The efficacy of early adjuvant radiation therapy for pt3n0 prostate cancer: a matched-pair analysis

Int. J. Radiation Oncology Biol. Phys., Vol. 45, No. 1, pp. 53–58, 1999 Copyright © 1999 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/99/$–see front matter

PII S0360-3016(99)00169-8

CLINICAL INVESTIGATION

Prostate

THE EFFICACY OF EARLY ADJUVANT RADIATION THERAPY FOR pT3N0 PROSTATE CANCER: A MATCHED-PAIR ANALYSIS RICHARD K. VALICENTI, M.D.,* LEONARD G. GOMELLA, M.D.,* MOHAMMED ISMAIL, M.D.,* STEVE E. STRUP, M.D.,* S. GRANT MULHOLLAND, M.D.,* ADAM P. DICKER, M.D.,* ROBERT O. PETERSEN, M.D.,* AND CRAIG J. NEWSCHAFFER, M.D.* *Departments of Radiation Oncology, Urology, Pathology, and Medicine, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA Purpose: This study examines the effect of adjuvant radiation therapy (RT) on outcome in patients with pT3N0 prostate cancer and makes comparisons to a matched control group. Methods and Materials: At our center, 149 patients undergoing radical prostatectomy were found to have pT3N0 prostate cancer, had an undetectable postoperative prostate-specific antigen (PSA) level, and had no immediate hormonal therapy. Fifty-two patients received adjuvant RT within 3 to 6 months of surgery. Ninety-seven underwent radical prostatectomy alone and were observed until PSA failure. From these two cohorts, we matched patients 1:1 according to preoperative PSA (<10 ng/ml vs. >10 ng/ml), Gleason score (<7 vs. >7), seminal vesicle invasion, and surgical margin status. Seventy-two patients (36 pairs) were included in the analysis. Median follow-up time was 41 months. We calculated a matched-pairs risk ratio for cumulative risk of PSA relapse (a rise above 0.2 ng/ml). Results: After controlling for the prognostic factors by matching, there was an 88% reduction (95% confidence interval [CI]: 78 –93%) in the risk of PSA relapse associated with adjuvant RT. The 5-year freedom from PSA relapse rate was 89% (95% CI: 76 –100%) for patients receiving adjuvant RT as compared to 55% (95% CI: 34 –79%) for those undergoing radical prostatectomy alone. Conclusions: These data suggest that adjuvant RT for pT3N0 prostate cancer may significantly reduce the risk of PSA failure as compared to radical prostatectomy alone. Its effect on clinical outcome awaits further follow-up. © 1999 Elsevier Science Inc. Prostate cancer, Adjuvant radiation therapy, Prostatectomy.

Over the past decade in the United States, there has been a gradual increase in the use of radical prostatectomy to treat men with prostate cancer (1). Despite accurate preoperative assessment to determine clinically localized disease, 30 to 60% of those undergoing surgery will be found to have microscopic tumor penetration of the prostatic capsule or positive surgical margins (2– 4). Although these men are likely to relapse biochemically and locally, the efficacy of early adjuvant radiation therapy (RT) remains controversial (5, 6). Many men at high risk of biochemical recurrence receive early adjuvant RT, with the intention that a reduction in the risk of biochemical recurrence will translate into improved overall survival. This is so, despite the fact that no completed Phase III randomized trial has been reported to demonstrate a benefit for using early adjuvant RT after radical prostatectomy. Because the combination of therapies increases the cost and may increase the risk of treatment-

related morbidity, there has been a trend to delay postoperative RT until evidence of cancer progression. Recently, clinical trials have been initiated to address the use of hormonal therapy in addition to salvage postoperative RT in men with an isolated biochemical failure after radical prostatectomy. Several prognostic factors have been identified that predict biochemical failure after radical prostatectomy alone for pT3N0M0 prostate cancer. Higher postoperative recurrence rates are associated with multiple positive surgical margins, seminal vesicle invasion (SVI), Gleason score of 7 or higher, and preoperative prostate-specific antigen (PSA) levels greater than 10 ng/ml (7–12). These factors may be used to stratify men into similar prognostic risk groups and to evaluate the effect of early adjuvant RT after radical prostatectomy. In the absence of mature data from Phase III trials, we carried out a matched-pair analysis of men with pT3N0M0 prostate cancer who underwent radical prostatectomy alone

Proferred paper presentation at ASTRO 98, Phoenix, AZ, October 28, 1998. Reprint requests to: Richard K. Valicenti, M.D., Department of Radi-

ation Oncology, Thomas Jefferson University Hospital, Bodine Center for Cancer Treatment, 111 S. 11th Street, Philadelphia, PA 19107. Accepted for publication 28 April 1999.

INTRODUCTION

53

54

I. J. Radiation Oncology

●

Biology

●

Physics

or in combination with early adjuvant RT. The purpose of this study was to determine the efficacy of adjuvant RT to prevent future PSA failure, local recurrence, and cancerspecific mortality. METHODS AND MATERIALS We evaluated 149 patients who had capsular penetration by cancer after radical retropubic prostatectomy, had a negative open pelvic lymph node dissection, and had an undetectable postoperative PSA level (⬍0.2 ng/ml). No patient received prior or adjuvant hormonal therapy or chemotherapy. The patients underwent treatment at our center between January 1988 and January 1996. Preoperatively, patients had history and physical examinations, serum PSA, abdominal/pelvic imaging, and radionuclide bone scan. Complete preoperative and postoperative PSA data were available for all men (Tandem R assay, Hybritech, San Diego, CA). Among the 149 patients studied, 52 received adjuvant RT within 6 months of radical prostatectomy. The remaining 97 patients did not receive any immediate adjuvant therapy. To control for possible confounding by prognostic factors, we compared a group of patients without RT with those who had similar baseline prognostic factors but received RT. To do this we matched patients pair-wise on preoperative PSA (⬍10 ng/ml vs. ⬎10 ng/ml), Gleason score (⬍7 vs. ⱖ7), SVI, and the presence of surgical margins. These features are highly predictive for recurrence in published analyses (7–12). When multiple patients matched, one was selected at random. All matching was done blind to patient outcome. Surgical specimens A single pathologist (R.O.P.) examined each radical prostatectomy specimen. Following amputation of the seminal vesicles, the prostate was weighed and measured. After inking of the outer surface, the entire prostate was serially sectioned in a transverse plane at 3-mm intervals beginning at the apex and continuing to the base. The first (apex) and the last (base) sections were further sectioned at 90 degrees to the surgical margins. The whole-mount serial sections were evaluated for tumor grade (Gleason system), capsular penetration, SVI, and surgical margin status. SVI was defined as the presence of tumor cells in the muscular coat of the seminal vesicles. Pathological as well as clinical stage was assigned according to the American Joint Committee on Cancer (13). As stated previously, only patients with pT3N0M0 prostate cancer were included in this study. Radiation therapy Generally, postoperative RT was delivered via a fourfield technique (anteroposterior, posteroanterior, and opposed laterals) using 25 MV photons. Custom blocking was used to minimize the dose delivered to normal adjacent tissues. Irradiation of the regional (pelvic) lymphatics was not routinely carried out. The clinical target volume (CTV) consisted of the prostatic/seminal vesicle bed and the

Volume 45, Number 1, 1999

periprostatic tissue. The fields were typically 10 by 10 cm or less. The daily doses were 1.8 to 2.0 Gy per day to the 93–95% isodose contour encompassing the CTV. Total RT doses ranged from 59.4 to 70.2 Gy (median ⫽ 64.8 Gy). Follow-up Patients were followed at 3- to 6-month intervals with history and physical examinations. A serum PSA level was obtained 4 to 6 weeks after radical prostatectomy and at all follow-up visits thereafter. For a rising serum PSA level, workup for recurrent disease included digital rectal exam, blood chemistries, chest X-ray, computed tomography of the abdomen and pelvis, and a radionuclide bone scan. From the date of surgery, the median follow-up time was 41 months. The median follow-up time was 43 and 40 months for the patients who did and did not receive adjuvant RT, respectively. Statistical analysis Patients were judged free from PSA failure (bNED) if the postoperative PSA value remained undetectable (⬍0.2 ng/ ml). For descriptive purposes, we estimated cumulative bNED survival by the Kaplan-Meier method (14). A matched-pair analysis for the cumulative risk of failure was performed to allow statistical testing, via McNemar test, of the null hypothesis that there is no difference between the two groups with respect to prognosis (15). An estimate of the adjusted, via matching, cumulative risk ratio is also given with approximate 95% confidence interval according to the method described by Rothman (16). Acute and late RT-related toxicities have been reported elsewhere (17). RESULTS A total of 36 matched pairs (72 patients) were evaluable for this analysis. Table 1 compares the patients included in the matched-pair analysis to the unmatched patients, stratified by adjuvant RT status. All men had disease confined to the prostate by rectal examination. Unmatched RT patients had prognostic factor distributions suggesting more advanced disease than the matched RT patients. However, while including these patients would likely lead to poorer outcome estimates for the RT group, these cases were excluded because comparable, poor-prognosis non-RT patients were not available. Consequently, their exclusion preserves the internal validity of the comparisons made in the matched-pair analysis. Also note that while excluded RT patients tended to be more likely to have markers of poor prognosis, the matched RT group is not devoid of patients with poor prognostic features. The distribution of most prognostic factors in the matched RT group is roughly comparable to the distribution in the total no adjuvant RT group. Outcome of the 52 patients who had adjuvant radiation therapy At a median follow-up time of 42 months, 43 adjuvant patients were alive and did not have any recurrence. The

Adjuvant RT for pT3N0 prostate cancer

● R. K. VALICENTI et al.

55

Table 1. Characteristics of 149 patients with pathologic T3N0 prostate cancer stratified by adjuvant radiation therapy status and inclusion in the matched pair analysis Adjuvant radiation therapy Patient Characteristics Age (years) Range Preoperative PSA (ng/ml) ⱕ10 ⬎10 Gleason score ⬍7 ⱖ7 Pathological stage T3a T3b Surgical margins Negative Positive Median follow-up (Months) Total

Matched No. (%)

Unmatched No. (%)

61 50–76

No adjuvant radiation therapy Total No. (%)

Matched No. (%)

Unmatched No. (%)

Total No. (%)

64 47–71

63 47–76

66 47–72

64 45–75

65 45–75

23 (64) 13 (36)

2 (13) 14 (87)

25 (48) 27 (52)

23 (64) 13 (36)

38 (62) 23 (38)

61 (63) 36 (37)

11 (31) 25 (69)

2 (13) 14 (87)

13 (25) 39 (75)

11 (31) 25 (69)

29 (47) 32 (53)

40 (41) 57 (59)

29 (81) 7 (19)

11 (69) 5 (31)

40 (77) 12 (23)

29 (81) 7 (19)

50 (82) 11 (18)

79 (81) 18 (19)

6 (17) 30 (83) 42

4 (25) 12 (75) 45

10 (19) 42 (83) 43

6 (17) 30 (83) 40

49 (80) 12 (20) 40

55 (57) 42 (43) 40

36 (69)

16 (31)

52 (100)

36 (37)

61 (63)

97 (100)

PSA ⫽ prostate-specific antigen.

bNED survival rates for the 52 patients were 88% (95% confidence interval [CI]: 79 –98%) at 3 years and 85% (95% CI: 74% to 98%) at 5 years (Fig. 1). Among the patients with recurrence, all have had isolated biochemical failure in the absence of clinical relapse. The median time from adjuvant RT to failure was 41 months, ranging from 29 to 59 months. After biochemical failure, the median time under observation was 12 months. Only 1 patient having failed postoperative RT is receiving hormonal therapy.

Fig. 1. bNED Survival for 52 adjuvantly irradiated patients with pT3N0 prostate cancer.

Matched pairs This analysis included 36 of the 97 patients undergoing radical prostatectomy alone, and 36 of the 52 patients receiving surgery and early adjuvant RT. As previously stated, the two cohorts were matched 1:1 according to preoperative PSA (⬍10 ng/ml vs. ⬎10 ng/ml), Gleason score (⬍7 vs. ⱖ7), SVI, and the presence of surgical margins. The median age was 61 years and 66 years for the adjuvant and matched cohorts, respectively. The respective proportion of African-Americans was 5.6% and 8.3% (p ⫽ 1.0). Figure 2 shows the bNED cumulative survival probabilities in the combined surgery and adjuvant radiation therapy compared to the surgery alone group. The 3-year bNED rate was 93% (95% CI: 84 –100%) for patients receiving early adjuvant RT and 66% (95% CI: 49 – 83%) for those undergoing radical prostatectomy alone. The corresponding 5-year bNED rate was 89% (95% CI: 76 –100%) and 55% (95% CI: 34 –79%). Table 2 summarizes the results from the matched-pair analysis. Of the 36 pairs, 11 had discordant outcome data (i.e., where one patient in the pair failed and the other did not). In 10 of those 11 cases it was the patient without adjuvant radiation therapy failing. Based on these data, after controlling for the influence via the matching, the cumulative risk of failure in patients with RT is 88% lower (95% CI 78 –93%) than that of the group without adjuvant RT among patients with comparable Gleason scores, PSAs, SVI, and surgical margin status. There were 3 biopsy-proven local failures, occurring in men who underwent surgery alone. There have been no other clinical recurrences. For the end-points of local recurrence, cancer-free survival, and overall survival, there were

56

I. J. Radiation Oncology

●

Biology

●

Physics

Fig. 2. bNED Survival for the 36 pT3N0 adjuvant patients compared to a matched cohort of 36 patients after radical prostatectomy alone.

too few events to meaningfully evaluate clinical outcome. Only one patient had died during follow-up. The cause of death was not cancer-related. Outcome of patients in biochemical relapse after prostatectomy alone Seventeen patients whose prostate cancer was treated by radical prostatectomy alone subsequently developed a rising PSA level. The median time from surgery to failure was 19 months, ranging from 9 to 57 months. After biochemical failure, the median time under observation was 30 months. Six men were treated by salvage postoperative radiation therapy; 9 were reported to have received hormonal therapy. The other patients remain under observation alone. Three of the 6 men who had salvage radiation therapy developed a second rising PSA level. Three men have developed a rising PSA level while receiving hormonal therapy. DISCUSSION In patients with prostate cancer extending beyond the prostatic capsule after radical prostatectomy, there is an Table 2. Results of matched pair analysis* No Adjuvant RT Adjuvant RT Failed bNED

Failed

bNED

2 10

1 23

RR ⫽ 0.12, 95% CI 0.07– 0.22. ␹2 ⫽ 5.82, p-value: 0.016. * The numbers represent the number of matched pairs not individual patients.

Volume 45, Number 1, 1999

increased probability of progression. Usually, the first indication of failure is the presence of a detectable PSA level during routine follow-up. Depending on the presence of nodal metastases, SVI, or positive surgical margins, the actuarial rates of PSA failure at 4 years have ranged from 29.4% to 73% (7, 8, 18, 19). It is unknown whether the isolated elevation in PSA in these patients represents local recurrence or occult distant metastases, thus making treatment decision and evaluation difficult. If an isolated PSA recurrence occurs after prostatectomy, long-term salvage has recently been reported to be unlikely with RT alone to standard doses (ⱕ64 Gy) (17, 20). It is also unclear whether routine adjuvant RT for pT3N0 prostate cancer with adverse prognostic features will prove more beneficial than the use of delayed salvage therapy. Ultimately, the success of immediate adjuvant RT will depend on our ability to select patients at high risk of biochemical progression who harbor underlying isolated local disease. Several studies have analyzed in a multivariate analysis which preoperative and pathological parameters independently correlate with progression after radical prostatectomy (9 –12). In a study of 337 cases, Kupelian et al. reported that preoperative PSA level, surgical Gleason score, extracapsular extension, and margin status were all independent prognostic factors to predict progression after radical prostatectomy (11). Although Gleason score was grouped differently, D’Amico et al. found that Gleason score, SVI, and margin status correlated with progression, but extraprostatic extension did not (10). Ohori et al. noted that SVI, Gleason score, and extraprostatic extension, but not margin status, predicted progression (12). In a subset of patients with surgical Gleason score of 7 in the absence of SVI or nodal metastasis, Epstein et al. also noted the strong prognostic significance of positive surgical margins in association with established extracapsular penetration (9). The lack of statistical significance in some studies, but not in others, for parameters predicting progression may relate to small sample sizes and not stratifying according to various prognostic parameters (9). None of the above studies specifically address parameters in pT3 prostate cancer correlating with progression after radical prostatectomy. To identify these parameters and to appropriately select patients for early adjuvant RT, Lowe and Lieberman carried out a prospective study of untreated pT3 patients (7). In their study, higher recurrence rates were associated with the presence of multiple positive surgical margins, Gleason scores of 7 or higher, and preoperative PSA level greater than 10 ng/ml. In another study, Epstein et al. found similar results (8). Based on this data and that of others, the preoperative PSA value (⬎10 ng/ml vs ⱕ10 ng/ml), Gleason score (ⱖ7 vs. ⬍7), surgical margin status, and SVI are strong predictors for biochemical failure after radical prostatectomy (9 –12). In the current study, we applied this information to group patients with pT3N0 prostate cancer according to similar prognostic risk categories. Historically, adjuvant RT has been used in pT3 patients with varying prognostic indications after radical prostatec-

Adjuvant RT for pT3N0 prostate cancer

tomy. Nevertheless, several studies have noted improved biochemical control and local tumor control in patients who had a radical prostatectomy and adjuvant RT rather than radical prostatectomy alone, but noted no significant survival difference (6, 18, 21). Conclusions from these studies as well as some others are limited by one or more of the following deficiencies (21– 23): 1) analyses used a case-control technique that failed to control for known risk factors; 2) prostates were not routinely serially sectioned; 3) studies included patients who receive hormonal therapy before and/or after surgery; 4) follow-up information antedated the availability of the PSA test to detect recurrence; 5) patients with an isolated PSA elevation in the immediate postoperative period were included; and 6) disease progression was compared without regard to duration of follow-up. To address these limitations, we performed a matchedpair analysis in a group of pT3N0 prostate cancer patients. The patients were matched 1:1 according to similar prognostic factors, had complete pre- and postoperative PSA data, and had not received hormonal therapy until time of recurrence. No patient had a detectable PSA level within 6 months after radical prostatectomy. In each case, pathological information was obtained by serially sectioning the prostate in its entirety. The results indicate that the addition of adjuvant RT is associated with a large and significant reduction in risk of treatment failure. The observed 5-year bNED rate after adjuvant RT was 89% (95% CI: 76 –100%) as compared to 55% (95% CI: 34 –79%) after surgery alone. Although the failure rate for the prostatectomy alone group is similar to corresponding rates noted in the literature, the failure rate for the adjuvant patients appears lower. Of note, by only including patients administered adjuvant postoperative RT without any prior evidence of disease progression, Schild found a 5-year bNED rate as high as 90% which is in concordance with our result (6). Similarly, at the Massachusetts General Hospital, the 3-year bNED rate was 88% if patients receiving salvage RT were excluded (24). With a median follow-up time from surgery of 42 months, we found a significant reduction in biochemical progression following adjuvant RT, but did not observe an

● R. K. VALICENTI et al.

57

effect on disease-free or overall survival. These data are in agreement with previous observations that early adjuvant RT affords no survival advantage (5, 6, 22). However, evaluation of our result must be tempered by the relatively short follow-up time after biochemical progression. The 17 patients with rising PSA levels after radical prostatectomy alone have been followed for a median time of 30 months since progression. Only 2 of these patients have been followed for more than 3 years. Of note, 3 patients have developed a rising PSA after salvage RT, and 3 have developed hormone refractory prostate cancer. Only a few patients in our study had clinical progression of disease. Unlike other reports, we found a survival equivalence that was due to the absence of clinical progression rather than to its occurrence, thus attesting to the potential efficacy of adjuvant RT and the need for longer follow-up. In addition to the length of follow-up, the small number of patients, the nonrandomized allocation of patients, and exclusion of unknown prognostic factors may limit conclusions of our study. Despite these limitations our data suggest that early adjuvant RT should be considered for men with pT3N0 prostate cancer. As previously reported, a potential advantage of early adjuvant RT over delayed salvage RT is that RT doses necessary to sustain PSA response are lower because the tumor burden may be smaller (17).

CONCLUSIONS Many men with pT3N0 prostate cancer but an undetectable postoperative PSA level eventually experience biochemical failure. For a matched group of patients, the use of early adjuvant RT reduces this risk significantly. Although most patients had adverse prognostic features (Gleason score ⱖ7 and positive surgical margins) suggesting eventual distant failure, there was nevertheless an improvement in the bNED rate associated with early adjuvant RT. Furthermore, adjuvant RT appears effective in sterilizing residual local disease in patients at risk for PSA failure after radical prostatectomy. Whether this is maintained and is translated into a long-term survival benefit remains to be seen.

REFERENCES 1. Mettlin C, Murphy GP, Menck H. Trends in treatment of localized prostate cancer by radical prostatectomy: Observations from the Commission on Cancer National Cancer Database. J Urol 1994;43:488. 2. Zincke H, Blute ML, Fallen MJ, et al. Radical prostatectomy for stage A adenocarcinoma of the prostate: Staging errors and their implication for treatment recommendations and disease outcome. J Urol 1991;146:1053. 3. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. JAMA 1997;277:1451. 4. Stamey TA, Villers AA, McNeal JE. Positive surgical margins at radical prostatectomy: Importance of the apical dissection. J Urol 1990;143:1166.

5. Anscher MS, Robertson CN, Prosnitz LR. Adjuvant radiotherapy for pathologic stage T3/T4 adenocarcinoma of the prostate: Ten year update. Int Radiat Oncol Biol Phys 1995;33:37. 6. Schild SE. Radiation therapy after prostatectomy: Now or later? Semin Radiat Oncol 1998;2:132. 7. Lowe BA, Lieberman SF. Disease recurrence and progression in untreated pathologic stage T3 prostate cancer: Selecting the patient for adjuvant therapy. J Urol 1997;158:1452. 8. Epstein JI, Carmichael M, Pizov G, et al. Influence of capsular penetration on progression following radical prostatectomy: A study of 196 cases with long-term followup. J Urol 1993;150: 135. 9. Epstein JI, Pound CR, Partin AW. Disease progression following radical prostatectomy in men with Gleason score 7 tumor. J Urol 1998;160:97.

58

I. J. Radiation Oncology

●

Biology

●

Physics

10. D’Amico AV, Whittington R, Malkowicz B. A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154:131. 11. Kupelian P, Katcher J, Levin H. Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 1996;48:249. 12. Ohori M, Wheeler TM, Kattan MW. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995;154:1818. 13. Fleming ID, Cooper JS, Henson DE, Hutter RV, Kennedy BJ, Murphy GP, O’Sullivan B, Sobin LH, Yarbro JW. American Joint Committee on Cancer: Manual for staging cancer, 4th ed. Philadelphia: J.B. Lippincott;1997. p. 221–224. 14. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457. 15. Armitage P, Berry G. Statistical methods in medical research. 2nd ed. Boston: Blackwell Scientific; 1985. p. 461. 16. Rothman K. Modern epidemiology. Boston: Little Brown; 1986. p. 276. 17. Valicenti RK, Gomella LG, Ismail M, Mulholland SG, Strup S, Petersen RO, Corn BW. Effect of higher radiation dose on biochemical control after radical prostatectomy for pT3N0 prostate cancer. Int J Rad Oncol Biol Phys 1998;42:501–506. 18. Stein A, deKernion JB, Dorey F, et al. Adjuvant radiotherapy in patients post-radical prostatectomy with tumor extending

Volume 45, Number 1, 1999

19.

20.

21.

22.

23.

24.

through capsule or positive seminal vesicles. J Urol 1992;39: 59. Zietman AL, Edelstein RA, Coen JJ, et al. Radical prostatectomy for adenocarcinoma of the prostate: The influence of preoperative and pathologic findings on biochemical diseasefree outcome. J Urol 1994;43:828. Cadeddu JA, Partin AW, DeWeese TL, et al. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998;159:173. Morgan WR, Zincke H, Rainwater LM, et al. Prostate specific antigen values after radical retropubic prostatectomy for adenocarcinoma of the prostate: Impact of adjuvant treatment (hormonal and radiation). J Urol 1991;145:319. Paulson DF, Moul JW, Robertson JE, Walther PJ. Postoperative radiotherapy of the prostate for patients undergoing radical prostatectomy with positive margins, seminal vesicle involvement and/or penetration through the capsule. J Urol 1990;143:1178. Gibbons RP, Cole BS, Richardson RG, Correa RJ Jr, Brannen GE, Mason JT, Taylor WJ, Hafermann MD. Adjuvant radiotherapy following radical prostatectomy: Results and complications. J Urol 1986;135:65. Morris MM, Dallow KC, Zietman AL, Park J, Althausen A, Henry NM, Shipley WU. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Onc Biol Phys 1997;38:731.