identification of patients who are more likely to have locallyadvanced disease, as well as the postoperative management of these patients are clinically important. Several major studieshave analyzed which patients with clinically localized disease will have pathologically advanced disease after surgicalstaging, with the most widely used being the Partin tables.3

Retrospective reviews have reported improvements in biochemical outcomes in these patients with the use ofadjuvant radiation.4-6 Three prospective phase 3 trials have been performed, all of which revealed an improvement inbiochemical outcome with early adjuvant radiation,7-9 and 1 was recently updated and reported improvement in overallsurvival after 12.6 years of follow-up.10

In the modern era, these patients are presenting more often with clinically localized CaP, likely secondary to stagemigration, as well as early detection programs.11 Therefore, we analyzed the Surveillance, Epidemiology, and End Results

DOI: 10.1002/cncr.25561, Received: May 11, 2010; Revised: July 5, 2010; Accepted: July 7, 2010, Published online August 24, 2010 in Wiley Online Library

(wileyonlinelibrary.com)

Corresponding author: David Schreiber, MD, Department of Radiation Oncology, SUNY Downstate Medical Center, 450 Clarkson Avenue, Box 1211, Brooklyn, NY

11230; Fax: (718) 270-1535; david.schreiber@downstate.edu

1Department of Radiation Oncology, State University of New York Downstate Medical Center, Brooklyn, New York; 2Department of Veterans Affairs, New York

Harbor Healthcare System, Brooklyn, New York; 3Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas;4Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut

We thank Dr. Jeremy Weedon for his help and guidance in writing this article.

Cancer December 15, 2010 5757

Original Article

(SEER) database to examine the pathologic outcomes ofpatients with clinically localized disease who undergoradical prostatectomy, thereby reporting results acrossmultiple regions of the country rather than limiting thereport to that from a single surgeon or group of surgeonsat a high-volume center and with a high degree ofexpertise. We also analyzed how often adjuvant radiationis being used for those patients who were determinedpathologically to have positive margins or extraprostaticextension (EPE).

MATERIALS AND METHODS

Data Source

SEER is a National Cancer Institute program serving asthe representative cancer registry of the United States.Data concerning individual patient demographics,diagnosis, treatment, surgical pathology, and survivaloutcomes are collected from 17 regions covering approxi-mately 26% of the US population. Beginning in 2004,SEER started reporting preoperative PSA data and pri-mary and secondary Gleason scores, in addition to theclinical stage and detailed pathologic information.

Study Cohort

We identified patients from 2004 to 2006 with clinicallystaged T1c-2cNx-0M0 prostate adenocarcinoma whounderwent radical prostatectomy. Patients with clinicallyor pathologically positive lymph nodes were excluded. Allpatients had detailed information regarding preoperativePSA levels as well as surgical Gleason scores. Patients wereexcluded from the analysis if they had missing preopera-tive PSA or Gleason score data, or if they had a discordanttotal Gleason score and Gleason score breakdown.Patients with histologies other than adenocarcinoma werealso excluded. Details regarding pathologic extent ofdisease, surgical margin status, and the use of postopera-tive external beam radiation were recorded in all patients.Patients were defined as having organ-confined diseasewith negative surgical margins, organ-confined diseasewith positive surgical margins, extracapsular extensionwith negative surgical margins, extracapsular extensionwith positive surgical margins, seminal vesicle involve-ment, or pathologic T4 disease. Details regarding postop-erative PSA are not available from the SEER database.

Collection of Adjuvant Radiation Data

SEER collects information regarding radiation usage if itwas considered part of the definitive first course of treat-

ment.12 Therefore, those patients who ultimately receivedadjuvant radiation for palliative or salvage purposeswould not be coded as having received adjuvant radiation.SEER does not code the date that adjuvant radiationwas received. Therefore, a possible limitation regardingadjuvant radiation use is that perhaps not all patients whoreceived adjuvant radiation were captured by the SEERdatabase. For example, the radiation treatment may havebeen delayed for several months to allow for healing andtherefore SEER never coded the patient as receiving thetreatment. However, SEER will record adjuvant radiationif it was recommended within 1 year from diagnosis,regardless of the duration of time that elapsed until thetreatment was delivered, making it likely that treatmentdelay was not a cause for under-reporting. In addition,unfortunately, SEER does not code the postoperative PSAvalues, which prevents us from confirming that radiationwas delivered in the adjuvant setting and not the salvagesetting. It is conceivable that SEER miscodes salvage radi-ation use as adjuvant radiation. This particular aspect ofSEER coding has not, to our knowledge, been studied.However, previous studies analyzing radiation usage inCaP and other malignancies have found SEER to haveaccurately coded radiation usage 93% to 95% of thetime.13

Statistical Analysis

Descriptive analyses regarding pathologic extent ofdisease, surgical margin status, and adjuvant radiation usewere performed and the data were stratified by Gleasonscore (Gleason score�6, 3þ 4, 4þ 3, and 8-10) and PSAgrouping (PSA �10 ng/mL, 10.1-20 ng/mL, and>20 ng/mL). PSA was grouped in this manner becausethese groups have been used to stratify patients into riskgroupings.14 We did not substratify the clinical T2 stagegrouping for the descriptive analysis because 56% of thepatients in the SEER database who had clinically stagedT2 disease were coded as T2 not otherwise specified(T2NOS). In addition, previous studies have suggestedthat there is no difference in progression rates for thevarious T2 subcategories.15 Pathologic extent of diseasewas also more broadly grouped into organ-confined withnegative margins (OC-) or non-organ–confined disease(EPE/OCþ) (defined for these purposes as organ-con-fined disease with positive surgical margins or EPE regard-less of surgical margin status). Logistic regression analysiswas performed to identify unadjusted and adjustedpredictors for EPE/OCþ disease. Variables includedin the analysis were age (continuous), SEER registry

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5758 Cancer December 15, 2010

location, PSA grouping (PSA �10 ng/mL, 10.1-20 ng/mL, and >20 ng/mL), Gleason score (Gleason score �6,3þ 4, 4þ 3, and 8-10), clinical T classification (T1c,T2a-c), and race (black, white, or other). The logisticregression analysis was also repeated using these same vari-ables, except PSA was grouped into 2-ng/mL incrementsstarting at 0.1 ng/mL until 20 ng/mL. This was done toassess whether an increasing PSA in smaller incrementswas also associated with a higher likelihood of EPE/OCþ,rather than just grouping the values broadly into 3 groups.

A separate logistic regression analysis using thesesame variables was performed only on patients with EPE/OCþ disease to identify unadjusted and adjusted pre-dictors of adjuvant radiation use in these patients. Allstatistical analyses were performed using SPSS statisticalsoftware (version 17.0; SPSS Inc, Chicago IL). Statisticalsignificance was defined as a 2-sided P value of�.05.

RESULTS

Patient Characteristics

A total of 35,642 patients were identified who met all theinclusion criteria and had no missing data. Patient charac-teristics are listed in Table 1. The median age of allpatients was 61 years. The median PSA was 5.7 ng/mL.For the entire cohort, 70.1% of the patients had organ-confined disease with negative margins. The remaining29.9% had either positive surgical margins (with orwithout organ-confined disease) or EPE (Table 1).

Pathologic Findings

The pathologic extent of disease was stratified by Gleasonscore and PSA based on whether the patients had clinicallystaged T1c or T2 diseases, and the results are available inTable 2. The rate of organ-confined disease with negativesurgical margins was between 80.1% and 86.2% forpatients with Gleason score �6 disease, regardless of thePSA value or T classification. However, beyond Gleasonscore 6 disease, there was a considerable decrease in therate of organ-confined disease with negative surgical mar-gins. In addition, for those patients with Gleason score 7(4þ 3) and a PSA of �10.1 ng/mL, or for those withGleason scores of 8 to 10 with any PSA, the rate of organ-confined disease with negative surgical margins was notedto decrease considerably below 50%.

Predictors of EPE/OC1

Logistic regression analysis revealed that increasing Glea-son score was the strongest unadjusted and adjusted

Table 1. Patient Characteristics

Variable No. (%)

Y of diagnosis2004 11,931 (33.5)

2005 10,816 (30.3)

2006 12,895 (36.2)

RaceWhite 29,941 (84)

Black 3537 (9.9)

Other 2164 (6.4)

PSA measurement, ng/mL£10 29,965 (84.1)

10.1-20 4047 (11.4)

>20 1630 (4.6)

T classificationT1c 21,156 (59.4)

T2a-c 14,486 (40.6)

Gleason score£6 15,460 (43.4)

7 (314) 12,916 (36.2)

7 (413) 3657 (10.3)

8-10 3609 (10.1)

Pathologic extent of diseaseOC, negative margins 24,968 (70.1)

OC, positive margins 4277 (12)

ECE, negative margins 2511 (7)

ECE, positive margins 1886 (5.3)

SVI 1557 (4.4)

pT4 443 (1.3)

Use of adjuvant radiotherapyNo radiation 34,225 (96)

Radiotherapy 1417 (4)

SEER registry locationUtah 1530 (4.3)

Seattle 2757 (7.7)

San Jose-Monterey 971 (2.7)

San Francisco-Oakland 1557 (4.4)

Rural Georgia 49 (0.1)

New Mexico 832 (2.3)

New Jersey 3961 (11.1)

Louisiana 4793 (13.4)

Kentucky 1718 (4.8)

Iowa 1817 (5.1)

Hawaii 536 (1.5)

Detroit 1881 (5.3)

Connecticut 1689 (4.7)

Californiaa 8875 (24.9)

Atlanta 825 (2.3)

Alaska 19 (0.1)

Los Angeles 4793 (13.4)

PSA indicates prostate-specific antigen; OC, organ-confined; ECE, extra-

capsular extension; SVI, seminal vesicle invasion; pT4, pathologically

staged T4 disease; SEER, Surveillance, Epidemiology, and End Results.a Excluding San Francisco, San Jose-Monterey, San Francisco-Oakland,

and Los Angeles.

Patterns of Care After Prostatectomy/Schreiber et al

Cancer December 15, 2010 5759

predictor for EPE/OCþ, as can be seen in Tables 3 and4. Increasing PSA grouping was also found to be astrong predictor. There was a wide variability in the rateof non-organ–confined disease depending on the SEERregistry location. Repeating the analysis with PSAgrouped into 2-ng/mL increments revealed that theunadjusted odds ratio for EPE/OCþ was 1.17 (95%confidence interval [95% CI], 1.16-1.18; P < .001) andthe adjusted odds ratio was 1.12 (95% CI, 1.103-1.127;P < .001), for each increase in PSA by 2 ng/mL (data notshown).

Adjuvant Radiation Indications and Use

A total of 10,674 patients had EPE/OCþ disease. Ofthose, 1186 (11.1%) received adjuvant radiation. Anadditional 231 patients of the 24,737 (0.9%) who werecoded as having organ-confined disease with negativesurgical margins also received postoperative radiation andwere excluded from the analysis of adjuvant radiation use.Logistic regression analysis again revealed that Gleasonscore was the strongest unadjusted and adjusted predictorfor subsequent delivery of adjuvant radiation (Tables 5and 6). Patients with Gleason scores of 8 to 10 disease,with a PSA of >20 ng/mL, or with pathologic findings ofextracapsular extension with positive surgical margins,seminal vesicle invasion, or pathologic T4 disease weremost likely to receive radiation. In patients with thesefindings, adjuvant radiation was delivered between 18.4%and 21.2%.

DISCUSSIONTo the best of our knowledge, the current study is thelargest review of pathologic outcomes for patients withclinically localized CaP, as well as for patterns of careregarding adjuvant radiation use. We have found thatthose patients with Gleason score 6 disease are ultimately

Table 2. Pathologic Extent of Disease for Patients WithClinically Localized Prostate Cancer Stratified by GleasonScore, PSA Grouping, and T Classification

Pathologic Extent PSA£10ng/mL

PSA 10.1to 20ng/mL

PSA>20ng/mL

cT1c prostate cancerGleason scores ≤6, n=9732 patients

OC, negative margins 84.8% 81.6% 84.9%

OC, positive margins 9.9% 10.7% 9.7%

ECE, negative margins 2.7% 3.8% 2.3%

ECE, positive margins 1.3% 1.2% 1.3%

SVI 0.6% 1.2% 0.7%

pT4 0.6% 0.8% 0.6%

Gleason score 7 (314), n=7650 patients

OC, negative margins 69.2% 57.6% 55.9%

OC, positive margins 15.3% 15.9% 15.3%

ECE, negative margins 7.5% 8.8% 11.4%

ECE, positive margins 5.0% 8.0% 8.1%

SVI 2.4% 7.4% 5.7%

pT4 0.7% 2.3% 3.6%

Gleason score 7 (413), n=1967 patients

OC, negative margins 58.7% 38.6% 37.8%

OC, positive margins 13.8% 15.5% 14.0%

ECE, negative margins 11.4% 12.5% 11.9%

ECE, positive margins 7.0% 14.3% 18.9%

SVI 7.9% 15.5% 13.3%

pT4 1.2% 3.6% 4.2%

Gleason score 8-10, n=1807 patients

OC, negative margins 46.9% 34.4% 28.1%

OC, positive margins 10.2% 13.1% 11.2%

ECE, negative margins 15.3% 10.7% 14.0%

ECE, positive margins 10.8% 17.5% 20.2%

SVI 14.4% 19.4% 20.2%

pT4 2.5% 4.9% 6.2%

cT2a-2c prostate cancerGleason score ≤6, n=5728 patients

OC, negative margins 84.7% 80.1% 86.2%

OC, positive margins 9.5% 11.4% 5.7%

ECE, negative margins 2.6% 3.7% 2.9%

ECE, positive margins 1.9% 2.8% 2.3%

SVI 0.7% 1.4% 1.7%

pT4 0.6% 0.4% 1.2%

Gleason score 7 (314), n=5266 patients

OC, negative margins 66.8% 52.6% 47.2%

OC, positive margins 13.7% 16.7% 14.8%

ECE, negative margins 10.1% 8.4% 9.3%

ECE, positive margins 5.2% 11.4% 15.3%

SVI 3.3% 9.4% 7.9%

pT4 0.9% 1.4% 5.6%

Gleason 7 score (413), n=1690 patients

OC, negative margins 55.2% 39.8% 31.0%

OC, positive margins 12.0% 11.3% 14.3%

ECE, negative margins 14.7% 13.2% 11.9%

ECE, positive margins 8.8% 16.5% 19.8%

SVI 7.8% 15.8% 15.9%

pT4 1.5% 3.4% 7.1%

Gleason score 8-10, n=1802 patients

OC, negative margins 44.2% 27.8% 19.8%

OC, positive margins 8.5% 10.3% 10.4%

(Continued)

Table 2. (Continued)

Pathologic Extent PSA£10ng/mL

PSA 10.1to 20ng/mL

PSA>20ng/mL

ECE, negative margins 15.2% 10.3% 8.9%

ECE, positive margins 13.1% 21.7% 25.2%

SVI 16.0% 25.8% 25.2%

pT4 3.0% 4.2% 10.4%

PSA indicates prostate-specific antigen; cT1c, clinically staged T1c dis-

ease; OC, organ-confined; ECE, extracapsular extension; SVI, seminal vesi-

cle invasion; pT4, pathologically staged T4 disease; cT2a-T2c, clinically

staged T2a-T2c disease.

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5760 Cancer December 15, 2010

determined to have organ-confined disease with negativesurgical margins >80% of the time after surgery, regard-less of PSA level or T classification. This should translateto a very high rate of cure in these patients regardless ofadjuvant therapy. However, with Gleason score 7 (3þ 4)disease and higher, the risk for EPE and/or positive surgi-cal margins rises dramatically.

Prior studies have shown that local control aftersurgery depends on the presence of extracapsular exten-

sion, seminal vesicle invasion, positive surgical margins,increased Gleason score, and high preoperative PSAlevels16-18 as does the risk of metastatic disease progres-sion.19 Therefore, identifying patients with these risk fac-tors plays an important role when discussing whetherthere may be a need for adjuvant treatment.

Although the data available in Table 2 provideuseful information regarding pathologic extent of disease,the Gleason score information collected by SEER

Table 3. Logistic Regression Analysis of Unadjusted Predictors for Non-Organ-Confined Disease

Variable Rate of EPE orPositive SurgicalMargins

OR 95% CI P

Gleason score6 15.5% 1

7 (314) 33.9% 2.80 2.64-2.96 <.001

7 (413) 47.5% 4.93 4.56-5.33 <.001

8-10 59.7% 8.05 7.43-8.71 <.001

RaceWhite 29.9% 1

Black 30.6% 1.03 0.96-1.11 .41

Other 29.8% 0.99 0.90-1.09 .994

PSA measurement, ng/mL£10 27.1% 1

10.1-20 43.4% 2.06 1.93-2.21 <.001

>20 48.5% 2.53 2.29-2.80 <.001

Age at diagnosis 1.02 1.02-1.02 <.001

T classificationT1c 28.2% 1

T2a-T2c 32.6% 1.23 1.18-1.30 <.001

SEER registry locationLos Angeles 34.1% 1

New Jersey 17.3% 0.40 0.37-0.45 <.001

Utah 36.8% 1.13 1.00-1.27 .05

Seattle 36.9% 1.13 1.03-1.25 .013

San Jose-Monterey 34.0% 1.00 0.86-1.15 .95

San Francisco-Oakland 26.2% 0.69 0.60-0.78 <.001

Rural Georgia 34.7% 1.03 0.57-1.86 .93

New Mexico 25.1% 0.65 0.55-0.77 <.001

Louisiana 27.6% 0.74 0.65-0.83 <.001

Kentucky 23.0% 0.58 0.51-0.66 <.001

Iowa 34.7% 1.03 0.92-1.15 .63

Hawaii 37.5% 1.16 0.96-1.40 .12

Detroit 31.3% 0.88 0.78-0.99 .03

Connecticut 29.8% 0.82 0.73-0.93 .001

Californiaa 32.2% 0.92 0.85-0.99 .03

Atlanta 15.3% 0.35 0.29-0.43 <.001

Alaska 15.8% 0.36 0.11-1.25 .35

Y of diagnosis2004 31.1% 1

2005 30.4% 0.97 0.92-1.03 .30

2006 28.5% 0.88 0.84-0.93 <.001

EPE indicates extraprostatic extension; OR, odds ratio; 95% CI, 95% confidence interval; PSA, prostate-specific antigen;

SEER, Surveillance, Epidemiology, and End Results.a Excluding San Francisco, San Jose-Monterey, San Francisco-Oakland, and Los Angeles.

Patterns of Care After Prostatectomy/Schreiber et al

Cancer December 15, 2010 5761

corresponds to the pathologic specimen rather than the bi-opsy. This may be a major limitation affecting interpreta-tion of these data as a predictive tool for patients.However, contemporary studies have revealed that theincidence of undergrading of biopsy scores has been dra-matically reduced in recent years and is mainly limited tobiopsies that reveal Gleason score 6 disease, whereas thosewith biopsies of Gleason score 7 or higher have a very highconcordance between biopsy and radical prostatec-

tomy.20-23 Therefore, although these data should not beused strictly as a predictive tool, it is patients with biopsyGleason scores of 6 who are most affected by this limita-tion and one should be aware that, if there is upgrading ofthe Gleason score after surgery, the risk of non-organ–confined disease will be dramatically different from whatis reported in Table 2. However, for those with biopsyGleason scores of 7 or higher, these results are useful inthat they provide pathologic outcomes in a large numberof patients in the community setting, in which theurologic surgeon may have less experience and where oneis less likely to find a dedicated urologic pathologist.

These data also provide additional important patho-logic information in the form of surgical margin statusreporting, making this, to our knowledge, the largest suchreport in the published literature. Positive surgicalmargins after prostatectomy have been correlated with anincreased risk of biochemical failure18,24,25 and have alsobeen proposed as part of nomograms to predict for anincreased risk of disease recurrence,26,27 thereby renderingit an important variable when assessing for possible adju-vant therapy after radical prostatectomy. Although SEERdoes report the surgical margin status, it does not givepathologic details regarding the margin status such as theextent or the number of positive surgical margins, andthese details may also impact the decision to offer adju-vant radiation. However, although the extent and numberof positive surgical margins do predict for an increasedrisk of disease recurrence,28 even a focally positive surgicalmargin confers an inferior biochemical outcome,29,30

therefore making it an important clinical parameter whenconsidering adjuvant treatment.

These SEER data also provide interesting informa-tion regarding the patterns of care of these patients aftersurgery. In this study, approximately 29.9% of all thepatients (n ¼ 10,674) had indications for adjuvant radia-tion, due to EPE or positive surgical margins. However,only 11.1% (n ¼ 1184) received adjuvant radiation.There has been debate in the literature regarding whetherthese patients should be treated immediately with radia-tion4-6 or observed closely with radiation reserved forsalvage therapy.20,31,32 Three randomized trials haverecently been performed comparing adjuvant radiationwith observation for patients with positive surgical mar-gins, extracapsular extension, or seminal vesicle invasion,and these trials have confirmed a benefit in biochemicalcontrol. The European Organization for Research andTreatment of Cancer (EORTC) 22911 trial revealed that,in addition to an improvement in biochemical

Table 4. Logistic Regression Analysis of Adjusted Predictorsfor Non-Organ-Confined Disease

Variable OR 95% CI P

Gleason score6 1

7 (314) 2.74 2.58-2.90 <.001

7 (413) 4.60 4.24-4.98 <.001

8-10 7.42 6.83-8.06 <.001

RaceWhite 1

Black 1.08 0.99-1.17 .09

Other 0.87 0.78-0.96 .009

PSA measurement, ng/mL£10 1

10.1-20 1.63 1.52-1.75 <.001

>20 1.91 1.72-2.13 <.001

Age at diagnosis 1 0.996-1.003 .74

T classificationT1c 1

T2a-T2c 1.07 1.02-1.12 .01

SEER registry locationLos Angeles 1

New Jersey 0.42 0.37-0.46 <.001

Utah 1.26 1.11-1.44 <.001

Seattle 1.08 0.97-1.20 .17

San Jose-Monterey 0.96 0.82-1.12 .61

San Francisco-Oakland 0.61 0.53-0.70 <.001

Rural Georgia 0.94 0.50-1.77 .75

New Mexico 0.63 0.53-0.75 <.001

Louisiana 0.70 0.62-0.80 <.001

Kentucky 0.60 0.52-0.69 <.001

Iowa 0.99 0.88-1.12 .92

Hawaii 1.03 0.84-1.26 .81

Detroit 0.83 0.73-0.93 .002

Connecticut 0.77 0.67-0.87 <.001

Californiaa 0.92 0.85-0.99 .04

Atlanta 0.35 0.29-0.43 <.001

Alaska 0.50 0.14-1.79 .29

Y of diagnosis2004 1

2005 0.96 0.90-1.02 .15

2006 0.87 0.82-0.92 <.001

OR indicates odds ratio; 95% CI, 95% confidence interval; PSA, prostate-

specific antigen; SEER, Surveillance, Epidemiology, and End Results.a Excluding San Francisco, San Jose-Monterey, San Francisco-Oakland,

and Los Angeles.

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5762 Cancer December 15, 2010

progression-free survival from 53% to 74% at 5 years (P< .001), there was also a significant reduction in clinicaldisease progression as well as local failure (15% vs 5%; P< .0001).7 A large randomized study out of Germany byWiegel et al revealed an improvement in biochemical pro-

gression-free survival from 54% to 72% at 5 years (P ¼.015).8 In both studies, there was no overall survivalbenefit with the addition of adjuvant radiation. However,it should also be noted that both trials were reported with5-year follow-up, which is too short to definitively show a

Table 5. Logistic Regression Analysis of Unadjusted Predictors of Adjuvant Radiotherapy in ThoseWith Non-Organ-Confined Disease or Positive Surgical Margins

Variable Radiotherapy Use OR 95% CI P

Gleason score6 4.7% 1

7 (314) 9.1% 2.04 1.64-2.53 <.001

7 (413) 12.4% 2.87 2.27-3.64 <.001

8-10 21.2% 5.44 4.39-6.75 <.001

RaceWhite 11.1% 1

Black 9.6% 0.85 0.69-1.05 .14

Other 13.7% 1.27 1.00-1.60 .05

PSA measurement, ng/mL£10 9.4% 1

10.1-20 14.8% 1.69 1.45-1.97 <.001

>20 20.9% 2.56 2.12-3.09 <.001

Age at diagnosis 0.99 0.98-0.99 <.001

T classificationT1c 9.8% 1

T2a-T2c 12.7% 1.34 1.19-1.51 <.001

Pathologic extentOC, positive margins 6.1% 1

ECE, negative margins 7.4% 1.22 1.00-1.48 .05

ECE, positive margins 19.0% 3.30 3.04-4.27 <.001

SVI 18.4% 3.46 2.90-4.14 <.001

pT4 21.0% 4.07 3.14-5.28 <.001

SEER registry locationLos Angeles 9.5% 1

New Jersey 13.7% 1.52 1.15-2.00 .03

Utah 9.1% 0.95 0.68-1.33 .76

Seattle 12.5% 1.36 1.06-1.74 .02

San Jose-Monterey 11.5% 1.24 0.85-1.81 .26

San Francisco-Oakland 12.7% 1.39 1.00-1.95 .05

Rural Georgia 0% 0 0 1

New Mexico 7.7% 0.79 0.46-1.35 .39

Louisiana 10.3% 1.10 0.79-1.53 .59

Kentucky 9.4% 0.99 0.68-1.44 .94

Iowa 12.4% 1.35 1.01-1.80 .04

Hawaii 25.4% 3.24 2.27-4.64 <.001

Detroit 14.6% 1.64 1.23-2.17 .001

Connecticut 7.8% 0.80 0.56-1.16 .24

Californiaa 10.5% 1.12 0.91-1.37 .30

Atlanta 7.9% 0.82 0.42-1.60 .57

Alaska 33% 4.77 0.43-52.92 .20

Y of diagnosis2004 12% 1

2005 10.7% 0.88 0.76-1.02 .09

2006 10.6% 0.87 0.75-1.00 .05

OR indicates odds ratio; 95% CI, 95% confidence interval; PSA, prostate-specific antigen; OC, organ-confined; ECE, extracap-

sular extension; SVI, seminal vesicle invasion; pT4, pathologic T4 disease; SEER, Surveillance, Epidemiology, and End Results.a Excluding San Francisco, San Jose-Monterey, San Francisco-Oakland, and Los Angeles.

Patterns of Care After Prostatectomy/Schreiber et al

Cancer December 15, 2010 5763

survival benefit. In addition, both trials were under-powered to definitively detect an overall survival benefit,because they were designed to detect improvements inprogression-free survival but not overall survival.

The Southwest Oncology Group (SWOG) recentlyupdated the results of SWOG 8794 and did report animprovement in the median overall survival from 13.3years to 15.2 years with a hazard ratio of 0.72 (P¼ .023).In their initial report, the authors noted a reduction in theincidence of distant metastasis and a reduced incidence ofinitiation of hormone therapy.9 In a companion quality oflife study,33 they also noted that although the acute geni-tourinary and gastrointestinal toxicity was worse in theradiation group, there was little difference between thegroups by 2 years. In addition, the global quality of lifewas initially worse for the adjuvant radiation group, butbecame similar by 2 years and was increasingly superior inthe radiation group during the following 3 years.

Although all 3 randomized trials have consistentlyreported improvements in biochemical control with theaddition of adjuvant radiation for those patients withEPE or positive margins, it is likely that they did nothave a major impact on the patterns of care regardingadjuvant radiation usage during the time period of thisstudy. The EORTC study was published in full manu-script form in 2005, the SWOG study in 2006, andthe German study in 2009, whereas the cases in thisstudy were ascertained from SEER between 2004 and2006. However, these data do provide a baseline of ad-juvant radiation usage of 11.1% that can be used forfuture comparison. It will be interesting to learnwhether the overall survival and quality of life resultsfrom the SWOG study, as well as the results from theother randomized trials, will impact on the use of ad-juvant radiation in the future. If the randomized trialsby Bolla et al and Wiegel et al do detect an overallsurvival benefit on longer follow-up, this should addvery strong evidence supporting the use of adjuvantradiation, particularly given that these studies wereunderpowered to detect a survival benefit. However, asof 2006, it appeared that observation, or perhaps hor-monal therapy, is the preferred therapy for patientswith extraprostatic disease or positive surgical margins.

A possible limitation of the analysis regarding adju-vant radiation use is that perhaps not all patients whoreceived adjuvant radiation were captured by the SEERdatabase. Virnig et al13 compared the use of radiation aspart of the first course of treatment as coded by SEERwith use of radiation in the months after diagnosis as

Table 6. Logistic Regression Analysis of Adjusted Predictorsof Adjuvant Radiotherapy in Those with Non-Organ-ConfinedDisease or Positive Surgical Margins

Variable OR 95% CI P

Gleason score6 1

7 (314) 1.81 1.45-2.26 <.001

7 (413) 2.17 1.69-2.78 <.001

8-10 3.64 2.88-4.59 <.001

RaceWhite 1

Black 0.74 0.59-0.93 .01

Other 0.98 0.75-1.29 .89

PSA measurement, ng/mL£10 1

10.1-20 1.26 1.07-1.48 .004

>20 1.63 1.33-1.99 <.001

Age at diagnosis 0.97 0.96-0.98 <.001

T classificationT1c 1

T2a-T2c 1.14 1.00-1.29 .05

Pathologic extentOC, positive margins 1

ECE, negative margins 0.97 0.79-1.19 .78

ECE, positive margins 2.69 2.25-3.22 <.001

SVI 2.35 1.94-2.86 <.001

pT4 3.09 2.35-4.07 <.001

SEER registry locationLos Angeles 1

New Jersey 1.57 1.17-2.09 .003

Utah 1.00 0.71-1.41 .99

Seattle 1.29 0.99-1.67 .06

San Jose-Monterey 1.29 0.87-1.90 .21

San Francisco-Oakland 1.35 0.95-1.92 .09

Rural Georgia 0 0 1

New Mexico 0.69 0.40-1.20 .19

Louisiana 1.03 0.73-1.45 .89

Kentucky 0.96 0.65-1.41 .82

Iowa 1.21 0.89-1.64 .22

Hawaii 3.35 2.23-5.03 <.001

Detroit 1.66 1.23-2.23 .001

Connecticut 0.76 0.52-1.12 .16

Californiaa 1.05 0.85-1.30 .63

Atlanta 0.82 0.41-1.64 .58

Alaska 9.49 0.74-122.4 .09

Y of diagnosis2004 1

2005 0.84 0.72-0.98 .03

2006 0.80 0.69-0.93 .004

OR indicates odds ratio; 95% CI, 95% confidence interval; OC, organ-con-

fined; ECE, extracapsular extension; SVI, seminal vesicle invasion; pT4,

pathologic T4 disease; SEER, Surveillance, Epidemiology, and End Results.a Excluding San Francisco, San Jose-Monterey, San Francisco-Oakland,

and Los Angeles.

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5764 Cancer December 15, 2010

identified by Medicare claims. They found a 93% correla-

tion between SEER and Medicare codes, indicating that

SEER is highly accurate in identifying radiation as part of

the first course of treatment in patients with CaP. In this

report, the accuracy of SEER in coding the use of adjuvant

radiation versus definitive radiation was not performed.

However, they did also analyze the use of radiation for

patients with breast cancer and endometrial cancer, in

whom radiation is nearly always delivered adjuvantly.

They found that the agreement between SEER and Medi-

care was between 94.2% and 94.8%, supporting the accu-

racy of SEER in this setting. In addition, as was noted

earlier, SEER does not report the postoperative PSA

values after surgery. Consequently, it is possible that some

patients had PSA values that never nadired down to 0 and

received immediate salvage radiation but were included in

the coding of having received postoperative radiation.

Therefore, the reported use of adjuvant radiation in

11.1% of patients with indications is likely actually an

overestimation of its use in the community.Other limitations of the current study include the

lack of central pathology review and the lack of other

pathologic variables such as perineural invasion, lympho-

vascular invasion, percent of biopsy cores that were posi-

tive, and tertiary Gleason scores of 5. Central review by

dedicated urologic pathologists has previously been shown

to result in the more accurate detection of EPE compared

with local pathologists.34 However, the SEER data repre-

sent the results of patients in the broader community

setting, in which there may not be dedicated urologic

pathologists and in which clinical decisions are based on

the available pathology reports without the benefit of

central pathology review.In conclusion, this large population-based study

provides data regarding the risk of EPE and positive surgi-

cal margins in the broader community setting, stratified

by T classification, PSA grouping, and Gleason score. Of

all patients who had EPE or positive surgical margins,

11.1% received adjuvant radiation, indicating that obser-

vation or hormonal therapy was the preferred initial

therapy for these patients in the community. This can

serve as a baseline for the usage of adjuvant radiation in a

large national cohort. It will be interesting to determine

whether the recently reported randomized trials affect the

use of adjuvant radiation in the future.

CONFLICT OF INTEREST DISCLOSURESThe authors made no disclosures.

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5766 Cancer December 15, 2010