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ht. J. Radiation

Biol.

Phys., Vol. 37, No. 5, pp. 1053- 1058, 1997 Copyright 0 1997 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/97 $17.00 + .OO

PII SO360-3016( 96)00633-5

ELSEVIER

l

Oncology

Clinical Investigation EQUIVALENT BIOCHEMICAL FAILURE-FREE SURVIVAL AFTER EXTERNAL BEAM RADIATION THERAPY OR RADICAL PROSTATECTOMY IN PATIENTS WITH A PRETREATMENT PROSTATE SPECIFIC ANTIGEN OF > 4-20 rig/ml

ANTHONY

V. D’ AMICO,

CLAIR

M.D., PH .D.,* RICHARD WHITTINGTON, M.D.,+ IRVING KAPLAN, M.D.,* BEARD, M.D.,* MICHAEL JIROUTEK, M.S.,” S. BRUCE MALKOWICZ, M.D.,$ ALAN WEIN, M.D.’ AND C. NORMAN COLEMAN, M.D.*

*Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA; Departments of ‘Radiation Oncology and *Urology, Hospital of the University of Pennsylvania, Philadelphia, PA; and “Department of Biostatistics, Harvard School of Public Health and Dana Farber Cancer Institute, Boston, MA Purpose: Biochemical failure-free survival stratified by the pretreatment prostate-specific antigen (PSA) and biopsyleason score (bG1) is determined for prostate cancer patients managed definitively with external beam radiation therapy or radical retropubic prostatectomy. Methods and Materials: A Cox regression multivariable analysis evaluating tbe variables of PSA, bGI, and clinical stage was used to evaluate the end point of time to PSA failure in 867 and 757 consecutive prostate cancer patients managed definitively wltb external beam radiation therapy or radical retropubic prostatectomy, respectively. PSA failure-free survival was determined using Kaplan-Meier analysis. Comparisons were made using the log rank test. Results: The pretreatment PSA, bG1, and clinical stage (T3,4 vs. Tl,T2) were found to be independent predictors of to post-treatment PSA failure for both surgically and radiation managed patients using Cox regression multivariable analysis. Patients with a pretreatment PSA of > 4 rig/ml and 5 20 rig/ml could be classified into risk groups for time to post-therapy PSA failure: low = PSA > 4-10 rig/ml and bG1 -= 4; intermediate = PSA > 4-10 and bG15-7; or PSA > lo-20 rig/ml and bGI 5 7; high = PSA > 4-20 rig/ml and bG1 2 8. Two-year PSA failure-free survival for surgically managed and radiation-managed patients, respectively, were 98% vs. 92% (p = 0.45), 77% vs. 81% (p = 0.86), and 51% vs. 53% (p = 0.48) for patients at low, intermediate, and high risk for post-therapy PSA failure. Conclusions: There was no statistical difference in tbe 2-year PSA failure-free survival for potentially curable patients managed definitively with surgery or radiation therapy when a retrospective comparison stratifying for the pretreatment PSA and bG1 was performed. 0 1997 Elsevier Science Inc. Prostate cancer, Prostate-specific antigen, Gleason score, Radiation therapy, Radical prostatectomy.

The American literature (6, 18, 24, 25, 30, 32) on the management of clinically localized adenocarcinoma of the prostate supports that patients accepted for definitive therapy with a radical prostatectomy generally have a lower pretreatment prostate-specific antigen (PSA) value than those referred for definitive management with external beam radiation therapy. PSA has been shown by nearly all surgical (6, 15, 18, 24, 25, 3 1) and radiation series (9, 11, 20, 21, 30) to be the most important clinical pretreatment predictor of post-therapy PSA failure-free survival (bNED). Therefore, it is of no surprise that surgical series, when compared retrospectively by stage or Gleason score

to external beam radiation series, appear to be superior. Considering the vast difference in the morbidity between radical prostatectomy and external beam radiation tberapy, favoring the latter (26)) it is unfortunate that a prospective comparison of the efficacy of these two therapeutic modalities has not been completed stratifying for known prognostic factors (PSA and Gleason score). In this report, a large external beam radiation and radical prostatectomy series from the PSA era are analyzed for post-therapy outcome (bNED) as a function of the known prognostic factors of PSA and the biopsy Gleason score. It has been previously established that patients with a pretreatment PSA > 20 rig/ml or 5 4 rig/ml are unlikely or very likely respectively to benefit from either a primary

Reprint requests to: A. V. D’Amico, M.D., Ph.D., JointCenter for Radiation Therapy, 330 Brookline Avenue, Boston,

MA 02215. Acceptedfor publication11 October 1996.

INTRODUCTION

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l

Table 1. Percent distribution of pretreatment clinical factors for 867 and 757 prostate cancer patients managed with external beam radiation therapy and radical prostatectomy. respectively* Clinical factor PSA > PSA > PSA > PSA > Biopsy Biopsy Biopsy Biopsy Clinical Clinical

O-4 nglml 4-10 rig/ml IO-20 rig/ml 20 rig/ml Gleason 2-4 Gleason 5-6 Gleason 7 Gleason S- 10 Stage T1.2 Stage T3.4

Radiation 15.9% (138) 36.1% (313) 23.1% (200) 24.9% (2 16) 13.8% (120) 45.9% (398) 27.7% (240) 12.6% (109) 86% (784) 14% (83)

Surgery 10.7% 52.7% 24.2% 12.4% 22.5% 54.4% 13.1% 10.0% 97% 3%

(81) (399) (183) (94) (170) (412) (99) (76) (734) (23)

p Value 0.0022 <0.0001 0.64 <0.0001 <0.0001 <0.0001 <0.0001 0.11 <0.0001 <0.0001

* Parentheses indicate absolute number of patients.

surgical (2, 5, 15) or radiation approach (8, 13, 23, 29). Therefore, the focus of this report is on the remaining patients who constitute the vast majority of prostate cancer patients. In particular, the group examined are patients with a presenting PSA < 4 rig/ml but not > 20 rig/ml. In thesepatients, the issueof optimal local therapy continues to be debated.

METHODS

AND MATERIALS

Patient selection Consecutive patients treated definitively with external beam radiation therapy at the Joint Center for Radiation Therapy (n = 867) or with a radical retropubic prostatectomy at the Hospital of the University of Pennsylvania (n = 757) for adenocarcinoma of the prostate between 1989 and 1995 form the basis of this study. Staging evaluation included a history and physical exam, including a digital rectal exam (DRE), serum PSA, computed tomography (CT) of the pelvis or magnetic resonanceimaging (MRI) with an endorectal and pelvic coil, bone scan, and a transrectal ultrasound guided (TRUS) needle biopsy of the prostate with Gleason sum histologic grading. A sextant biopsy was performed using a 18-g Tru-Cut needle (Travenol Laboratories, Deerfield, IL) via a transrectal approach with additional biopsies taken in areasof palpable abnormalities on digital rectal examination. The clinical stage was obtained from the DRE using the 1992 American Joint Committee on Cancer (AJCC) staging system ( 1). The PSA was obtained on an ambulatory basisprior to radiologic studies and biopsy. All PSA measurements were made using the Hybritech assay ( 16). Patient treatment All patients managed with definitive external beam radiation therapy were treated using 2 IO-MV photons and a conformal shapedfour-field technique to a median total dose of 67 Gy (range 66-69) _Patients received 45 Gy in 1.8-Gy fractions to the prostate and seminal vesicles with a 1.5-2.0-cm margin and a cone down to the prostate with

Volume 37, Number 5, 1997

a 1.5-2.0-cm margin for an additional 22-24 Gy. In general, patients with PSA < 10 ngfml and biopsy Gleason sum 2-4 were treated to the prostate only with a 1.5-2.0cm margin to 66 Gy in 2-Gy fractions. All surgically managed patients underwent a bilateral pelvic lymph nodal sampling followed by a radical retropubic prostatectomy. Surgically managedpatients found to have positive pelvic lymph nodes (n = 9) had the prostatectomy aborted and were managedwith total androgen suppression.Thesepatients were included in the surgical database. Patients managed with radiation therapy did not have a surgical assessmentof the pelvic lymph nodes.No patient received androgen ablative therapy or other systemic therapy prior to, during, or after radiation therapy or surgery up to the time of their follow-up in this study. FoEEow-up. The patients were seen 1 month after external beam radiation therapy or radical prostatectomy, then at 3-month intervals up to 2 years, and then every 6 months to 5 years, and annually thereafter. At each followup a DRE was performed and serum PSA obtained. Two serial rising or two detectable PSAs obtained at least 3 months apart after a nadir level or nondetectable level were considered evidence of a biochemical failure in radiation and surgically managedpatients, respectively. The time of PSA failure was defined as the time of the first rising or detectable PSA. In addition to this requirement in the radiation managed patients, a PSA nadir above 1.0 was also considered a biochemical failure. This definition was employed to minimize the potential overestimation of bNED rates in radiation-managed patients that can occur owing to patients whose biochemical failure occurs late (e.g., > 4 years). All baseline values of PSA obtained prior to treatment were obtained within 3 weeks of the day of surgery or the first day of radiation therapy. No patient was lost to follow-up, and treatment at the time of PSA failure was at the discretion of the responsible physician. StatisticaE methods. A Cox regression multivariable analysis (4) evaluating the variables of PSA (continuous), biopsy Gleason score (discrete integer 2- 10, inclusive), and clinical stage (Tl vs. T2 vs. T3.4) was employed to evaluate the end point of time to PSA failure. Time zero was defined as the last day of radiation therapy or the day of surgery. Actuarial freedom from PSA failure was calculated using an actuarial method described by Kaplan and Meier ( 12), and comparisons were made using the log rank test. Proportions of patients in radiation vs. surgically managed subgroups were compared using a Pearson’s chi-squared test.

RESULTS Patient characteristics The distribution of the clinical stage, PSA, and biopsy Gleason sum for the 867 and 757 consecutive patients treated with either external beam radiation therapy or radical prostatectomy are listed in Table 1. There was a statistically significant increase in the clinical factors of T3,4

Equivalent bNED after radiation or surgery l A. V. D’Amico ei al. Table 2. Summary of p valuesfrom Cox regression

multivariableanalysisfor radiation-managed and surgically-managed patients* Clinical factor PSA Biopsy Gleasonscore Clinical StageTl Clinical StageT2 Clinical StaeeT3.4

Radiation (p value)

Surgery (p value)

0.0001 0.01

0.000 1

0.0001

NS

NS 0.005

0.006

NS = p > 0.05. A p value is not given for clinical StageTl becausethis is the baselinegroupto which T2 andT3,4 patients are compared.

(14% vs. 3%: p < O.OOOl), PSA > 20 rig/ml (24.9% vs. 12.4%; p < O.OOOl), and biopsy Gleason score of 7 (27.7% vs. 13.1%; p < 0.0001) in the radiation-managed patients. Conversely, surgically managed patients had a statistically significant increase in favorable clinical factors including clinical stage T1,2 (97% vs. 86%; p < O.OOOl), PSA > 4-10 rig/ml (52.7% vs. 36.1%; p < O.OOOl), and biopsy Gleason scores of 2-4 (22.5% vs. 13.8%; p < 0.0001) and 5-6 (54.4% vs. 45.9%; p < 0.0001), Cox regression multivariable analysis The median follow-up for the radiation and surgically managed patients without PSA failure was 2.2 and 2.5 years, respectively. The median time to PSA failure was 1.42 and 1.33 years for patients treated with radiation or

1055

surgery, respectively. The pretreatment PSA, biopsy Gleason score, and clinical stage (T3,4 vs. Tl, T2) were significant predictors of time to PSA failure after management with either external beamradiation therapy or radical prostatectomy; Table 2 summarizes the results. PSA failure-free survival following definitive local therapy The bNED outcome for all surgically (n = 582) and radiation (n = 5 13) managedpatients with a pretreatment PSA > 4 rig/ml and 5 20 rig/ml is shown in Fig. 1. The statistically significant increase (p < 0.0001) in T3,4 patients treated with radiation, and the significant increase (p < 0.0001) in patients with a pretreatment PSA > 410 rig/ml and biopsy Gleason score 2-6 managed surgically can account for the numerical, but not statistically significant difference in the 3- and 4-year bNED rates (73% vs. 62%; 64% vs. 47%; p = 0.96) for the surgical and radiation therapy groups, respectively. Using the results of Cox regression multivariable analysis, it was possible to group patients using the PSA and biopsy Gleason score in a manner which allows for the stratification of patients with a pretreatment PSA > 4-20 rig/ml into low ( 5 lo%), intermediate ( -25% ), and high risk (-50%) for post-therapy PSA failure within 2 years. The risk groups are defined as follows: low = PSA > 4-10 rig/ml and bG1 5 4; intermediate = PSA > 4-10 and bG15-7; or PSA > lo-20 rig/ml and bG1 I 7; high = PSA > 4-20 rig/ml and bG1 2 8. The PSA failure-free survival for the surgically and radiation-managed patients grouped using this stratification are shown in Fig. 2. Interestingly, for each group there is

p=o.9638

0% _I

582

NW.)

3.48

1 0

I 0.5

I 1.0

199 I 1.5

Fig. 1. Prostate-specific antigen (PSA) failure-free pretreatment PSA > 4 rig/ml and 520 rig/ml.

I 2.0

‘08 I 2.5

39

IO

I

I

I

I

1

3.0

3.5

4.0

4.5

5.0

survival for the surgically and radiation-managed

patients with

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no statistical difference in the bNED outcome between surgical and radiation-managed patients. In particular, 2year PSA failure-free survival for surgically and radiationmanaged patients, respectively, were 98% vs. 92% (p = 0.45), 77% vs. 81% (p = 0.86), and 51% vs. 53% (p = 0.47) for patients at low, intermediate, and high risk for post-therapy PSA failure. Most (85-90%) patients with pathologic organ-confined disease have been shown to remain disease-free clinically at 10 years postoperatively (27). Interestingly, the 2-year PSA failure-free rates computed using an actuarial calculation closely approximate (within - 10%) the pathologic organ confinement rate for all patients, as shown in Table 3. This suggests that with further follow-up, 85-90% of the patients who are bNED at 2 years may remain without clinical evidence of diseasefor 10 years. That these 2-year bNED values are not significantly different (p 2 0.45) among radiation- and surgically managed patients suggests the equivalence of sterilization of local disease by either local modality when the disease is still pathologically organ-confined. However, it is important to note that up to a third of patients considered to be recurrence-free by clinical criteria at 10 years after external beam radiation therapy have been reported to have a rising PSA (22,24) which will likely translate into a clinical failure given enough time. Therefore, the clinical relevance of a lo-year clinical NED rate must be considered on an individual basis, taking into account the patient’s age, comorbidity status,.and wishes.

Volume 37, Number 5, 1997 Table 3. Two-year PSA failure-free survival rates calculated using an actuarial method for surgically andradiation-managed patients stratified by risk group on the basis of pretreatment PSA and biopsy Gleason score* Risk group Low PSA > 4-10 Intermediate PSA > 4-10 > lo-20 High PSA > 4-20

rig/ml and bG1 5 4 and bG15-7; PSA rig/ml and bG1 5 7 q/ml and bG1 2 8

pOC dz = pathologic

pOC dz

RT

Sx

p Value

87%

92%

98%

0.45

71%

81%

77%

0.86

47%

53%

51%

0.48

organ-confined

disease; RT = radiation

therapy. Sx = surgery.

DISCUSSION There has been a single prospective, randomized trial performed in the United States comparing external beam radiation therapy to radical prostatectomy; this was performed by the Uro-Oncology group and published by Paulson et al. in 1982 ( 19). The multiple flaws in this trial which resulted in a comparison skewed toward clinical stage T3 prostate cancer managedby radiation vs. clinical stage Tlb,2 prostate cancer managed with surgery have been previously elucidated by Dr. Hanks (7 ) . Today, with the advent of PSA, treatment failures after therapy can be assessedin a rigorous and nonbiased manner. However, a

a f 4

_______________---_____

I p-o.4770

iFi! sliw

Fig. 2. Prostate-specific antigen (PSA) failure-free survival for surgically and radiation-managed patients stratified into risk groups (lr = low risk; ir = intermediate risk, hr = high risk) usingthepretreatmentPSA andbiopsyGleason score.Low risk = PSA > 4-10 nglml andbG15 4; intermediaterisk = PSA > 4-10 andbG15-7; PSA > lo20 rig/ml and bG1 5 7; high risk = PSA > 4-20 nglml and bG1 z 8.

Equivalent bNED after radiation or surgery 0 A. V. D’Amico et al.

trial of surgery vs. external beam radiation therapy in the current medical environment would be difficult because of a variety of factors, including physician bias and the media ( 10). Considering the vast difference in the morbidity (26) between radical prostatectomy and external beam radiation therapy, favoring the latter, which have been recently quantified in a prospective multi-institutional setting, it is unfortunate that a prospective comparison of the efficacy of these two therapeutic modalities has not been completed stratifying for all known prognostic factors (PSA or Gleason score). Currently, this leaves retrospective comparisons such as the one presented in this report to provide a basis for therapeutic recommendations. The pretreatment PSA has been shown to be a powerful tool for assessingthe likelihood that the cancer is pathologically organ-confined (15, 17, 31), and therefore potentially curable with a local therapy. As a result, when evaluating PSA failure-free survival after therapy for all patients treated at a single institution, surgery will appear to have a better outcome compared to radiation because of an imbalance (in favor of surgery) of the pretreatment prognostic factors (e.g., PSA). As shown in this retrospective study and others ( 13)) once the clinically significant predictors of time to PSA failure are stratified for in both treatment groups, PSA failure-free survival rates are not statistically different at 2 years. Only in the low-risk group consisting of patients with well-differentiated (biopsy Gleason sum 2-4) and small-volume (PSA of at least 4 nglml but not > 10 ng/ ml) lesions was there a substantial (6%) but not significant (p = 0.45) numerical difference. Further followup and larger numbers in this group will define whether the difference is significant. However, it is important to consider that some investigators (3) defend watchful waiting in this patient subgroup given an appropriate clinical setting (e.g., advanced age and significant comorbidities) . Therefore, the clinical relevance of a potential difference in this patient population is currently not clear. It is also interesting that the 2-year PSA failure-free survival values in both the radiation and surgical series closely approximate (within - 10%) the pathologic organ confinement rate (Table 3). Eighty-five to 90% of patients found to have pathologic organ-confined disease have been shown to remain disease-free clinically at 10 years, respectively, postoperatively. This finding suggests that 85-90% of patients who are biochemically failure-free at 2 years may remain without clinical evidence of disease at 10 years as a result of either definitive local therapy. External beam radiation therapy, however, causes a significantly lower risk of genitourinary morbidity and sexual dysfunction as shown recently in a prospective multi-institutional study by Talcott and colleagues (26) (Table 4). From the numerical concordance of pathologic organ confinement rates and 2-year PSA failure-free rates ob-

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Table4. Percentgastrointestinalor genitourinarycomplications and sexualdysfunction following definitive externalbeam radiationtherapy or radicalprostatectomy* Symptom

Rx Baseline 12 mot

At leastmild tenderness or urgencyduring bowel movements Sx RT

3% 2% p > 0.05

Urinary incontinence requiring pads (in last week)

sx

RT Had no erections (in last 4 weeks)

sx RT

6% 19% p 5 0.01

24 mo*

2% 18% p 5 0.01

2%

35% 42% 5% 5% p > 0.05 p < 0.001 p < 0.001

1%

11% 18%

75% 67% 33% 39% p > 0.05 p < 0.001 p < 0.001

* Data aretakenfrom anASCO abstract(26), with permission. Rx = treatment;RT = externalbeamradiationtherapy(n = 135); Sx = radical retropubic

prostatectomy

(n = 125).

+ 12-monthdatarepresentresponses from 85% of all patients. * 24-monthdatarepresentresponses from 51% of all patients.

tained using either local modality, one could postulate that disease that is pathologically organ-confined, and therefore curable in 85-90% of cases with a surgical approach, is also radiocurable using conventional radiotherapeutic doses. Conversely, disease that has penetrated the capsule may not be curable by either local modality despite negative surgical margins or wider radiation fields because of associated occult micrometastatic disease. The latter conjecture raises the issue of whether some patients (i.e., with occult hormone-sensitive metastatic disease) in this subgroup can be cured with the addition of androgen suppressiontherapy. Current ongoing Phase three trials (e.g., Radiation Therapy Oncology Group 9408) will help to address this issue. In summary, this retrospective comparison of external beam radiation therapy and radical prostatectomy stratified for the known prognostic factors of PSA and biopsy Gleason score demonstrates comparability in the 2-year PSA failure-free results for patients with a pretreatment PSA > 4 and 5 20 rig/ml. Biochemical failure-free rates at 2 years in this population are numerically similar to the pathologic organ confinement rates, suggesting that with further follow-up, the 2-year bNED rates may translate into long-term (lo-year) clinical control of the disease. A prospective assessmentof the relative genitourinary morbidity as well as sexual dysfunction is now available from a multi-institutional setting, concluding in favor of radiation therapy. Therefore, with further follow-up, if the equivalence in bNED rates remains between surgery and external beam radiation therapy, then radiation therapy should be the preferred method of local management for patients with adenocarcinoma of the prostate.

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REFERENCES 1. Beahrs, 0. H.; Henson, D. E.; Hutter, R. V. P.; Kennedy, B. J. American Joint Committee on Cancer manual for staging cancer, 4th ed. Philadelphia, PA: J. P. Lippincott; 1992. 2. Catalona, W. J.; Smith, D. S. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J. Urol. 152:1837- 1842; 1994. 3. Chodak, G. W.; Thisted, R. A.; Gerber, G. S.; Johansson, J. E.; Adolfsson, J.; Jones, G. W.; Chisholm, G. D.; Moskovitz, B.; Livine, P. M.; Warner, J. Results of conservative management of clinically localized prostate cancer. N. Engl. J. Med. 330:242-248; 1994. 4. Cox, D. R. Regression models and life tables. J. R. Stat. Sot. B34:l; 1972. 5. D’Amico, A. V.; Whittington, R.; Malkowicz, S. B.; Schnall, M.; Tomaszewski, J. E.; Schultz, D.; Wein, A. A multivariate analysis of clinical and pathological factors which predict for prostate-specific antigen failure after radical prostatectomy after prostate cancer. J. Urol. 154: 131- 138; 1995. 6. Frazier, H. A.; Robertson, J. E.; Humphrey, P. A.; Paulson, D. F. Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy? J. Urol. 149:516; 1993. Research Group 7. Hanks, G. E. More on the Uro-Oncology report of radical surgery versus radiotherapy for adenocarcinema of the prostate. Int. J. Radiat. Oncol. Biol. Phys. 14:1053- 1057; 1988. 8. Hanks, G. E.; Hanlon, A. L.; Hudes, G.; Lee, W. R.; Winlove, S.; Schultheiss, T. Patterns-of-failure analysis of patients with high pretreatment prostate-specific-antigen levels treated by radiation therapy: The need for improved systemic and local regional therapy. J. Clin. Oncol. 14:1093-1097; 1996. 9. Hanks, G. E.; Perez, C. A.; Kozar, M. B.; Asbell, S. 0.; Pilepich, M. V.; Kaplan, R. Prostate specific antigen confirmation of long term cure of prostate cancer treated by external beam radiation in the RTOG. Int. J. Radiat. Oncol. Biol. Phys. 27(Suppl. 1): 192; 1993 (abstr). 10. Jaroff, L. The man’s cancer. Time Magazine. 147:58-66; April 1, 1996. 11. Kaplan, I. D.; Cox, R. S.; Bagshaw, M. A. Prostate specific antigen after external beam radiotherapy for prostatic cancer: Followup. J. Urol. 149:519; 1993. 12. Kaplan, E. L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 53:457-481; 1958. A. M.; Schellhammer, P. F. 13. Kuban, D. A.; El-Mahdi, Prostate-specific antigen for pretreatment and post-treatment evaluation of outcome after definitive irradiation for prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 32:307316; 1995. 14. Kupelian, P.; Levin, H.; Zippe, C.; Klein, E. A contemporary series of external beam radiotherapy versus radical prostatectomy for localized prostate cancer: A single institution experience: Proceedings of the 32nd meeting of ASCO. J. Clin. Oncol. 15:252; 1996 (abstr). 15. Lange, P. H.; Ercole, C. J.; Lightner, D. J.; Fraley, E. E.; Vessella, R. The value of prostate specific antigen determinations before and after radical prostatectomy. J. Urol. 141:873; 1989. 16. Myrtle, J. F.; Klimley, P. G.; Ivor, L. P.; and Brun, J. F.; Clinical utility of prostate-specific antigen (PSA) in the management of prostate cancer. Adv. Cancer Diagn. Hybritech, Inc., San Diego, CA.; 1986. 17. Ohori, M.; Wheeler, T. M.; Dunn, J. K.; Stamey, T. A.; Scardino, P. T. The pathological features and prognosis of pros-

18.

19.

20.

21.

22. 23.

24.

25.

26.

27.

28. 29.

30.

31.

32.

tate cancer detectable with current diagnostic tests. J. Urol. 152:1714-1720; 1994. Partin, A. W.; Pound, C. R.; Quentin Clemens, J.; Epstein, J. I.; Walsh, P. C. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol. Clin. N. Am. 20:713; 1993. Paulson, D. F.; Lin, G. H.; Hinshaw, W.; Stephani, S.; and the Uro-Oncology Research Group. Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J. Urol. 128:502; 1982. Pisansky, T. M.; Cha, S. S.; Earle, J. D.; Durr, E. D.; Kozelsky, T. F.; Wieand, S.; Oesterling, J. E. Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer. J. Clin. Oncol. 11:2158; 1993. Ritter, M. A.; Messing, E. M.; Shanahan, T. G.; Potts, S.; Chappell, R. J.; Kinsella, T. S. Prostate specific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer. J. Clin. Oncol. 10:1208; 1992. Rosenzweig, K. E.; Morgan, W. R.; Lytton, B.; Peschel, R. E. Prostate specific antigen following radiotherapy for local prostate cancer. J. Urol. 153:1561; 1995. Sandler, H. M.; McLaughlin, P. W.; Kish, K. E.; Lichter, A. Results of 3D conformal radiotherapy for the treatment of 707 patients with localized prostate cancer: Proceedings of the 37th ASTRO. Int. J. Radiat. Oncol. Biol. Phys. 32(Suppl. 1):141; 1995 (abstr). Schellhammer, P. F.; El-Mahdi, A. M.; Wright, G. L.; Kolm, P.; Rale, R. Prostate-specific antigen to determine progression free survival after radiation therapy for localized carcinoma of the prostate. Urology 42:13; 1993. Stein, A.; de Kemion, J. B.; Smith, R. B.; Dorey, F.; Patel, H. Prostate specific antigen levels after radical prostatectomy in patients with organ confined and locally extensive prostate carcinoma. J. Urol. 147:942; 1992. Talcott, J. A.; Rieker, P.; Propert, K. J.; Clark, J.; Kantoff, P.; Beard, C.; Kaplan, I.; Loughlin, K.; Richie, J.; Wishnow, K. Long-term complications of treatment for early prostate cancer: 2-year followup in a prospective multi-institutional outcomes study: Proceedings of the 32nd meeting of ASCO. J. Clin. Oncol. 15:252; 1996 (abstr). Trapasso, J. G.; deKemion, J. B.; Smith, R. B.; Dorey, F. Incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J. Urol. 152:1821-1825; 1994. Zagars, G. K.: Prostate specific antigen as outcome variable for Tl and T2 prostate cancer treated by radiation therapy. J Urol. 152:1786-1791; 1994. Zagars, G. K.; Pollack, A.; Von Eschenbach, A. C. Prostate cancer and radiation therapy-The message conveyed by serum prostate-specific antigen. Int J. Radiat. Oncol. Biol. Phys. 33:23-35; 1995. Zietman, A. L.; Coen, J. J.; Shipley, W. U.; Efird, J. Radical radiation therapy in the management of prostate adenocarcinema: The initial PSA value as a predictor of treatment outcome. J. Urol. 151640; 1994. Zietman, A. L.; Edelstein, R. A.; Coen, J. J.; Babayan, R. K.; Krane, R. J. Radical prostatectomy for adenocarcinoma of the prostate: The influence of preoperative and pathologic findings on biochemical disease-free outcome. Urology 43:828; 1994. Zietman, A. L.; Shipley, W. U.; Coen, J. J. Radical prostatectomy and radical radiation therapy for clinical Stages Tl to 2 adenocarcinoma of the prostate: New insights into outcome from repeat biopsy and prostate specific antigen followup. J. Urol. 152:1806-1812; 1994.