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Keywords:

  • prostate cancer;
  • radical prostatectomy;
  • radiation;
  • Surveillance, Epidemiology, and End Results program;
  • adjuvant radiation

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

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 pathologic 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 (4 + 3) 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. © 2010 American Cancer Society.

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

Retrospective reviews have reported improvements in biochemical outcomes in these patients with the use of adjuvant radiation.4-6 Three prospective phase 3 trials have been performed, all of which revealed an improvement in biochemical outcome with early adjuvant radiation,7-9 and 1 was recently updated and reported improvement in overall survival 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 stage migration, as well as early detection programs.11 Therefore, we analyzed the Surveillance, Epidemiology, and End Results (SEER) database to examine the pathologic outcomes of patients with clinically localized disease who undergo radical prostatectomy, thereby reporting results across multiple regions of the country rather than limiting the report to that from a single surgeon or group of surgeons at a high-volume center and with a high degree of expertise. We also analyzed how often adjuvant radiation is being used for those patients who were determined pathologically to have positive margins or extraprostatic extension (EPE).

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Data Source

SEER is a National Cancer Institute program serving as the representative cancer registry of the United States. Data concerning individual patient demographics, diagnosis, treatment, surgical pathology, and survival outcomes are collected from 17 regions covering approximately 26% of the US population. Beginning in 2004, SEER started reporting preoperative PSA data and primary and secondary Gleason scores, in addition to the clinical stage and detailed pathologic information.

Study Cohort

We identified patients from 2004 to 2006 with clinically staged T1c-2cNx-0M0 prostate adenocarcinoma who underwent radical prostatectomy. Patients with clinically or pathologically positive lymph nodes were excluded. All patients had detailed information regarding preoperative PSA levels as well as surgical Gleason scores. Patients were excluded from the analysis if they had missing preoperative PSA or Gleason score data, or if they had a discordant total Gleason score and Gleason score breakdown. Patients with histologies other than adenocarcinoma were also excluded. Details regarding pathologic extent of disease, surgical margin status, and the use of postoperative external beam radiation were recorded in all patients. Patients were defined as having organ-confined disease with negative surgical margins, organ-confined disease with positive surgical margins, extracapsular extension with negative surgical margins, extracapsular extension with positive surgical margins, seminal vesicle involvement, or pathologic T4 disease. Details regarding postoperative PSA are not available from the SEER database.

Collection of Adjuvant Radiation Data

SEER collects information regarding radiation usage if it was considered part of the definitive first course of treatment.12 Therefore, those patients who ultimately received adjuvant radiation for palliative or salvage purposes would not be coded as having received adjuvant radiation. SEER does not code the date that adjuvant radiation was received. Therefore, a possible limitation regarding adjuvant radiation use is that perhaps not all patients who received adjuvant radiation were captured by the SEER database. For example, the radiation treatment may have been delayed for several months to allow for healing and therefore SEER never coded the patient as receiving the treatment. However, SEER will record adjuvant radiation if it was recommended within 1 year from diagnosis, regardless of the duration of time that elapsed until the treatment was delivered, making it likely that treatment delay was not a cause for under-reporting. In addition, unfortunately, SEER does not code the postoperative PSA values, which prevents us from confirming that radiation was delivered in the adjuvant setting and not the salvage setting. It is conceivable that SEER miscodes salvage radiation use as adjuvant radiation. This particular aspect of SEER coding has not, to our knowledge, been studied. However, previous studies analyzing radiation usage in CaP and other malignancies have found SEER to have accurately coded radiation usage 93% to 95% of the time.13

Statistical Analysis

Descriptive analyses regarding pathologic extent of disease, surgical margin status, and adjuvant radiation use were performed and the data were stratified by Gleason score (Gleason score ≤6, 3 + 4, 4 + 3, and 8-10) and PSA grouping (PSA ≤10 ng/mL, 10.1-20 ng/mL, and >20 ng/mL). PSA was grouped in this manner because these groups have been used to stratify patients into risk groupings.14 We did not substratify the clinical T2 stage grouping for the descriptive analysis because 56% of the patients in the SEER database who had clinically staged T2 disease were coded as T2 not otherwise specified (T2NOS). In addition, previous studies have suggested that there is no difference in progression rates for the various T2 subcategories.15 Pathologic extent of disease was also more broadly grouped into organ-confined with negative margins (OC-) or non-organ–confined disease (EPE/OC+) (defined for these purposes as organ-confined disease with positive surgical margins or EPE regardless of surgical margin status). Logistic regression analysis was performed to identify unadjusted and adjusted predictors for EPE/OC+ disease. Variables included in the analysis were age (continuous), SEER registry location, PSA grouping (PSA ≤10 ng/mL, 10.1-20 ng/mL, and >20 ng/mL), Gleason score (Gleason score ≤6, 3 + 4, 4 + 3, and 8-10), clinical T classification (T1c, T2a-c), and race (black, white, or other). The logistic regression analysis was also repeated using these same variables, except PSA was grouped into 2-ng/mL increments starting at 0.1 ng/mL until 20 ng/mL. This was done to assess whether an increasing PSA in smaller increments was also associated with a higher likelihood of EPE/OC+, rather than just grouping the values broadly into 3 groups.

A separate logistic regression analysis using these same variables was performed only on patients with EPE/OC+ disease to identify unadjusted and adjusted predictors of adjuvant radiation use in these patients. All statistical analyses were performed using SPSS statistical software (version 17.0; SPSS Inc, Chicago IL). Statistical significance was defined as a 2-sided P value of ≤.05.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

Patient Characteristics

A total of 35,642 patients were identified who met all the inclusion criteria and had no missing data. Patient characteristics are listed in Table 1. The median age of all patients 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 remaining 29.9% had either positive surgical margins (with or without organ-confined disease) or EPE (Table 1).

Table 1. Patient Characteristics
VariableNo. (%)
  • PSA indicates prostate-specific antigen; OC, organ-confined; ECE, extracapsular 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.

Y of diagnosis
 200411,931 (33.5)
 200510,816 (30.3)
 200612,895 (36.2)
Race
 White29,941 (84)
 Black3537 (9.9)
 Other2164 (6.4)
PSA measurement, ng/mL
 ≤1029,965 (84.1)
 10.1-204047 (11.4)
 >201630 (4.6)
T classification
 T1c21,156 (59.4)
 T2a-c14,486 (40.6)
Gleason score
 ≤615,460 (43.4)
 7 (3+4)12,916 (36.2)
 7 (4+3)3657 (10.3)
 8-103609 (10.1)
Pathologic extent of disease
 OC, negative margins24,968 (70.1)
 OC, positive margins4277 (12)
 ECE, negative margins2511 (7)
 ECE, positive margins1886 (5.3)
 SVI1557 (4.4)
 pT4443 (1.3)
Use of adjuvant radiotherapy
 No radiation34,225 (96)
 Radiotherapy1417 (4)
SEER registry location
 Utah1530 (4.3)
 Seattle2757 (7.7)
 San Jose-Monterey971 (2.7)
 San Francisco-Oakland1557 (4.4)
 Rural Georgia49 (0.1)
 New Mexico832 (2.3)
 New Jersey3961 (11.1)
 Louisiana4793 (13.4)
 Kentucky1718 (4.8)
 Iowa1817 (5.1)
 Hawaii536 (1.5)
 Detroit1881 (5.3)
 Connecticut1689 (4.7)
 Californiaa8875 (24.9)
 Atlanta825 (2.3)
 Alaska19 (0.1)
 Los Angeles4793 (13.4)

Pathologic Findings

The pathologic extent of disease was stratified by Gleason score and PSA based on whether the patients had clinically staged T1c or T2 diseases, and the results are available in Table 2. The rate of organ-confined disease with negative surgical margins was between 80.1% and 86.2% for patients with Gleason score ≤6 disease, regardless of the PSA value or T classification. However, beyond Gleason score 6 disease, there was a considerable decrease in the rate of organ-confined disease with negative surgical margins. In addition, for those patients with Gleason score 7 (4 + 3) and a PSA of ≥10.1 ng/mL, or for those with Gleason scores of 8 to 10 with any PSA, the rate of organ-confined disease with negative surgical margins was noted to decrease considerably below 50%.

Table 2. Pathologic Extent of Disease for Patients With Clinically Localized Prostate Cancer Stratified by Gleason Score, PSA Grouping, and T Classification
Pathologic ExtentPSA ≤10 ng/mLPSA 10.1 to 20 ng/mLPSA >20 ng/mL
  1. PSA indicates prostate-specific antigen; cT1c, clinically staged T1c disease; OC, organ-confined; ECE, extracapsular extension; SVI, seminal vesicle invasion; pT4, pathologically staged T4 disease; cT2a-T2c, clinically staged T2a-T2c disease.

cT1c prostate cancer
 Gleason scores ≤6, n=9732 patients
  OC, negative margins84.8%81.6%84.9%
  OC, positive margins9.9%10.7%9.7%
  ECE, negative margins2.7%3.8%2.3%
  ECE, positive margins1.3%1.2%1.3%
  SVI0.6%1.2%0.7%
  pT40.6%0.8%0.6%
 Gleason score 7 (3+4), n=7650 patients
  OC, negative margins69.2%57.6%55.9%
  OC, positive margins15.3%15.9%15.3%
  ECE, negative margins7.5%8.8%11.4%
  ECE, positive margins5.0%8.0%8.1%
  SVI2.4%7.4%5.7%
  pT40.7%2.3%3.6%
 Gleason score 7 (4+3), n=1967 patients
  OC, negative margins58.7%38.6%37.8%
  OC, positive margins13.8%15.5%14.0%
  ECE, negative margins11.4%12.5%11.9%
  ECE, positive margins7.0%14.3%18.9%
  SVI7.9%15.5%13.3%
  pT41.2%3.6%4.2%
 Gleason score 8-10, n=1807 patients
  OC, negative margins46.9%34.4%28.1%
  OC, positive margins10.2%13.1%11.2%
  ECE, negative margins15.3%10.7%14.0%
  ECE, positive margins10.8%17.5%20.2%
  SVI14.4%19.4%20.2%
  pT42.5%4.9%6.2%
cT2a-2c prostate cancer
 Gleason score ≤6, n=5728 patients
  OC, negative margins84.7%80.1%86.2%
  OC, positive margins9.5%11.4%5.7%
  ECE, negative margins2.6%3.7%2.9%
  ECE, positive margins1.9%2.8%2.3%
  SVI0.7%1.4%1.7%
  pT40.6%0.4%1.2%
 Gleason score 7 (3+4), n=5266 patients
  OC, negative margins66.8%52.6%47.2%
  OC, positive margins13.7%16.7%14.8%
  ECE, negative margins10.1%8.4%9.3%
  ECE, positive margins5.2%11.4%15.3%
  SVI3.3%9.4%7.9%
  pT40.9%1.4%5.6%
 Gleason 7 score (4+3), n=1690 patients
  OC, negative margins55.2%39.8%31.0%
  OC, positive margins12.0%11.3%14.3%
  ECE, negative margins14.7%13.2%11.9%
  ECE, positive margins8.8%16.5%19.8%
  SVI7.8%15.8%15.9%
  pT41.5%3.4%7.1%
 Gleason score 8-10, n=1802 patients
  OC, negative margins44.2%27.8%19.8%
  OC, positive margins8.5%10.3%10.4%
  ECE, negative margins15.2%10.3%8.9%
  ECE, positive margins13.1%21.7%25.2%
  SVI16.0%25.8%25.2%
  pT43.0%4.2%10.4%

Predictors of EPE/OC+

Logistic regression analysis revealed that increasing Gleason score was the strongest unadjusted and adjusted predictor for EPE/OC+, as can be seen in Tables 3 and 4. Increasing PSA grouping was also found to be a strong predictor. There was a wide variability in the rate of non-organ–confined disease depending on the SEER registry location. Repeating the analysis with PSA grouped into 2-ng/mL increments revealed that the unadjusted odds ratio for EPE/OC+ was 1.17 (95% confidence interval [95% CI], 1.16-1.18; P < .001) and the adjusted odds ratio was 1.12 (95% CI, 1.103-1.127; P < .001), for each increase in PSA by 2 ng/mL (data not shown).

Table 3. Logistic Regression Analysis of Unadjusted Predictors for Non-Organ-Confined Disease
VariableRate of EPE or Positive Surgical MarginsOR95% CIP
  • 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.

Gleason score
 615.5%1  
 7 (3+4)33.9%2.802.64-2.96<.001
 7 (4+3)47.5%4.934.56-5.33<.001
 8-1059.7%8.057.43-8.71<.001
Race
 White29.9%1  
 Black30.6%1.030.96-1.11.41
 Other29.8%0.990.90-1.09.994
PSA measurement, ng/mL
 ≤1027.1%1  
 10.1-2043.4%2.061.93-2.21<.001
 >2048.5%2.532.29-2.80<.001
Age at diagnosis 1.021.02-1.02<.001
T classification
 T1c28.2%1  
 T2a-T2c32.6%1.231.18-1.30<.001
SEER registry location
 Los Angeles34.1%1  
 New Jersey17.3%0.400.37-0.45<.001
 Utah36.8%1.131.00-1.27.05
 Seattle36.9%1.131.03-1.25.013
 San Jose-Monterey34.0%1.000.86-1.15.95
 San Francisco-Oakland26.2%0.690.60-0.78<.001
 Rural Georgia34.7%1.030.57-1.86.93
 New Mexico25.1%0.650.55-0.77<.001
 Louisiana27.6%0.740.65-0.83<.001
 Kentucky23.0%0.580.51-0.66<.001
 Iowa34.7%1.030.92-1.15.63
 Hawaii37.5%1.160.96-1.40.12
 Detroit31.3%0.880.78-0.99.03
 Connecticut29.8%0.820.73-0.93.001
 Californiaa32.2%0.920.85-0.99.03
 Atlanta15.3%0.350.29-0.43<.001
 Alaska15.8%0.360.11-1.25.35
Y of diagnosis
 200431.1%1  
 200530.4%0.970.92-1.03.30
 200628.5%0.880.84-0.93<.001
Table 4. Logistic Regression Analysis of Adjusted Predictors for Non-Organ-Confined Disease
VariableOR95% CIP
  • 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.

Gleason score
 61  
 7 (3+4)2.742.58-2.90<.001
 7 (4+3)4.604.24-4.98<.001
 8-107.426.83-8.06<.001
Race
 White1  
 Black1.080.99-1.17.09
 Other0.870.78-0.96.009
PSA measurement, ng/mL
 ≤101  
 10.1-201.631.52-1.75<.001
 >201.911.72-2.13<.001
Age at diagnosis10.996-1.003.74
T classification
 T1c1  
 T2a-T2c1.071.02-1.12.01
SEER registry location
 Los Angeles1  
 New Jersey0.420.37-0.46<.001
 Utah1.261.11-1.44<.001
 Seattle1.080.97-1.20.17
 San Jose-Monterey0.960.82-1.12.61
 San Francisco-Oakland0.610.53-0.70<.001
 Rural Georgia0.940.50-1.77.75
 New Mexico0.630.53-0.75<.001
 Louisiana0.700.62-0.80<.001
 Kentucky0.600.52-0.69<.001
 Iowa0.990.88-1.12.92
 Hawaii1.030.84-1.26.81
 Detroit0.830.73-0.93.002
 Connecticut0.770.67-0.87<.001
 Californiaa0.920.85-0.99.04
 Atlanta0.350.29-0.43<.001
 Alaska0.500.14-1.79.29
Y of diagnosis
 20041  
 20050.960.90-1.02.15
 20060.870.82-0.92<.001

Adjuvant Radiation Indications and Use

A total of 10,674 patients had EPE/OC+ disease. Of those, 1186 (11.1%) received adjuvant radiation. An additional 231 patients of the 24,737 (0.9%) who were coded as having organ-confined disease with negative surgical margins also received postoperative radiation and were excluded from the analysis of adjuvant radiation use. Logistic regression analysis again revealed that Gleason score was the strongest unadjusted and adjusted predictor for subsequent delivery of adjuvant radiation (Tables 5 and 6). Patients with Gleason scores of 8 to 10 disease, with a PSA of >20 ng/mL, or with pathologic findings of extracapsular extension with positive surgical margins, seminal vesicle invasion, or pathologic T4 disease were most likely to receive radiation. In patients with these findings, adjuvant radiation was delivered between 18.4% and 21.2%.

Table 5. Logistic Regression Analysis of Unadjusted Predictors of Adjuvant Radiotherapy in Those With Non-Organ-Confined Disease or Positive Surgical Margins
VariableRadiotherapy UseOR95% CIP
  • OR indicates odds ratio; 95% CI, 95% confidence interval; PSA, prostate-specific antigen; OC, organ-confined; 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.

Gleason score
 64.7%1  
 7 (3+4)9.1%2.041.64-2.53<.001
 7 (4+3)12.4%2.872.27-3.64<.001
 8-1021.2%5.444.39-6.75<.001
Race
 White11.1%1  
 Black9.6%0.850.69-1.05.14
 Other13.7%1.271.00-1.60.05
PSA measurement, ng/mL
 ≤109.4%1  
 10.1-2014.8%1.691.45-1.97<.001
 >2020.9%2.562.12-3.09<.001
Age at diagnosis 0.990.98-0.99<.001
T classification
 T1c9.8%1  
 T2a-T2c12.7%1.341.19-1.51<.001
Pathologic extent
 OC, positive margins6.1%1  
 ECE, negative margins7.4%1.221.00-1.48.05
 ECE, positive margins19.0%3.303.04-4.27<.001
 SVI18.4%3.462.90-4.14<.001
 pT421.0%4.073.14-5.28<.001
SEER registry location
 Los Angeles9.5%1  
 New Jersey13.7%1.521.15-2.00.03
 Utah9.1%0.950.68-1.33.76
 Seattle12.5%1.361.06-1.74.02
 San Jose-Monterey11.5%1.240.85-1.81.26
 San Francisco-Oakland12.7%1.391.00-1.95.05
 Rural Georgia0%001
 New Mexico7.7%0.790.46-1.35.39
 Louisiana10.3%1.100.79-1.53.59
 Kentucky9.4%0.990.68-1.44.94
 Iowa12.4%1.351.01-1.80.04
 Hawaii25.4%3.242.27-4.64<.001
 Detroit14.6%1.641.23-2.17.001
 Connecticut7.8%0.800.56-1.16.24
 Californiaa10.5%1.120.91-1.37.30
 Atlanta7.9%0.820.42-1.60.57
 Alaska33%4.770.43-52.92.20
Y of diagnosis
 200412%1  
 200510.7%0.880.76-1.02.09
 200610.6%0.870.75-1.00.05
Table 6. Logistic Regression Analysis of Adjusted Predictors of Adjuvant Radiotherapy in Those with Non-Organ-Confined Disease or Positive Surgical Margins
VariableOR95% CIP
  • OR indicates odds ratio; 95% CI, 95% confidence interval; OC, organ-confined; 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.

Gleason score
 61  
 7 (3+4)1.811.45-2.26<.001
 7 (4+3)2.171.69-2.78<.001
 8-103.642.88-4.59<.001
Race
 White1  
 Black0.740.59-0.93.01
 Other0.980.75-1.29.89
PSA measurement, ng/mL
 ≤101  
 10.1-201.261.07-1.48.004
 >201.631.33-1.99<.001
Age at diagnosis0.970.96-0.98<.001
T classification
 T1c1  
 T2a-T2c1.141.00-1.29.05
Pathologic extent
 OC, positive margins1  
 ECE, negative margins0.970.79-1.19.78
 ECE, positive margins2.692.25-3.22<.001
 SVI2.351.94-2.86<.001
 pT43.092.35-4.07<.001
SEER registry location
 Los Angeles1  
 New Jersey1.571.17-2.09.003
 Utah1.000.71-1.41.99
 Seattle1.290.99-1.67.06
 San Jose-Monterey1.290.87-1.90.21
 San Francisco-Oakland1.350.95-1.92.09
 Rural Georgia001
 New Mexico0.690.40-1.20.19
 Louisiana1.030.73-1.45.89
 Kentucky0.960.65-1.41.82
 Iowa1.210.89-1.64.22
 Hawaii3.352.23-5.03<.001
 Detroit1.661.23-2.23.001
 Connecticut0.760.52-1.12.16
 Californiaa1.050.85-1.30.63
 Atlanta0.820.41-1.64.58
 Alaska9.490.74-122.4.09
Y of diagnosis
 20041  
 20050.840.72-0.98.03
 20060.800.69-0.93.004

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

To the best of our knowledge, the current study is the largest review of pathologic outcomes for patients with clinically localized CaP, as well as for patterns of care regarding adjuvant radiation use. We have found that those patients with Gleason score 6 disease are ultimately determined to have organ-confined disease with negative surgical margins >80% of the time after surgery, regardless of PSA level or T classification. This should translate to a very high rate of cure in these patients regardless of adjuvant therapy. However, with Gleason score 7 (3 + 4) disease and higher, the risk for EPE and/or positive surgical margins rises dramatically.

Prior studies have shown that local control after surgery depends on the presence of extracapsular extension, seminal vesicle invasion, positive surgical margins, increased Gleason score, and high preoperative PSA levels16-18 as does the risk of metastatic disease progression.19 Therefore, identifying patients with these risk factors plays an important role when discussing whether there may be a need for adjuvant treatment.

Although the data available in Table 2 provide useful information regarding pathologic extent of disease, the Gleason score information collected by SEER corresponds to the pathologic specimen rather than the biopsy. This may be a major limitation affecting interpretation of these data as a predictive tool for patients. However, contemporary studies have revealed that the incidence of undergrading of biopsy scores has been dramatically reduced in recent years and is mainly limited to biopsies that reveal Gleason score 6 disease, whereas those with biopsies of Gleason score 7 or higher have a very high concordance between biopsy and radical prostatectomy.20-23 Therefore, although these data should not be used strictly as a predictive tool, it is patients with biopsy Gleason scores of 6 who are most affected by this limitation and one should be aware that, if there is upgrading of the Gleason score after surgery, the risk of non-organ–confined disease will be dramatically different from what is reported in Table 2. However, for those with biopsy Gleason scores of 7 or higher, these results are useful in that they provide pathologic outcomes in a large number of patients in the community setting, in which the urologic surgeon may have less experience and where one is less likely to find a dedicated urologic pathologist.

These data also provide additional important pathologic information in the form of surgical margin status reporting, making this, to our knowledge, the largest such report in the published literature. Positive surgical margins after prostatectomy have been correlated with an increased risk of biochemical failure18, 24, 25 and have also been proposed as part of nomograms to predict for an increased risk of disease recurrence,26, 27 thereby rendering it an important variable when assessing for possible adjuvant therapy after radical prostatectomy. Although SEER does report the surgical margin status, it does not give pathologic details regarding the margin status such as the extent or the number of positive surgical margins, and these details may also impact the decision to offer adjuvant radiation. However, although the extent and number of positive surgical margins do predict for an increased risk of disease recurrence,28 even a focally positive surgical margin confers an inferior biochemical outcome,29, 30 therefore making it an important clinical parameter when considering adjuvant treatment.

These SEER data also provide interesting information regarding the patterns of care of these patients after surgery. In this study, approximately 29.9% of all the patients (n = 10,674) had indications for adjuvant radiation, due to EPE or positive surgical margins. However, only 11.1% (n = 1184) received adjuvant radiation. There has been debate in the literature regarding whether these patients should be treated immediately with radiation4-6 or observed closely with radiation reserved for salvage therapy.20, 31, 32 Three randomized trials have recently been performed comparing adjuvant radiation with observation for patients with positive surgical margins, extracapsular extension, or seminal vesicle invasion, and these trials have confirmed a benefit in biochemical control. The European Organization for Research and Treatment of Cancer (EORTC) 22911 trial revealed that, in addition to an improvement in biochemical progression-free survival from 53% to 74% at 5 years (P < .001), there was also a significant reduction in clinical disease progression as well as local failure (15% vs 5%; P < .0001).7 A large randomized study out of Germany by Wiegel et al revealed an improvement in biochemical progression-free survival from 54% to 72% at 5 years (P = .015).8 In both studies, there was no overall survival benefit with the addition of adjuvant radiation. However, it should also be noted that both trials were reported with 5-year follow-up, which is too short to definitively show a survival benefit. In addition, both trials were underpowered to definitively detect an overall survival benefit, because they were designed to detect improvements in progression-free survival but not overall survival.

The Southwest Oncology Group (SWOG) recently updated the results of SWOG 8794 and did report an improvement in the median overall survival from 13.3 years to 15.2 years with a hazard ratio of 0.72 (P = .023). In their initial report, the authors noted a reduction in the incidence of distant metastasis and a reduced incidence of initiation of hormone therapy.9 In a companion quality of life study,33 they also noted that although the acute genitourinary and gastrointestinal toxicity was worse in the radiation group, there was little difference between the groups by 2 years. In addition, the global quality of life was initially worse for the adjuvant radiation group, but became similar by 2 years and was increasingly superior in the radiation group during the following 3 years.

Although all 3 randomized trials have consistently reported improvements in biochemical control with the addition of adjuvant radiation for those patients with EPE or positive margins, it is likely that they did not have a major impact on the patterns of care regarding adjuvant radiation usage during the time period of this study. The EORTC study was published in full manuscript form in 2005, the SWOG study in 2006, and the German study in 2009, whereas the cases in this study were ascertained from SEER between 2004 and 2006. However, these data do provide a baseline of adjuvant radiation usage of 11.1% that can be used for future comparison. It will be interesting to learn whether the overall survival and quality of life results from the SWOG study, as well as the results from the other randomized trials, will impact on the use of adjuvant radiation in the future. If the randomized trials by Bolla et al and Wiegel et al do detect an overall survival benefit on longer follow-up, this should add very strong evidence supporting the use of adjuvant radiation, particularly given that these studies were underpowered to detect a survival benefit. However, as of 2006, it appeared that observation, or perhaps hormonal therapy, is the preferred therapy for patients with extraprostatic disease or positive surgical margins.

A possible limitation of the analysis regarding adjuvant radiation use is that perhaps not all patients who received adjuvant radiation were captured by the SEER database. Virnig et al13 compared the use of radiation as part of the first course of treatment as coded by SEER with use of radiation in the months after diagnosis as identified by Medicare claims. They found a 93% correlation 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 Medicare was between 94.2% and 94.8%, supporting the accuracy 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, lymphovascular invasion, percent of biopsy cores that were positive, 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 represent 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 surgical 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 observation 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES

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

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. CONFLICT OF INTEREST DISCLOSURES
  8. REFERENCES
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