0022-534 7/92/14 73-0952$03.00/0 JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 147, 952-955, March 1992
THE
Printed in U.S.A.
DETECTION OF LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY BY PROSTATE SPECIFIC ANTIGEN AND TRANSRECTAL ULTRASOUND ANTOINE S. ABI-AAD, MICHAEL T. MACFARLANE, AVI STEIN AND JEAN B. DEKERNION* From the Department of Surgery, Division of Urology, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California
ABSTRACT
Twenty patients with detectable levels of-prostate specific antigen (PSA) after radical prost-aiectomy with no identifiable distant metastases were evaluated for local recurrence by digital rectal examination and transrectal ultrasound combined with biopsies. Of the patients 9 (45%) were found to have histological evidence of local recurrence at the initial assessment. All 4 patients with an abnormal digital rectal examination had recurrent disease. Transrectal ultrasound displayed abnormalities in 12 of the 20 patients, 7 of whom had positive biopsies. Random biopsies of the vesicourethral junction were performed in 8 patients who had negative ultrasound findings and an unremarkable digital rectal examination, of whom 2 had histological documentation of local recurrence. Complications occurred in 1 patient (5%) who presented with clot retention. We conclude that PSA is an excellent tool for identification of recurrent disease after radical prostatectomy, and transrectal ultrasound guided biopsy is a useful diagnostic approach in patients suspected of local failure, especially when the digital rectal examination is unremarkable. KEY WORDS:
prostatic neoplasms; prostatectomy; neoplasm recurrence, local; antigens, differentiation; ultrasonics
Local recurrence after radical prostatectomy reflects incomplete resection of benign or neoplastic cells. Patients with seminal vesicle invasion, positive surgical margins or capsular penetration are at increased risk for local recurrence. Local failure may occur even when the tumor is reported to be confined to the prostate by histological examination. Before the use of prostate specific antigen (PSA) the incidence of local failure after radical surgery in patients having received no adjuvant therapy was 161 to 17% 2 and 30% 2 for pathological stages B and C disease, respectively. Local failure can be suspected in the presence of an abnormal rectal examination or elevation of the serum PSA value. Elevation of PSA often indicates distant metastases, detectable by standard scans and radiography. However, a number of patients have "isolated PSA elevation" with no detectable metastases. Some of these patients will have local recurrence, potentially curable by judicious radiotherapy, while others may have undetectable metastatic disease. We believe that before instituting radiation therapy histological documentation is important, especially in patients with a normal digital rectal examination. Such documentation can be accomplished by random biopsies of the bladder neck in case of a negative digital rectal examination, digitally guided biopsies of an abnormal finding on the digital rectal examination or transrectal ultrasound oriented biopsies. In this study 20 patients with isolated PSA elevations and negative metastatic studies were completely evaluated to ascertain the incidence of detectable local recurrence, the accuracy of digital rectal examination and transrectal ultrasound, and the effect of local radiotherapy.
(greater than 0.4 ng./ml. determined by the Tandem-R immunoassay) and a negative metastatic study that included a bone scan, computerized tomography of the pelvis and a chest x-ray. Pathological staging as determined by histological examination of the pelvic lymph nodes and whole mount step sections of the prostate was as follows: stage A-incidental pathological disease that was not palpable on digital rectal examination, stage B-palpable disease determined pathologically to be confined within the prostatic capsule, stage C-tumor penetration of the prostatic capsule and/or seminal vesicle involvement and/or extension through the periprostatic fat with or without extension to the surgical margins and stage DI-nodal involvement. An abnormal digital rectal examination was defined as palpation of a mass, induration or irregularity in the area of the previous prostatic bed. After an enema and prophylactic antibiotics (500 mg. ciprofloxacin), transrectal examination was performed with a Diasonics ultrasound using a 7.5 MHz. high frequency rectal transducer. The bladder must be full to identify the vesicourethral junction. Ultrasound findings of a mass effect or fullness in the area of the urethral anastomosis were considered evidence of possible local recurrence. Ultrasound guided biopsies were performed with a Bioptyt gun and an 18 gauge biopsy needle of any abnormalities visible on ultrasound. Patients with a negative ultrasound received random biopsies of the urethrovesical junction. Only histological demonstration of an adenocarcinoma of the prostate within biopsies was considered as local recurrence.
MATERIALS AND METHODS
RESULTS
Patients who undergo radical prostatectomy are seen 3 months after surgery and every 6 months subsequently. In addition to digital rectal examination, serum samples are taken for PSA and prostatic acid phosphatase assays at every followup visit. Our study comprised 20 patients with elevated PSA
Patient characteristics and the PSA value as well as the interval for PSA to increase after surgery are summarized in table 1. Local recurrence was initially diagnosed in 9 patients (45%), including 4 and 5 patients with pathological stages B and C disease, respectively. All 4 patients with an abnormal digital rectal examination had local failure; however, the clini-
Accepted for publication July 19, 1991. * Requests for reprints: UCLA Center for the Health Sciences, Room 66-137, Los Angeles, California 90024. 952
t Bard Urological, Covington, Georgia.
DETECTION OF LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY TABLE l.
Patient characteristics
Pathological stage: A B
DISCUSSION 1 10
C
9
PSA value (ng./m!.): Range Mean Time of PSA to increase (mos.): Range Mean
TABLE 2.
0.6-111 3 3-60 16
Patients with positive biopsy and abnormal transrectal ultrasound Echogenecity
No. Pts. (%)
Isoechoic* Hypoechoic Hyperechoic
4 (57) 3 (43) 0
* Isoechoic abnormality of the urethrovesical junction.
3. Correlation between digital rectal examination and transrectal ultrasound with the pathological findings
TABLE
Pos. Biopsy (9 pts.)
--------------Digital rectal examination: Abnormal Unremarkable Transrectal ultrasound: Abnormal Neg.
Neg. Biopsy (11 pts.)
4
5
11
7 2*
5 6
* Random biopsies of the urethrovesical junction.
cal examination was considered negative in 5 patients who had positive biopsies. No patient with a negative biopsy had an abnormal digital rectal examination. Transrectal ultrasound identified abnormal findings in 12 patients, of whom 7 had proved local recurrence and 3 had a negative digital rectal examination. Echogenicity pattern is reported in table 2. Biopsies of the vesicourethral junction were performed in 8 patients with a negative ultrasound examination and a negative digital rectal examination, of whom 2 were found to have microscopic local failure. The size of the lesions detected by transrectal ultrasound ranged from 0.5 to 2 cm. Correlation between digital rectal examination and transrectal ultrasound with the pathological findings is shown in table 30 Complications related to the needle biopsies occurred in 1 patient who required in and out catheter evacuation for clot retention. One patient was treated with hormonal therapy that lowered the PSA value. Of 8 patients who received external beam radiation (6,000 rad delivered to the prostatic bed) 6 had decreased PSA levels, including 5 to an undetectable level (less than 0.2 ng,/ml.). Two patients had persistent increases in the PSA value despite radiation, and they were found subsequently to have bone metastases and received hormonal treatment. The features of the patients with positive biopsies as well as the PSA values at the time of diagnosis and after therapy are reported in table 4. Of the 11 patients with negative initial biopsies the PSA continued to increase in 7 (group 1) and it stabilized in 4 (group 2). In 4 of the 7 group 1 patients bone metastases developed and they received endocrine therapy, 2 still have negative studies and are scheduled for a second transrectal ultrasound with biopsies, and 1 initially with an unremarkable digital rectal examination presented 8 months later with induration. In this latter patient transrectal ultrasound identified a hypoechoic lesion and biopsy documented a local recurrence. Presently he is receiving external radiotherapy. In the group 2 patients the PSA level has remained unchanged (0.6 to 2.1 ng./ml.) during 6 to 24 months of followup. Evaluation for distant and local recurrence remains negative.
Although the role of PSA in the preoperative selection of men with clinically organ confined prostate cancer who are candidates for potential cure remains ill-defined, it appears that it is a sensitive biochemical marker to detect recurrent prostatic cancer and it may be the most effective tool to follow patients after radical prostatectomy. 3 PSA should be undetectable if all prostatic tissue, benign or malignant, has been removed at surgery. Killian et al found that 92% of the patients who had recurrence after definitive therapy for disease confined to the pelvis had elevated serum PSA concentration at least 12 months (mean lead time) before clinical manifestation. 4 In a study by Lightner et al local recurrence diagnosed with digitally guided biopsies was initially found in 42% of the patients with elevated PSA after radical prostatectomy with no evidence of distant disease. 5 Many of these patients had local disease in the urethrovesical anastomotic area despite an apparently unremarkable digital rectal examination. The authors conclude that digital rectal examination is often an unreliable early indicator of local cancer and state that it is a subjective examination that cannot readily distinguish between malignant and benign tissues. All 4 patients in our small series with an abnormal digital rectal examination had local failure but this examination missed 5 cases with positive biopsies" It is important to note that digital rectal examination findings depend on the bulk of the disease. Since our intention is to treat local failure as soon as possible, with the goal of sterilizing the lesion, we evaluated the use of transrectal ultrasound in terms of early diagnosis. Of the 9 patients with local had recurrence and a normal digital rectal examination 3 an abnormality on the ultrasound examination. These patients later underwent external radiation therapy and the PSA value decreased to undetectable levels, less than 0.4 ng./ml., in 2 patients with an average followup of 17 months" However randomized studies with long-term followup are required to determine if survival is improved in this group of patients compared to late or digitally diagnosed local failure. In a retrospective study Ray et al reported on 19 patients with local recurrent disease and a palpable mass on the digital rectal examination treated with external beam radiation. 6 Local control determined by digital rectal examination was obtained in 58% of the patients, and the 10-year survival rate free of disease was only 26%. The rationale for the use of external beam radiation in patients with the diagnosis of local failure is to sterilize the tumor cells while they auoai:entlv are still of low volume< Multiple studies have shown that local control is with postoperative in "°'""''·'·'"" with pathological stage C prostate cancer. 6 - 8 Link et al assume that theoretically administering radiation as soon as PSA is detected, we would the of cure and long-term local disease control. 9 Not all patients with elevated PSA levels after radical prostatectomy will have reduction of PSA to undetectable range after adjuvant radiation therapy. 9- 11 In a recent study by Lange et al, even when the biopsy of the urethrovesical anastomosis was negative, adjuvant radiation therapy decreased PSA levels in 70% of the patients and to undetectable levels in 30% compared to 89% and 50%, respectively, in patients with positive biopsies. 10 No patient with a positive needle biopsy whose PSA decreased to normal levels after radiation has had a subsequent PSA elevation for a median followup of 9.3 ± 3.6 months. Another report focused on the effect of adjuvant radiation therapy on detectable PSA with no evidence of distant metastases following radical prostatectomy. 11 Of an initial 9 patients who had a decrease in PSA values to the undetectable
954
ABI-AAD AND ASSOCIATES TABLE 4.
Pt.
Pathological Stage
sv
cc WC
HF VJ NE
WM IW MD
C C C B C B C B B
Digital Recta! Examination Neg. Neg. Neg. Neg. Neg. Pos. Pos. Pos. Pos.
Characteristic of patients with positive biopsies
Transrectal Ultrasound Pos. Neg. Pos. Pos. Neg Pos. Pos. Pos. Pos.
PSAat Biopsy (ng./ml.)
Adjuvant Therapy
3.4 1.6 3.8 8.4 4.5 84 45 2.9 4.2
External irradiation External irradiation External irradiation External irradiation Hormonal therapy External irradiation External irradiation External irradiation External irradiation
PSA After Adjuvant Therapy (ng./ml.) Less than Less than Less than 1.0 2.0 140t 50t Less than Less than
0.2* 0.2* 0.2*
0.2* 0.2*
Followup Since lnitiation of Radiotherapy (mos.) 17 14 18 16 16 27 36 28 8
* Undetectable.
t Two patients who, despite external radiation, maintained PSA levels; they were found later to have bone metastases.
range 3 had demonstrated an increasing level 3 to 6 months afterwards, underlining the need for long followup. When administered as adjuvant therapy for local recurrence external beam radiation is generally well tolerated. However, in some patients it may decrease the urinary sphincter and may result in impotence. 11 To evaluate any modality of treatment a well defined group of patients with an objective feature, such as isolated proved local recurrence after radical prostatectomy, must be identified. For these reasons we contend that histological documentation is important before instituting adjuvant radiotherapy. We recognize that the data concerning radiation therapy for local recurrence are tenuous and that long-term followup is necessary to know the true value of this form of treatment, which is why we do not recommend blind irradiation on every patient with isolated PSA elevation after radical prostatectomy. Of the 9 patients with proved local failure 7 (77%) had abnormal findings on transrectal ultrasound, whereas the digital rectal examination was considered abnormal in 4 (44%). Because of these findings we believe that the combination of PSA and transrectal ultrasound is helpful in the early diagnosis of local failure, especially when the digital rectal examination is unremarkable. Furthermore, we have shown that random biopsies of the urethrovesical junction can be positive even if transrectal ultrasound and the digital rectal examination are negative. Although this can be accomplished with digitally guided biopsies, transrectal ultrasound is extremely helpful to guide these biopsies. In our series 2 patients (22%) had microscopic disease at this location. Interpretation of the ultrasound images, especially when the normal anatomy has been distorted such as after radical surgery, depends on physician experience. Ultrasound also does not differentiate between malignant disease and scar tissue. Of the 12 patients with abnormal lesions on ultrasound only 7 were found to have malignancy on the biopsies. Another limitation of ultrasound is its lack of specificity in term of echogenicity. Parra et al noted that recurrent neoplasm, prostate and bladder, in the pelvis presented a hypoechoic pattern in 71.5 % of the cases. 12 In our experience local recurrences were isoechoic in 57% and hypoechoic in 43%. The histological documentation of adenocarcinoma of the prostate on 45% of the biopsies at the initial evaluation may not reflect the true incidence of local failure in our patients for several reasons. In some cases the disease may have been missed by our biopsies altogether. In others the recurrence is still microscopic with no architectural alteration, and random as well as repeated biopsies are warranted. Repeat transrectal ultrasound with biopsy is justified, especially if the PSA is increasing and distant metastatic lesions are ruled out. Culp documented the interval to local failure for lesions confined clinically to the prostate. 13 He found that two-thirds of 33 patients had recurrence within the first 5 years after therapy but 15% did not have local failure until after 10 years. Despite negative metastatic studies and transrectal biopsies,
4 of our patients (20%) have maintained stable PSA levels (less than 4 ng./ml.) for 6 to 24 months. Since PSA is an organ specific marker, this finding indicates the presence of residual prostatic tissue. The fact that the PSA level remains unchanged may reflect its production by benign tissue or low grade adenocarcinoma of the prostate even when the initial biopsies are negative. The management of these patients is unclear. Currently we perform a complete evaluation with biopsy of the vesicourethral junction. However, if this evaluation is negative and PSA is stable we recommend a conservative approach with serial PSA levels and a digital rectal examination every 6 months. If either the PSA or the digital rectal examination findings change biopsy is repeated. Persistently detectable PSA values cannot distinguish patients with residual pelvic disease from those with occult distant metastases. Currently, biopsy of the former prostatic bed is the only objective method to identify local recurrence. In our experience transrectal ultrasound guided biopsy is helpful in patients with isolated PSA elevation after radical prostatectomy and a normal digital rectal examination. REFERENCES
1. Jewett, H.J.: The present status of radical prostatectomy for stages
A and B prostatic cancer. Urol. Clin. N. Amer., 2: 105, 1975. 2. Schellhammer, P. F.: Radical prostatectomy for carcinoma of the prostate and 15 year analysis of survival and local control. J. Urol., part 2, 135: 247A, abstract 574, 1986. 3. 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. 4. Killian, C. 8., Yang, N., Emrich, L. J., Vargas, 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 stage B2 to Dl prostate cancer. Cancer Res., 45: 886, 1985. 5. Lightner, D. J., Lange, P.H., Reddy, P. K. and Moore, L.: Prostate specific antigen and local recurrence after radical prostatectomy. J. Urol., 144: 921, 1990. 6. Ray, G. R., Bagshaw, M.A. andFreiha, F.: External beam radiation salvage for residual local tumor following radical prostatectomy. J. Urol., 132: 926, 1984. 7. Gibbons, R. P., Cole, B. 8., 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. 8. Anscher, M. 8. 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.
DETECTION 01~ LOCAL RECURRENCE AFTER R"ADICAL PROSTATECTOl\!IY
9. Link, P., Freiha, F. S. and Stamey, T. A.: Adjuvant radiation therapy in patients with detectable prostate specific antigen following radical prostatectomy. J. Urol., 145: 532, 1991. 10. Lange, P.H., Lightner, D. J., Medini, E., Reddy, P. K. and Vessella, R. L.: The effect of radiation therapy after radical prostatectomy in patients with elevated prostate specific antigen levels. J. Urol., 144: 927, 1990. 11. Hudson, M. A. and Catalona, W. J.: Effect of adjuvant radiation
955
therapy on prostate specific antigen following radical prostatectomy. J. Uroi., 143: 1174, 1990. 12. Parra, R. 0., Wolf, RM. and Huben, R. P.: The use oftransrectal ultrasound in the detection and evaluation of local pelvic recurrences after a radical urological pelvic operation. J. Urol., 144: 707, 1990. 13. Culp, 0. S.: Radical perinea! prostatectomy: its past, present and possible future. J. Urol., 98: 618, 1967.
Vol. 147, 952-955, March 1992
THE
Printed in U.S.A.
DETECTION OF LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY BY PROSTATE SPECIFIC ANTIGEN AND TRANSRECTAL ULTRASOUND ANTOINE S. ABI-AAD, MICHAEL T. MACFARLANE, AVI STEIN AND JEAN B. DEKERNION* From the Department of Surgery, Division of Urology, UCLA School of Medicine and Jonsson Comprehensive Cancer Center, Los Angeles, California
ABSTRACT
Twenty patients with detectable levels of-prostate specific antigen (PSA) after radical prost-aiectomy with no identifiable distant metastases were evaluated for local recurrence by digital rectal examination and transrectal ultrasound combined with biopsies. Of the patients 9 (45%) were found to have histological evidence of local recurrence at the initial assessment. All 4 patients with an abnormal digital rectal examination had recurrent disease. Transrectal ultrasound displayed abnormalities in 12 of the 20 patients, 7 of whom had positive biopsies. Random biopsies of the vesicourethral junction were performed in 8 patients who had negative ultrasound findings and an unremarkable digital rectal examination, of whom 2 had histological documentation of local recurrence. Complications occurred in 1 patient (5%) who presented with clot retention. We conclude that PSA is an excellent tool for identification of recurrent disease after radical prostatectomy, and transrectal ultrasound guided biopsy is a useful diagnostic approach in patients suspected of local failure, especially when the digital rectal examination is unremarkable. KEY WORDS:
prostatic neoplasms; prostatectomy; neoplasm recurrence, local; antigens, differentiation; ultrasonics
Local recurrence after radical prostatectomy reflects incomplete resection of benign or neoplastic cells. Patients with seminal vesicle invasion, positive surgical margins or capsular penetration are at increased risk for local recurrence. Local failure may occur even when the tumor is reported to be confined to the prostate by histological examination. Before the use of prostate specific antigen (PSA) the incidence of local failure after radical surgery in patients having received no adjuvant therapy was 161 to 17% 2 and 30% 2 for pathological stages B and C disease, respectively. Local failure can be suspected in the presence of an abnormal rectal examination or elevation of the serum PSA value. Elevation of PSA often indicates distant metastases, detectable by standard scans and radiography. However, a number of patients have "isolated PSA elevation" with no detectable metastases. Some of these patients will have local recurrence, potentially curable by judicious radiotherapy, while others may have undetectable metastatic disease. We believe that before instituting radiation therapy histological documentation is important, especially in patients with a normal digital rectal examination. Such documentation can be accomplished by random biopsies of the bladder neck in case of a negative digital rectal examination, digitally guided biopsies of an abnormal finding on the digital rectal examination or transrectal ultrasound oriented biopsies. In this study 20 patients with isolated PSA elevations and negative metastatic studies were completely evaluated to ascertain the incidence of detectable local recurrence, the accuracy of digital rectal examination and transrectal ultrasound, and the effect of local radiotherapy.
(greater than 0.4 ng./ml. determined by the Tandem-R immunoassay) and a negative metastatic study that included a bone scan, computerized tomography of the pelvis and a chest x-ray. Pathological staging as determined by histological examination of the pelvic lymph nodes and whole mount step sections of the prostate was as follows: stage A-incidental pathological disease that was not palpable on digital rectal examination, stage B-palpable disease determined pathologically to be confined within the prostatic capsule, stage C-tumor penetration of the prostatic capsule and/or seminal vesicle involvement and/or extension through the periprostatic fat with or without extension to the surgical margins and stage DI-nodal involvement. An abnormal digital rectal examination was defined as palpation of a mass, induration or irregularity in the area of the previous prostatic bed. After an enema and prophylactic antibiotics (500 mg. ciprofloxacin), transrectal examination was performed with a Diasonics ultrasound using a 7.5 MHz. high frequency rectal transducer. The bladder must be full to identify the vesicourethral junction. Ultrasound findings of a mass effect or fullness in the area of the urethral anastomosis were considered evidence of possible local recurrence. Ultrasound guided biopsies were performed with a Bioptyt gun and an 18 gauge biopsy needle of any abnormalities visible on ultrasound. Patients with a negative ultrasound received random biopsies of the urethrovesical junction. Only histological demonstration of an adenocarcinoma of the prostate within biopsies was considered as local recurrence.
MATERIALS AND METHODS
RESULTS
Patients who undergo radical prostatectomy are seen 3 months after surgery and every 6 months subsequently. In addition to digital rectal examination, serum samples are taken for PSA and prostatic acid phosphatase assays at every followup visit. Our study comprised 20 patients with elevated PSA
Patient characteristics and the PSA value as well as the interval for PSA to increase after surgery are summarized in table 1. Local recurrence was initially diagnosed in 9 patients (45%), including 4 and 5 patients with pathological stages B and C disease, respectively. All 4 patients with an abnormal digital rectal examination had local failure; however, the clini-
Accepted for publication July 19, 1991. * Requests for reprints: UCLA Center for the Health Sciences, Room 66-137, Los Angeles, California 90024. 952
t Bard Urological, Covington, Georgia.
DETECTION OF LOCAL RECURRENCE AFTER RADICAL PROSTATECTOMY TABLE l.
Patient characteristics
Pathological stage: A B
DISCUSSION 1 10
C
9
PSA value (ng./m!.): Range Mean Time of PSA to increase (mos.): Range Mean
TABLE 2.
0.6-111 3 3-60 16
Patients with positive biopsy and abnormal transrectal ultrasound Echogenecity
No. Pts. (%)
Isoechoic* Hypoechoic Hyperechoic
4 (57) 3 (43) 0
* Isoechoic abnormality of the urethrovesical junction.
3. Correlation between digital rectal examination and transrectal ultrasound with the pathological findings
TABLE
Pos. Biopsy (9 pts.)
--------------Digital rectal examination: Abnormal Unremarkable Transrectal ultrasound: Abnormal Neg.
Neg. Biopsy (11 pts.)
4
5
11
7 2*
5 6
* Random biopsies of the urethrovesical junction.
cal examination was considered negative in 5 patients who had positive biopsies. No patient with a negative biopsy had an abnormal digital rectal examination. Transrectal ultrasound identified abnormal findings in 12 patients, of whom 7 had proved local recurrence and 3 had a negative digital rectal examination. Echogenicity pattern is reported in table 2. Biopsies of the vesicourethral junction were performed in 8 patients with a negative ultrasound examination and a negative digital rectal examination, of whom 2 were found to have microscopic local failure. The size of the lesions detected by transrectal ultrasound ranged from 0.5 to 2 cm. Correlation between digital rectal examination and transrectal ultrasound with the pathological findings is shown in table 30 Complications related to the needle biopsies occurred in 1 patient who required in and out catheter evacuation for clot retention. One patient was treated with hormonal therapy that lowered the PSA value. Of 8 patients who received external beam radiation (6,000 rad delivered to the prostatic bed) 6 had decreased PSA levels, including 5 to an undetectable level (less than 0.2 ng,/ml.). Two patients had persistent increases in the PSA value despite radiation, and they were found subsequently to have bone metastases and received hormonal treatment. The features of the patients with positive biopsies as well as the PSA values at the time of diagnosis and after therapy are reported in table 4. Of the 11 patients with negative initial biopsies the PSA continued to increase in 7 (group 1) and it stabilized in 4 (group 2). In 4 of the 7 group 1 patients bone metastases developed and they received endocrine therapy, 2 still have negative studies and are scheduled for a second transrectal ultrasound with biopsies, and 1 initially with an unremarkable digital rectal examination presented 8 months later with induration. In this latter patient transrectal ultrasound identified a hypoechoic lesion and biopsy documented a local recurrence. Presently he is receiving external radiotherapy. In the group 2 patients the PSA level has remained unchanged (0.6 to 2.1 ng./ml.) during 6 to 24 months of followup. Evaluation for distant and local recurrence remains negative.
Although the role of PSA in the preoperative selection of men with clinically organ confined prostate cancer who are candidates for potential cure remains ill-defined, it appears that it is a sensitive biochemical marker to detect recurrent prostatic cancer and it may be the most effective tool to follow patients after radical prostatectomy. 3 PSA should be undetectable if all prostatic tissue, benign or malignant, has been removed at surgery. Killian et al found that 92% of the patients who had recurrence after definitive therapy for disease confined to the pelvis had elevated serum PSA concentration at least 12 months (mean lead time) before clinical manifestation. 4 In a study by Lightner et al local recurrence diagnosed with digitally guided biopsies was initially found in 42% of the patients with elevated PSA after radical prostatectomy with no evidence of distant disease. 5 Many of these patients had local disease in the urethrovesical anastomotic area despite an apparently unremarkable digital rectal examination. The authors conclude that digital rectal examination is often an unreliable early indicator of local cancer and state that it is a subjective examination that cannot readily distinguish between malignant and benign tissues. All 4 patients in our small series with an abnormal digital rectal examination had local failure but this examination missed 5 cases with positive biopsies" It is important to note that digital rectal examination findings depend on the bulk of the disease. Since our intention is to treat local failure as soon as possible, with the goal of sterilizing the lesion, we evaluated the use of transrectal ultrasound in terms of early diagnosis. Of the 9 patients with local had recurrence and a normal digital rectal examination 3 an abnormality on the ultrasound examination. These patients later underwent external radiation therapy and the PSA value decreased to undetectable levels, less than 0.4 ng./ml., in 2 patients with an average followup of 17 months" However randomized studies with long-term followup are required to determine if survival is improved in this group of patients compared to late or digitally diagnosed local failure. In a retrospective study Ray et al reported on 19 patients with local recurrent disease and a palpable mass on the digital rectal examination treated with external beam radiation. 6 Local control determined by digital rectal examination was obtained in 58% of the patients, and the 10-year survival rate free of disease was only 26%. The rationale for the use of external beam radiation in patients with the diagnosis of local failure is to sterilize the tumor cells while they auoai:entlv are still of low volume< Multiple studies have shown that local control is with postoperative in "°'""''·'·'"" with pathological stage C prostate cancer. 6 - 8 Link et al assume that theoretically administering radiation as soon as PSA is detected, we would the of cure and long-term local disease control. 9 Not all patients with elevated PSA levels after radical prostatectomy will have reduction of PSA to undetectable range after adjuvant radiation therapy. 9- 11 In a recent study by Lange et al, even when the biopsy of the urethrovesical anastomosis was negative, adjuvant radiation therapy decreased PSA levels in 70% of the patients and to undetectable levels in 30% compared to 89% and 50%, respectively, in patients with positive biopsies. 10 No patient with a positive needle biopsy whose PSA decreased to normal levels after radiation has had a subsequent PSA elevation for a median followup of 9.3 ± 3.6 months. Another report focused on the effect of adjuvant radiation therapy on detectable PSA with no evidence of distant metastases following radical prostatectomy. 11 Of an initial 9 patients who had a decrease in PSA values to the undetectable
954
ABI-AAD AND ASSOCIATES TABLE 4.
Pt.
Pathological Stage
sv
cc WC
HF VJ NE
WM IW MD
C C C B C B C B B
Digital Recta! Examination Neg. Neg. Neg. Neg. Neg. Pos. Pos. Pos. Pos.
Characteristic of patients with positive biopsies
Transrectal Ultrasound Pos. Neg. Pos. Pos. Neg Pos. Pos. Pos. Pos.
PSAat Biopsy (ng./ml.)
Adjuvant Therapy
3.4 1.6 3.8 8.4 4.5 84 45 2.9 4.2
External irradiation External irradiation External irradiation External irradiation Hormonal therapy External irradiation External irradiation External irradiation External irradiation
PSA After Adjuvant Therapy (ng./ml.) Less than Less than Less than 1.0 2.0 140t 50t Less than Less than
0.2* 0.2* 0.2*
0.2* 0.2*
Followup Since lnitiation of Radiotherapy (mos.) 17 14 18 16 16 27 36 28 8
* Undetectable.
t Two patients who, despite external radiation, maintained PSA levels; they were found later to have bone metastases.
range 3 had demonstrated an increasing level 3 to 6 months afterwards, underlining the need for long followup. When administered as adjuvant therapy for local recurrence external beam radiation is generally well tolerated. However, in some patients it may decrease the urinary sphincter and may result in impotence. 11 To evaluate any modality of treatment a well defined group of patients with an objective feature, such as isolated proved local recurrence after radical prostatectomy, must be identified. For these reasons we contend that histological documentation is important before instituting adjuvant radiotherapy. We recognize that the data concerning radiation therapy for local recurrence are tenuous and that long-term followup is necessary to know the true value of this form of treatment, which is why we do not recommend blind irradiation on every patient with isolated PSA elevation after radical prostatectomy. Of the 9 patients with proved local failure 7 (77%) had abnormal findings on transrectal ultrasound, whereas the digital rectal examination was considered abnormal in 4 (44%). Because of these findings we believe that the combination of PSA and transrectal ultrasound is helpful in the early diagnosis of local failure, especially when the digital rectal examination is unremarkable. Furthermore, we have shown that random biopsies of the urethrovesical junction can be positive even if transrectal ultrasound and the digital rectal examination are negative. Although this can be accomplished with digitally guided biopsies, transrectal ultrasound is extremely helpful to guide these biopsies. In our series 2 patients (22%) had microscopic disease at this location. Interpretation of the ultrasound images, especially when the normal anatomy has been distorted such as after radical surgery, depends on physician experience. Ultrasound also does not differentiate between malignant disease and scar tissue. Of the 12 patients with abnormal lesions on ultrasound only 7 were found to have malignancy on the biopsies. Another limitation of ultrasound is its lack of specificity in term of echogenicity. Parra et al noted that recurrent neoplasm, prostate and bladder, in the pelvis presented a hypoechoic pattern in 71.5 % of the cases. 12 In our experience local recurrences were isoechoic in 57% and hypoechoic in 43%. The histological documentation of adenocarcinoma of the prostate on 45% of the biopsies at the initial evaluation may not reflect the true incidence of local failure in our patients for several reasons. In some cases the disease may have been missed by our biopsies altogether. In others the recurrence is still microscopic with no architectural alteration, and random as well as repeated biopsies are warranted. Repeat transrectal ultrasound with biopsy is justified, especially if the PSA is increasing and distant metastatic lesions are ruled out. Culp documented the interval to local failure for lesions confined clinically to the prostate. 13 He found that two-thirds of 33 patients had recurrence within the first 5 years after therapy but 15% did not have local failure until after 10 years. Despite negative metastatic studies and transrectal biopsies,
4 of our patients (20%) have maintained stable PSA levels (less than 4 ng./ml.) for 6 to 24 months. Since PSA is an organ specific marker, this finding indicates the presence of residual prostatic tissue. The fact that the PSA level remains unchanged may reflect its production by benign tissue or low grade adenocarcinoma of the prostate even when the initial biopsies are negative. The management of these patients is unclear. Currently we perform a complete evaluation with biopsy of the vesicourethral junction. However, if this evaluation is negative and PSA is stable we recommend a conservative approach with serial PSA levels and a digital rectal examination every 6 months. If either the PSA or the digital rectal examination findings change biopsy is repeated. Persistently detectable PSA values cannot distinguish patients with residual pelvic disease from those with occult distant metastases. Currently, biopsy of the former prostatic bed is the only objective method to identify local recurrence. In our experience transrectal ultrasound guided biopsy is helpful in patients with isolated PSA elevation after radical prostatectomy and a normal digital rectal examination. REFERENCES
1. Jewett, H.J.: The present status of radical prostatectomy for stages
A and B prostatic cancer. Urol. Clin. N. Amer., 2: 105, 1975. 2. Schellhammer, P. F.: Radical prostatectomy for carcinoma of the prostate and 15 year analysis of survival and local control. J. Urol., part 2, 135: 247A, abstract 574, 1986. 3. 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. 4. Killian, C. 8., Yang, N., Emrich, L. J., Vargas, 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 stage B2 to Dl prostate cancer. Cancer Res., 45: 886, 1985. 5. Lightner, D. J., Lange, P.H., Reddy, P. K. and Moore, L.: Prostate specific antigen and local recurrence after radical prostatectomy. J. Urol., 144: 921, 1990. 6. Ray, G. R., Bagshaw, M.A. andFreiha, F.: External beam radiation salvage for residual local tumor following radical prostatectomy. J. Urol., 132: 926, 1984. 7. Gibbons, R. P., Cole, B. 8., 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. 8. Anscher, M. 8. 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.
DETECTION 01~ LOCAL RECURRENCE AFTER R"ADICAL PROSTATECTOl\!IY
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therapy on prostate specific antigen following radical prostatectomy. J. Uroi., 143: 1174, 1990. 12. Parra, R. 0., Wolf, RM. and Huben, R. P.: The use oftransrectal ultrasound in the detection and evaluation of local pelvic recurrences after a radical urological pelvic operation. J. Urol., 144: 707, 1990. 13. Culp, 0. S.: Radical perinea! prostatectomy: its past, present and possible future. J. Urol., 98: 618, 1967.
