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Effect of Adjuvant Radiation Therapy on Prostate Specific Antigen Following Radical Prostatectomy
0022-5347/90/1436-1174$02.00/0 THE JOURNAL OF UROLOGY Copyright© 1990 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 143, June
Printed in U.S. A.
EFFECT OF ADJUVANT RADIATION THERAPY ON PROSTATE SPECIFIC ANTIGEN FOLLOWING RADICAL PROSTATECTOMY M'LISS A. HUDSON*
AND
WILLIAM J. CATALONA
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
A total of 21 patients received adjuvant radiation therapy after radical prostatectomy for a persistently detectable prostate specific antigen value (more than 0.6 ng. per ml.) postoperatively. Adjuvant radiation therapy decreased serum prostate specific antigen values to the undetectable range in 6 of 21 patients (29%) all of whom have remained free of tumor recurrence with a mean followup of 12.6 months (range 6 to 30). Three patients initially showed a decrease in serum prostate specific antigen to undetectable levels but they subsequently demonstrated an increasing level within 12 months after adjuvant radiation therapy. Additionally, 7 of 13 patients whose prostate specific antigen values remained in the detectable range despite adjuvant radiation therapy have had clinical evidence of tumor recurrence. Further followup will be required to determine what ultimate impact adjuvant radiation therapy will have on survival free of tumor. (J. Ural., 143: 11741177, 1990)
The greatest clinical usefulness for prostate specific antigen (PSA) appears to be to monitor the response to therapy after treatment of prostate cancer. 1- 5 After radical prostatectomy for clinically localized prostate cancer serum PSA should, in theory, decrease to undetectable levels because all prostatic tissue should be removed with this operation. In patients undergoing radical cystoprostatectomy for invasive bladder cancer PSA values have been observed routinely to decrease to undetectable levels. 6 In several clinical series, including 1 at our institution, it has been shown that PSA values do indeed decrease to undetectable levels in approximately 90% of the patients with pathologically confirmed, organ-confined prostate cancer. 3 •5- 7 In our series only a third of the patients with seminal vesicle invasion or lymph node involvement demonstrated a decrease in PSA levels to the undetectable range following radical prostatectomy. 6 This finding implies that residual tumor may remain (possibly only in the pelvis) in up to two-thirds of these patients. Of the patients with seemingly organ-confined prostate cancer confirmed on pathological examination after radical prostatectomy 10% demonstrate persistently detectable PSA levels and, therefore, they also may be harboring residual tumor. 3 • 5 - 7 Based on these data several investigators have recommended adjuvant radiation therapy for patients with persistently detectable PSA levels after radical prostatectomy. 2• 8 Adjuvant radiation therapy has been shown to decrease serum PSA levels to the undetectable range in some patients with persistently detectable PSA values after radical prostatectomy, although only a small number of patients have been reported on to date. 2 •8 We report our experience with adjuvant radiation therapy after radical prostatectomy in patients with a detectable PSA level postoperatively and no evidence of distant metastases. MATERIALS AND METHODS
Patients. A total of 250 men with biopsy proved adenocarcinoma of the prostate underwent radical retropubic prostatectomy between February 1983 and October 1988 for clinically localized cancer as judged by rectal examination, a negative bone scan and a negative computerized tomography (CT) scan Accepted for publication December 15, 1989. * Requests for reprints: Division of Urologic Surgery, Washington University School of Medicine, 4960 Audubon Ave., St. Louis, Missouri 63110.
of the abdomen. Adjuvant radiation therapy was offered to 80 patients with a detectable PSA value postoperatively. A total of 21 patients elected to receive adjuvant radiation therapy after radical prostatectomy and were followed until September 1989. These patients had PSA levels that had never decreased into the undetectable range. Of the 21 patients 19 underwent adjuvant radiation therapy based solely on a detectable serum PSA value after radical prostatectomy, while 2 received radiation therapy for a local recurrence before the serum PSA assay was available in our laboratory. Patients with increased PSA levels underwent restaging with a bone scan, and CT scan of the abdomen and pelvis as well as a digital rectal examination. Patients with a palpable abnormality on rectal examination or a soft tissue mass on a CT scan underwent transperineal digitally directed biopsy, which demonstrated a local recurrence in 6 patients. Of the patients receiving adjuvant radiation therapy the radical prostatectomy specimen revealed organ-confined disease in 4, positive surgical margins in 7, seminal vesicle invasion in 7 and microscopic lymph node metastases in 2. Mean followup in these patients was 19.6 months (range 3 weeks to 45 months) before initiation of adjuvant radiation. Adjuvant radiation therapy. Patients received a total of 6,000 cGy. local field irradiation via linear accelerator to the prostatic fossa and periprostatic tissues in 200 cGy. fractions for a total of 30 treatments. Bilateral arcs 30 degrees from lateral were focused in an 8 X 10 cm. rectangular area over the prostatic fossa from anterior to posterior to deliver the 6,000 cGy. A perineal boost technique was not used to the pelvic nodes. Examination of surgical specimens. At operation the bladder neck and urethral margins were removed from the prostate by grasping the retracted urethra including its mucosal edges with small Allis forceps and circumferentially excising the 2 to 3 mm. urethral stump. The bladder neck was similarly circumferentially excised including the mucosal edges and bladder neck muscle. These margins were sent as separate specimens. If the specimens on histological examination contained cancer they were considered to be positive surgical margins. The excised prostate was dipped in india ink and immediately fixed in Bouin's solution to prevent the india ink from spreading into the tissue planes. The specimen then was breadloafed in 2 to 5 mm. segments, depending on the size of the gland, and fixed overnight in 10% phosphate buffered formalin solution. Three hematoxylin and eosin-stained sections from the right
1174
1175
EFFECT OF ADJUVANT RADIATION THERAPY AFTER RADICAL PROSTATECTOMY , 00
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inal vesicles and no evidence of pelvic lymph node metastases on histological examination. Microscopically positive margins refers to patients with tumor present at the urethral or bladder neck margin, or extension through the prostatic capsule to the surgical margin on histological examination. Isolated penetration ~hrough the prostatic capsule with a negative surgical margm was not observed. Seminal vesicle invasion refers to patients with involvement of the seminal vesicles or the fascia surrounding the seminal vesicles on histological examination. Microscopically positive lymph node metastases refers to patients with documented lymph node metastases on permanent section~ after frozen sections were reported as being negative, otherwise a radical prostatectomy would not have been performed on these patients. PSA assay. PSA levels were determined with the Tandem-R radioimmunometric assay.* For the purposes of this study the lower limit of detectability as reported previously by our laboratory was 0.6 ng./ml. RESULTS
.6
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II
•
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®SV
0 Recurrence D1
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PATHOLOGICAL STAGE FIG. 2. PSA levels after adjuvant radiation therapy according to pathological stage after radical prostatectomy.
and 3 from the left halves of the prostate were examined for the peripheral surgical margins. In addition, 2 longitudinal sections through the apex of the prostate also were examined. The presence of cancer at the prostatic apex but not in the urethral margin was considered to be a positive anterior and/ or posterior margin. If the tumor extended to an inked margin it was called a positive lateral, anterior or posterior surgical margin. Staging. Clinical staging of prostate cancer was defined with a modification of the Whitmore-Jewett system as described previously. 6 Pathological staging for prostate cancer was defined as organ-confined disease if tumors showed no evidence of extensions through the prostatic capsule, no extension to the bladder neck, urethral margins or fascia surrounding the sem-
Effect of adjuvant radiation therapy on serum PSA values . Over-all, of the 21 patients who received adjuvant radiation therapy after radical prostatectomy 14 (67%) are without evidence of recurrent tumor. Of the patients 9 (43%) showed a decrease in serum PSA levels to the undetectable range and 4 (19%) demonstrated a steadily decreasing but still detectable PSA level and were without evidence of disease after adjuvant radiation therapy during a mean followup of 12.6 months (range 6 to 30 months, fig. 1). Of the initial 9 patients who had a decrease in PSA values to the undetectable range 3 have since demonstrated an increasing value. All 7 patients whose PSA values did not decrease significantly despite adjuvant radiation therapy have had recurrent tumor during a mean followup of 15.0 months (range 6 to 31 months, fig. 1). Of 4 patients with pathologically confirmed, organ-confined disease 2 had a persistently detectable PSA value after radiation, including 1 with progressive disease. Of 7 patients with microscopically positive surgical margins after radical prostatectomy 3 have undetectable PSA values after adjuvant radiation therapy and are without evidence of recurrent tumor. Of 8 patients with seminal vesicle invasion who received adjuvant radiation therapy only 2 had progressive cancer and only 1 had an undetectable PSA value after adjuvant radiation therapy. * Hybritech, Inc., San Diego, California.
--1176
HUDSON AND CATALONA
Both patients with pelvic lymph node metastases had persistent elevations in serum PSA values and progressive cancer despite adjuvant radiation therapy. No patient with an undetectable PSA level after adjuvant radiation therapy has had recurrent tumor during a mean of 13.5 months (range 6 to 30 months, fig. 2). Of 8 patients with a documented local tumor recurrence at referral for radiation therapy 2 currently are free of disease by clinical parameters and demonstrate an undetectable PSA value to date. Morbidity of adjuuant radiation therapy. The majority of patients experienced mild to moderate symptoms of diarrhea, and urinary frequency and urgency in association with the radiation treatments. One patient experienced rectal discomfort, 1 rectal bleeding, 1 decreased urinary sphincter control and 2 loss of erectile function after radiation therapy. No patient required hospitalization or an operation for side effects from radiation and none died. DISCUSSION
The greatest clinical value of PSA has been suggested to be to monitor response to therapy in patients undergoing treatment for prostate cancer. 1- 9 It also has been suggested that an increasing PSA level may precede other clinical parameters in detection of recurrent tumor. 8 • 9 In patients with clinically localized prostate cancer undergoing radical prostatectomy all prostatic tissue should be removed by the operation. Since PSA has been localized to prostatic tissue, 1 PSA levels should become undetectable after radical prostatectomy. The presence of a detectable serum PSA value after radical prostatectomy strongly suggests residual or recurrent tumor and has been correlated with further tumor progression. Oesterling and associates noted that serum PSA levels decreased to the undetectable range in 95% of 81 patients with organ-confined disease, compared to only 75% of 20 with capsular penetration and 19% of 26 with seminal vesicle invasion or lymph node metastases. 3 Of 31 patients in their series with detectable serum PSA levels after radical prostatectomy 8 (26%) had recurrent tumor. In a previous series from our institution 89% of the patients with pathologically confirmed, organ-confined disease had undetectable PSA values postoperatively, compared to only 34% of those with seminal vesicle or lymph node involvement. 6 Of the patients with elevated PSA values after radical prostatectomy in that series 50% have had recurrent cancer to date. Among 59 men undergoing radical prostatectomy Lange and associates observed cancer progression in 100% of those whose postoperative PSA level was detectable within 6 months postoperatively, compared to only 9% of those with an undetectable level in the initial postoperative period. 5 An elevated serum PSA level preceded clinical evidence of recurrence by 12 to 43 months in their series. Stamey and associates also reported that the majority of patients will have an undetectable serum PSA level after radical prostatectomy.2 Additionally, of 4 patients in the latter series with detectable serum PSA values postoperatively who received adjuvant radiation therapy 3 had a decrease to undetectable levels after adjuvant radiation therapy. Controversy exists in the literature as to whether adjuvant radiation therapy is of benefit to patients who have positive surgical margins, seminal vesicle invasion and/or pelvic lymph node metastases after radical prostatectomy. 10- 12 Although radiation therapy has demonstrated clearly improved disease control locally in the pelvis, it has not been shown to affect significantly the development of distant metastases. 10- 12 From these clinical data it is unclear whether patients who have metastatic disease had subclinical but incompletely controlled local disease that subsequently metastasized or occult distant metastases before definitive treatment. It is likely that there are patients who fall into both categories.
Although persistently detectable PSA values cannot distinguish patients with residual pelvic disease from those with occult distant metastases, it does appear to serve as an important serum marker indicating the presence of persistent disease in some patients who potentially may be cured with further therapy. Based on these data we have offered adjuvant radiation therapy to patients following radical prostatectomy who demonstrated a detectable PSA value. In our experience 6 of 21 (29%) patients who received adjuvant radiation therapy had serum PSA decrease to undetectable levels after radiation therapy and currently are without evidence of disease after a mean of 12.6 months of followup. Since 3 patients initially showed a decrease in PSA levels to the undetectable range but subsequently demonstrated an increasing level longer followup will be required to determine if this decrease in PSA values following radiation therapy is transient or will be equated with longterm cure. Four patients have a steadily decreasing but still detectable PSA level and are without evidence of disease following adjuvant radiation therapy. All 7 patients (33%) with persistently elevated PSA values despite radiation therapy have had tumor recurrences (fig. 2). Lightner and associates treated 26 patients with serum PSA values of greater than 0.4 ng./ml. after radical prostatectomy with adjuvant radiation therapy and noted a decrease to an undetectable level in 38%.8 Stamey and associates reported a decrease to the undetectable range after adjuvant radiation therapy in 3 of 4 patients with a detectable PSA value following radical prostatectomy. 2 Of our patients with pelvic lymph node metastases who underwent adjuvant radiation therapy 2 have had a persistently detectable PSA value after radiation and progressive cancer developed. The patient in the series by Stamey and associates whose prostate specific antigen level did not become undetectable after adjuvant radiation therapy had lymph node metastases. 2 Although the number of patients is small it may be that those with pelvic lymph node involvement are at a higher risk for distant micrometastases that would not be treated effectively with adjunctive radiation to the prostatic fossa. However, 2 of 5 patients with pelvic lymph node metastases in the series by Lightner and associates had undetectable PSA values after adjuvant radiation therapy and had no evidence of recurrence at followup. 8 Therefore, it appears that even some patients with pelvic nodal metastases may benefit from adjuvant radiation therapy, perhaps with a more extended field of radiation. Adjuvant radiation therapy appears to cause serum PSA to decrease to undetectable levels in an appreciable number of patients (43%) with persistently detectable PSA after radical prostatectomy. However, 3 of 9 of these patients (33%) again demonstrated an increasing level within 12 months after adjuvant radiation therapy. Although the mean followup in our series is too short to equate an undetectable PSA level following adjuvant radiation therapy with long-term cure, the early results suggest that approximately a third of the patients may benefit from this therapy. In conclusion, our data and other series demonstrate that a significant proportion (up to 100%) 5 of patients with persistently detectable prostate specific antigen levels following radical prostatectomy are at risk for further progression. To date adjuvant radiation therapy appears to cause a decrease in serum prostate specific antigen levels in approximately a third of the post-radical prostatectomy patients with a persistently detectable prostate specific antigen value postoperatively. Adjuvant radiation therapy was generally well tolerated. Further followup is needed to determine if an undetectable prostate specific antigen value after radiation therapy will result in long-term cure. REFERENCES
1. Wang, M. C., Papsidero, L. D., Kuriyama, M., Valenzuela, L.A., Murphy, G. P. and Chu, F. M.: Prostate antigen: a new potential marker for prostatic cancer. Prostate, 2: 89, 1981.
EFFECT OF ADJUVAN-T RADIAl!ON- TJ-IERAPY A:F'TER RADICAL PROSTATEC1.,0I\i1Y 2.
3.
4.
5.
6.
7.
T A., Yang, N., Hay, A. R., McNeal, J.E., Freiha, F. S. Redwine, E.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317: 909, 1987. Oesterling, J. E., Chan, D. W., Epstein, J. I., Kimball, A. W., Jr., Bruzek, D. J., Rock, R. C., Brendler, C. B. and Walsh, P. C.: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J. Urol., 139: 766, 1988. Ercole, C. J., Lange, P. H., Mathisen, M., Chiou, R. K., Reddy, P. K. and Vessella, R. L.: Prostate specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J. Ural., 138: 1181, 1987. Lange, P. H., Ercole, C. J., Lightner, D. J., Fraley, E. E. and Vassella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Ural., 141: 873, 1989. Hudson, M. A., Bahnson, R. R. and Catalana, W. J.: Clinical use of prostate specific antigen in patients with prostate cancer. J. Urol., 142: 1011, 1989. Stamey, T. A., Kabalin, J. N., McNeal, J. E., Johnstone, I. M., Freiha, F., Redwine, E. A. and Yang, N.: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the pros-
8.
9.
10.
11. 12.
tat6. II. Radical prostatectomy treated patients. J. Urol., 141: 1076, 1989. Lightner, D. J., Reddy, P. K. and Lange, P. H.: PSA response to radiation therapy (RT) after radical prostatectomy (RP): correlation with biopsy (Bx) and rectal exam. J. Ural., part 2, 141: 183A, abstract 55, 1989. Killian, C. S., Yang, N., Emrich, L. J., Vargus, F. P., Kuriyama, M., Wang, M. C., Slack, N. H., Papsidero, L. D., Murphy, G. P., Chu, T. M. and the Investigators of the National Prostatic Cancer Project: Prognostic importance of prostate-specific antigen for monitoring patients with stages B2 to Dl prostate cancer. Cancer Res., 45: 886, 1985. Gibbons, R. P., Cole, B. S., Richardson, R. G., Correa, R. J., Jr., Brannen, G. E., Mason, J. T., Taylor, W. J. and Hafermann, M. D.: Adjuvant radiotherapy following radical prostatectomy: results and complications. J. Urol., 135: 65, 1986. Lange, P. H., Reddy, P. K., Medini, E., Levitt, S. and Fraley, E. E.: Radiation therapy as adjuvant treatment after radical prostatectomy. Natl. Cancer Inst. Monogr., 7: 141, 1988. Anscher, M. S. and Prosnitz, L. R.: Postoperative radiotherapy for patients with carcinoma of the prostate undergoing radical prostatectomy with positive surgical margins, seminal vesicle involvement and/or penetration through the capsule. J. Urol., 138: 1407, 1987.
Vol. 143, June
Printed in U.S. A.
EFFECT OF ADJUVANT RADIATION THERAPY ON PROSTATE SPECIFIC ANTIGEN FOLLOWING RADICAL PROSTATECTOMY M'LISS A. HUDSON*
AND
WILLIAM J. CATALONA
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
A total of 21 patients received adjuvant radiation therapy after radical prostatectomy for a persistently detectable prostate specific antigen value (more than 0.6 ng. per ml.) postoperatively. Adjuvant radiation therapy decreased serum prostate specific antigen values to the undetectable range in 6 of 21 patients (29%) all of whom have remained free of tumor recurrence with a mean followup of 12.6 months (range 6 to 30). Three patients initially showed a decrease in serum prostate specific antigen to undetectable levels but they subsequently demonstrated an increasing level within 12 months after adjuvant radiation therapy. Additionally, 7 of 13 patients whose prostate specific antigen values remained in the detectable range despite adjuvant radiation therapy have had clinical evidence of tumor recurrence. Further followup will be required to determine what ultimate impact adjuvant radiation therapy will have on survival free of tumor. (J. Ural., 143: 11741177, 1990)
The greatest clinical usefulness for prostate specific antigen (PSA) appears to be to monitor the response to therapy after treatment of prostate cancer. 1- 5 After radical prostatectomy for clinically localized prostate cancer serum PSA should, in theory, decrease to undetectable levels because all prostatic tissue should be removed with this operation. In patients undergoing radical cystoprostatectomy for invasive bladder cancer PSA values have been observed routinely to decrease to undetectable levels. 6 In several clinical series, including 1 at our institution, it has been shown that PSA values do indeed decrease to undetectable levels in approximately 90% of the patients with pathologically confirmed, organ-confined prostate cancer. 3 •5- 7 In our series only a third of the patients with seminal vesicle invasion or lymph node involvement demonstrated a decrease in PSA levels to the undetectable range following radical prostatectomy. 6 This finding implies that residual tumor may remain (possibly only in the pelvis) in up to two-thirds of these patients. Of the patients with seemingly organ-confined prostate cancer confirmed on pathological examination after radical prostatectomy 10% demonstrate persistently detectable PSA levels and, therefore, they also may be harboring residual tumor. 3 • 5 - 7 Based on these data several investigators have recommended adjuvant radiation therapy for patients with persistently detectable PSA levels after radical prostatectomy. 2• 8 Adjuvant radiation therapy has been shown to decrease serum PSA levels to the undetectable range in some patients with persistently detectable PSA values after radical prostatectomy, although only a small number of patients have been reported on to date. 2 •8 We report our experience with adjuvant radiation therapy after radical prostatectomy in patients with a detectable PSA level postoperatively and no evidence of distant metastases. MATERIALS AND METHODS
Patients. A total of 250 men with biopsy proved adenocarcinoma of the prostate underwent radical retropubic prostatectomy between February 1983 and October 1988 for clinically localized cancer as judged by rectal examination, a negative bone scan and a negative computerized tomography (CT) scan Accepted for publication December 15, 1989. * Requests for reprints: Division of Urologic Surgery, Washington University School of Medicine, 4960 Audubon Ave., St. Louis, Missouri 63110.
of the abdomen. Adjuvant radiation therapy was offered to 80 patients with a detectable PSA value postoperatively. A total of 21 patients elected to receive adjuvant radiation therapy after radical prostatectomy and were followed until September 1989. These patients had PSA levels that had never decreased into the undetectable range. Of the 21 patients 19 underwent adjuvant radiation therapy based solely on a detectable serum PSA value after radical prostatectomy, while 2 received radiation therapy for a local recurrence before the serum PSA assay was available in our laboratory. Patients with increased PSA levels underwent restaging with a bone scan, and CT scan of the abdomen and pelvis as well as a digital rectal examination. Patients with a palpable abnormality on rectal examination or a soft tissue mass on a CT scan underwent transperineal digitally directed biopsy, which demonstrated a local recurrence in 6 patients. Of the patients receiving adjuvant radiation therapy the radical prostatectomy specimen revealed organ-confined disease in 4, positive surgical margins in 7, seminal vesicle invasion in 7 and microscopic lymph node metastases in 2. Mean followup in these patients was 19.6 months (range 3 weeks to 45 months) before initiation of adjuvant radiation. Adjuvant radiation therapy. Patients received a total of 6,000 cGy. local field irradiation via linear accelerator to the prostatic fossa and periprostatic tissues in 200 cGy. fractions for a total of 30 treatments. Bilateral arcs 30 degrees from lateral were focused in an 8 X 10 cm. rectangular area over the prostatic fossa from anterior to posterior to deliver the 6,000 cGy. A perineal boost technique was not used to the pelvic nodes. Examination of surgical specimens. At operation the bladder neck and urethral margins were removed from the prostate by grasping the retracted urethra including its mucosal edges with small Allis forceps and circumferentially excising the 2 to 3 mm. urethral stump. The bladder neck was similarly circumferentially excised including the mucosal edges and bladder neck muscle. These margins were sent as separate specimens. If the specimens on histological examination contained cancer they were considered to be positive surgical margins. The excised prostate was dipped in india ink and immediately fixed in Bouin's solution to prevent the india ink from spreading into the tissue planes. The specimen then was breadloafed in 2 to 5 mm. segments, depending on the size of the gland, and fixed overnight in 10% phosphate buffered formalin solution. Three hematoxylin and eosin-stained sections from the right
1174
1175
EFFECT OF ADJUVANT RADIATION THERAPY AFTER RADICAL PROSTATECTOMY , 00
A. Patients receiving XRT within 6 months following RRP and currently NED
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. FIG. 1. PSA levels (e) in relation to interval after radical prostatectomy (RRP) and adjuvant radiation therapy (XRT). NED no evidence of disease. '
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inal vesicles and no evidence of pelvic lymph node metastases on histological examination. Microscopically positive margins refers to patients with tumor present at the urethral or bladder neck margin, or extension through the prostatic capsule to the surgical margin on histological examination. Isolated penetration ~hrough the prostatic capsule with a negative surgical margm was not observed. Seminal vesicle invasion refers to patients with involvement of the seminal vesicles or the fascia surrounding the seminal vesicles on histological examination. Microscopically positive lymph node metastases refers to patients with documented lymph node metastases on permanent section~ after frozen sections were reported as being negative, otherwise a radical prostatectomy would not have been performed on these patients. PSA assay. PSA levels were determined with the Tandem-R radioimmunometric assay.* For the purposes of this study the lower limit of detectability as reported previously by our laboratory was 0.6 ng./ml. RESULTS
.6
Organ Confined
II
•
C
C
®margins
®SV
0 Recurrence D1
® nodes
PATHOLOGICAL STAGE FIG. 2. PSA levels after adjuvant radiation therapy according to pathological stage after radical prostatectomy.
and 3 from the left halves of the prostate were examined for the peripheral surgical margins. In addition, 2 longitudinal sections through the apex of the prostate also were examined. The presence of cancer at the prostatic apex but not in the urethral margin was considered to be a positive anterior and/ or posterior margin. If the tumor extended to an inked margin it was called a positive lateral, anterior or posterior surgical margin. Staging. Clinical staging of prostate cancer was defined with a modification of the Whitmore-Jewett system as described previously. 6 Pathological staging for prostate cancer was defined as organ-confined disease if tumors showed no evidence of extensions through the prostatic capsule, no extension to the bladder neck, urethral margins or fascia surrounding the sem-
Effect of adjuvant radiation therapy on serum PSA values . Over-all, of the 21 patients who received adjuvant radiation therapy after radical prostatectomy 14 (67%) are without evidence of recurrent tumor. Of the patients 9 (43%) showed a decrease in serum PSA levels to the undetectable range and 4 (19%) demonstrated a steadily decreasing but still detectable PSA level and were without evidence of disease after adjuvant radiation therapy during a mean followup of 12.6 months (range 6 to 30 months, fig. 1). Of the initial 9 patients who had a decrease in PSA values to the undetectable range 3 have since demonstrated an increasing value. All 7 patients whose PSA values did not decrease significantly despite adjuvant radiation therapy have had recurrent tumor during a mean followup of 15.0 months (range 6 to 31 months, fig. 1). Of 4 patients with pathologically confirmed, organ-confined disease 2 had a persistently detectable PSA value after radiation, including 1 with progressive disease. Of 7 patients with microscopically positive surgical margins after radical prostatectomy 3 have undetectable PSA values after adjuvant radiation therapy and are without evidence of recurrent tumor. Of 8 patients with seminal vesicle invasion who received adjuvant radiation therapy only 2 had progressive cancer and only 1 had an undetectable PSA value after adjuvant radiation therapy. * Hybritech, Inc., San Diego, California.
--1176
HUDSON AND CATALONA
Both patients with pelvic lymph node metastases had persistent elevations in serum PSA values and progressive cancer despite adjuvant radiation therapy. No patient with an undetectable PSA level after adjuvant radiation therapy has had recurrent tumor during a mean of 13.5 months (range 6 to 30 months, fig. 2). Of 8 patients with a documented local tumor recurrence at referral for radiation therapy 2 currently are free of disease by clinical parameters and demonstrate an undetectable PSA value to date. Morbidity of adjuuant radiation therapy. The majority of patients experienced mild to moderate symptoms of diarrhea, and urinary frequency and urgency in association with the radiation treatments. One patient experienced rectal discomfort, 1 rectal bleeding, 1 decreased urinary sphincter control and 2 loss of erectile function after radiation therapy. No patient required hospitalization or an operation for side effects from radiation and none died. DISCUSSION
The greatest clinical value of PSA has been suggested to be to monitor response to therapy in patients undergoing treatment for prostate cancer. 1- 9 It also has been suggested that an increasing PSA level may precede other clinical parameters in detection of recurrent tumor. 8 • 9 In patients with clinically localized prostate cancer undergoing radical prostatectomy all prostatic tissue should be removed by the operation. Since PSA has been localized to prostatic tissue, 1 PSA levels should become undetectable after radical prostatectomy. The presence of a detectable serum PSA value after radical prostatectomy strongly suggests residual or recurrent tumor and has been correlated with further tumor progression. Oesterling and associates noted that serum PSA levels decreased to the undetectable range in 95% of 81 patients with organ-confined disease, compared to only 75% of 20 with capsular penetration and 19% of 26 with seminal vesicle invasion or lymph node metastases. 3 Of 31 patients in their series with detectable serum PSA levels after radical prostatectomy 8 (26%) had recurrent tumor. In a previous series from our institution 89% of the patients with pathologically confirmed, organ-confined disease had undetectable PSA values postoperatively, compared to only 34% of those with seminal vesicle or lymph node involvement. 6 Of the patients with elevated PSA values after radical prostatectomy in that series 50% have had recurrent cancer to date. Among 59 men undergoing radical prostatectomy Lange and associates observed cancer progression in 100% of those whose postoperative PSA level was detectable within 6 months postoperatively, compared to only 9% of those with an undetectable level in the initial postoperative period. 5 An elevated serum PSA level preceded clinical evidence of recurrence by 12 to 43 months in their series. Stamey and associates also reported that the majority of patients will have an undetectable serum PSA level after radical prostatectomy.2 Additionally, of 4 patients in the latter series with detectable serum PSA values postoperatively who received adjuvant radiation therapy 3 had a decrease to undetectable levels after adjuvant radiation therapy. Controversy exists in the literature as to whether adjuvant radiation therapy is of benefit to patients who have positive surgical margins, seminal vesicle invasion and/or pelvic lymph node metastases after radical prostatectomy. 10- 12 Although radiation therapy has demonstrated clearly improved disease control locally in the pelvis, it has not been shown to affect significantly the development of distant metastases. 10- 12 From these clinical data it is unclear whether patients who have metastatic disease had subclinical but incompletely controlled local disease that subsequently metastasized or occult distant metastases before definitive treatment. It is likely that there are patients who fall into both categories.
Although persistently detectable PSA values cannot distinguish patients with residual pelvic disease from those with occult distant metastases, it does appear to serve as an important serum marker indicating the presence of persistent disease in some patients who potentially may be cured with further therapy. Based on these data we have offered adjuvant radiation therapy to patients following radical prostatectomy who demonstrated a detectable PSA value. In our experience 6 of 21 (29%) patients who received adjuvant radiation therapy had serum PSA decrease to undetectable levels after radiation therapy and currently are without evidence of disease after a mean of 12.6 months of followup. Since 3 patients initially showed a decrease in PSA levels to the undetectable range but subsequently demonstrated an increasing level longer followup will be required to determine if this decrease in PSA values following radiation therapy is transient or will be equated with longterm cure. Four patients have a steadily decreasing but still detectable PSA level and are without evidence of disease following adjuvant radiation therapy. All 7 patients (33%) with persistently elevated PSA values despite radiation therapy have had tumor recurrences (fig. 2). Lightner and associates treated 26 patients with serum PSA values of greater than 0.4 ng./ml. after radical prostatectomy with adjuvant radiation therapy and noted a decrease to an undetectable level in 38%.8 Stamey and associates reported a decrease to the undetectable range after adjuvant radiation therapy in 3 of 4 patients with a detectable PSA value following radical prostatectomy. 2 Of our patients with pelvic lymph node metastases who underwent adjuvant radiation therapy 2 have had a persistently detectable PSA value after radiation and progressive cancer developed. The patient in the series by Stamey and associates whose prostate specific antigen level did not become undetectable after adjuvant radiation therapy had lymph node metastases. 2 Although the number of patients is small it may be that those with pelvic lymph node involvement are at a higher risk for distant micrometastases that would not be treated effectively with adjunctive radiation to the prostatic fossa. However, 2 of 5 patients with pelvic lymph node metastases in the series by Lightner and associates had undetectable PSA values after adjuvant radiation therapy and had no evidence of recurrence at followup. 8 Therefore, it appears that even some patients with pelvic nodal metastases may benefit from adjuvant radiation therapy, perhaps with a more extended field of radiation. Adjuvant radiation therapy appears to cause serum PSA to decrease to undetectable levels in an appreciable number of patients (43%) with persistently detectable PSA after radical prostatectomy. However, 3 of 9 of these patients (33%) again demonstrated an increasing level within 12 months after adjuvant radiation therapy. Although the mean followup in our series is too short to equate an undetectable PSA level following adjuvant radiation therapy with long-term cure, the early results suggest that approximately a third of the patients may benefit from this therapy. In conclusion, our data and other series demonstrate that a significant proportion (up to 100%) 5 of patients with persistently detectable prostate specific antigen levels following radical prostatectomy are at risk for further progression. To date adjuvant radiation therapy appears to cause a decrease in serum prostate specific antigen levels in approximately a third of the post-radical prostatectomy patients with a persistently detectable prostate specific antigen value postoperatively. Adjuvant radiation therapy was generally well tolerated. Further followup is needed to determine if an undetectable prostate specific antigen value after radiation therapy will result in long-term cure. REFERENCES
1. Wang, M. C., Papsidero, L. D., Kuriyama, M., Valenzuela, L.A., Murphy, G. P. and Chu, F. M.: Prostate antigen: a new potential marker for prostatic cancer. Prostate, 2: 89, 1981.
EFFECT OF ADJUVAN-T RADIAl!ON- TJ-IERAPY A:F'TER RADICAL PROSTATEC1.,0I\i1Y 2.
3.
4.
5.
6.
7.
T A., Yang, N., Hay, A. R., McNeal, J.E., Freiha, F. S. Redwine, E.: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. New Engl. J. Med., 317: 909, 1987. Oesterling, J. E., Chan, D. W., Epstein, J. I., Kimball, A. W., Jr., Bruzek, D. J., Rock, R. C., Brendler, C. B. and Walsh, P. C.: Prostate specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J. Urol., 139: 766, 1988. Ercole, C. J., Lange, P. H., Mathisen, M., Chiou, R. K., Reddy, P. K. and Vessella, R. L.: Prostate specific antigen and prostatic acid phosphatase in the monitoring and staging of patients with prostatic cancer. J. Ural., 138: 1181, 1987. Lange, P. H., Ercole, C. J., Lightner, D. J., Fraley, E. E. and Vassella, R.: The value of serum prostate specific antigen determinations before and after radical prostatectomy. J. Ural., 141: 873, 1989. Hudson, M. A., Bahnson, R. R. and Catalana, W. J.: Clinical use of prostate specific antigen in patients with prostate cancer. J. Urol., 142: 1011, 1989. Stamey, T. A., Kabalin, J. N., McNeal, J. E., Johnstone, I. M., Freiha, F., Redwine, E. A. and Yang, N.: Prostate specific antigen in the diagnosis and treatment of adenocarcinoma of the pros-
8.
9.
10.
11. 12.
tat6. II. Radical prostatectomy treated patients. J. Urol., 141: 1076, 1989. Lightner, D. J., Reddy, P. K. and Lange, P. H.: PSA response to radiation therapy (RT) after radical prostatectomy (RP): correlation with biopsy (Bx) and rectal exam. J. Ural., part 2, 141: 183A, abstract 55, 1989. Killian, C. S., Yang, N., Emrich, L. J., Vargus, F. P., Kuriyama, M., Wang, M. C., Slack, N. H., Papsidero, L. D., Murphy, G. P., Chu, T. M. and the Investigators of the National Prostatic Cancer Project: Prognostic importance of prostate-specific antigen for monitoring patients with stages B2 to Dl prostate cancer. Cancer Res., 45: 886, 1985. Gibbons, R. P., Cole, B. S., Richardson, R. G., Correa, R. J., Jr., Brannen, G. E., Mason, J. T., Taylor, W. J. and Hafermann, M. D.: Adjuvant radiotherapy following radical prostatectomy: results and complications. J. Urol., 135: 65, 1986. Lange, P. H., Reddy, P. K., Medini, E., Levitt, S. and Fraley, E. E.: Radiation therapy as adjuvant treatment after radical prostatectomy. Natl. Cancer Inst. Monogr., 7: 141, 1988. Anscher, M. S. and Prosnitz, L. R.: Postoperative radiotherapy for patients with carcinoma of the prostate undergoing radical prostatectomy with positive surgical margins, seminal vesicle involvement and/or penetration through the capsule. J. Urol., 138: 1407, 1987.