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Intermediate-Term Survival Results in Clinically Understaged Prostate Cancer Patients Following Radical Prostatectomy
0022-5347 /88/1403-0540$02.00/0 Vol. 140, September Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1988 by The Williams & Wilkins Co.
INTERMEDIATE-TERM SURVIVAL RESULTS IN CLINICALLY UNDERSTAGED PROSTATE CANCER PATIENTS FOLLOWING RADICAL PROSTATECTOMY WILLIAM J. CATALONA,* DONALD R. MILLER
AND
LOUIS R. KAVOUSSI
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
To determine the natural history of clinically understaged prostatic cancer patients who were followed without adjuvant therapy for at least 6 years after radical prostatectomy we reviewed the clinical courses of 21 patients (1 with clinical stage A and 20 with clinical stage B disease). All patients underwent radical retropubic prostatectomy and 9 had pathological stage C disease (6 with capsular penetration only and 3 with seminal vesicle invasion). A total of 12 patients had pathological stage Dl disease by virtue of positive nodes on permanent sections after frozen sections were read as negative. Among the patients with pathological stage C disease 67 per cent were free of recurrence 6 years after radical prostatectomy. Of the patients with seminal vesicle invasion 33 per cent had recurrence compared to 17 per cent of those with capsular penetration only. Among the 12 stage Dl cancer patients 75 per cent were free of recurrence at 6 years. In both groups patients who were followed beyond 7 years had a diminished survival free of tumor owing to late tumor recurrences. The results indicate that the intermediate survival rates free of tumor in patients with clinically understaged A or B prostatic cancer are remarkably good without adjuvant therapy. However, survival without recurrence appears to decrease after 7 years. All patients who failed treatment did so distantly; no patient failed with local recurrence alone. These results may be important in the evaluation of adjuvant therapy protocols currently under investigation for patients with clinically understaged prostate cancer. (J. Ural., 140: 540-543, 1988) Radical prostatectomy frequently is used in the treatment of patients with clinically localized carcinoma of the prostate. Approximately 20 per cent of the patients with clinical stage A2, 15 per cent with clinical stage Bl and 40 per cent with clinical stage B2 disease have histological evidence of local extracapsular tumor extension and/or seminal vesicle invasion in the surgical specimen. 1 In addition, 18 to 35 per cent of the patients with stages A and B disease have unsuspected pelvic lymph node metastases. 2 The management of patients with clinically localized carcinoma of the prostate and pathological stage C or Dl disease after radical prostatectomy is controversial. Some investigators have recommended treatment with adjunctive hormonal or radiation therapy. Others have advised expectant management, treating only those patients who have clinical evidence of tumor recurrence. Many studies have reported only short-term (5year) projected survival results. We examine the courses of clinically understaged cancer patients followed without adjuvant therapy for a minimum of 6 years (range 6 to 10 years or until death) after radical prostatectomy. We refer to this followup interval as intermediate-term for prostate cancer patients. MATERIALS AND METHODS
The study group included 21 patients between 56 and 73 years old, of whom 1 had clinical stage A2 and 20 had stage B prostate cancer (see table). All patients were treated with staging pelvic lymphadenectomy and radical retropubic prostatectomy and the disease had been clinically understaged. All patients were operated on between 1976 and 1980. The closing Accepted for publication January 12, 1988. Read at annual meeting of American Urological Association, Anaheim, California, May 17-21, 1987. * Requests for reprints: Division of Urologic Surgery, Washington University School of Medicine, 4960 Audubon Ave., St. Louis, Missouri 63110.
date for followup was March 1987. Specimens were examined in the routine fashion by the surgical pathology staff at Barnes Hospital. Specimens were graded as either well, moderately or poorly differentiated adenocarcinoma according to the grading system used at Barnes Hospital. All of the stage C cancer patients were followed for at least 6 years, with a range of 6 to 10 years or until death. All of the stage Dl cancer patients were followed for at least 7 years, with a range of 7 to 10 years or until death. No patient received any form of adjuvant therapy before tumor recurrence. Followup included digital rectal examination, serum acid phosphatase (thymolphthalein monophosphate) determinations and bone scans when clinically indicated (acid phosphatase elevation or bone pain). Acid phosphatase elevation was considered to be evidence of treatment failure. Followup intervals were 3 to 6 months for the first 4 postoperative years, then annually. RESULTS
Five patients had well, 10 moderately and 6 poorly differentiated tumors. Of 9 patients with pathological stage C disease 6 had capsular penetration only and 3 had seminal vesicle invasion. Twelve patients had lymph node metastases on permanent sections after frozen sections were read as negative and, thus, the disease was upstaged to stage DL Nine patients had 1, 2 had 2 and 1 had 4 positive nodes. Of the 12 stage Dl cancer patients 6 (50 per cent) also had capsular penetration and 2 (17 per cent) also had seminal vesicle involvement. The survival data are expressed in terms of direct survival free of recurrence. Figure 1 depicts the survival rates in the 9 pathological stage C cancer patients. At 6 years 67 per cent of the patients were free of recurrence, 1 died of unrelated causes without evidence of tumor and 2 had recurrence at a mean of 3.25 years postoperatively. The latter 2 patients had distant metastases with 1 failing locally (palpable mass that was not biopsied) as well. One of 3 patients (33 per cent) with seminal
540
541
SURVIVAL IN CLII¾HCALL'Y Ui'JDERSTAGED PROSTATE CANCER PArfIENTS
Ciinicopathological data on patients Pt. Yr. of Clinical No.-Age Operation Stage
No. Pos. Seminal Local Yrs. to Margins Metastases Nodes Recurrence Vesicle Recurrence
Grade
Pathological stage C Ca Pos. Neg. Neg.
Neg.
1980
B2
Well differentiated
2-70 3-69
1976 1978
A2 Bl
Poorly differentiated Moderately differentiated
Pos. Pos.
Pos. Neg.
Pos. Neg.
Pos. Neg.
3
4-64 5-58
1976 1980
B2 Bl
Moderately differentiated Moderately differentiated
Pos. Pos.
Pos. Neg.
Neg. Neg.
Pos. Neg.
4
6-66
1978
B2
Poorly differentiated
Pos.
Neg.
Neg.
Neg.
7-56 8-56
1975 1976
B2 B2
Well differentiated Moderately differentiated
Pos. Pos.
Neg. Neg.
Neg. Neg.
Pos. Neg.
9-73
1980
B2
Well differentiated
Pos.
Pos.
Neg.
Neg.
1-61
1976
Bl
Well differentiated
1/25
Pathological stage D Ca Pos. Pos. Neg.
Neg.
2-57 3-65 4-63 5-61
1976 1977 1977 1977
Bl Bl Bl A2
Moderately differentiated Poorly differentiated Poorly differentiated Well differentiated
4/16 1/17 1/31 2/46
Pos. Neg. Neg. Neg.
Neg. Pos. Pos. Neg.
Neg. Pos. Pos. Neg.
Pos. Pos. Pos. Neg.
7.5 2 3
6-57 7-58
1977 1978
Bl B2
Moderately differentiated Moderately differentiated
1/12 1/23
Neg. Neg.
Neg. Neg.
Neg. Neg.
Pos. Neg.
8
8-69
1978
Bl
Moderately differentiated
1/36
Pos.
Neg.
Neg.
Neg.
9-55 10-68 11-56 12-72
1978 1978 1979 1980
Bl B2 B2 B2
Poorly differentiated Moderately differentiated Poorly differentiated Moderately differentiated
1/14 1/40 1/25 1/10
Pos. Neg. Pos. Pos.
Neg. Neg. Neg. Neg.
Neg. Pos. Neg. Neg.
Pos. Pos. Pos. Neg.
%
STAGE C RECURRENCE-FREE SURVIVAL (n=9)
Foilowup (yrs.)
No evidence of disease Death of Ca No evidence of disease Death of Ca No evidence of disease Death of intercurrent disease Lost to followup No evidence of disease No evidence of disease
1-65
%
Current Status
9
1.5 7 5
7 3 9 6 6 2 9 10
7
No evidence of disease Alive with Ca Death of Ca Death of Ca No evidence of disease Alive with Ca No evidence of disease No evidence of disease Death of Ca Death of Ca Death with Ca No evidence of disease
10 10 4
6 9 9 9 9 4
7 6 7
STAGE D1 RECURRENCE-FREE SURVIVAL (n=12)
10/12
80 7/9
9/12
70
70
60
60
50
50
40
40
30
30
20 -
20
10
10
2 2
4
5
7
a
10
YEARS AFTER OPERATION
Fm. l. Direct survival free of recurrence in 9 clinically understaged patients with pathological stage C prostatic cancer after radical prostatectomy without adjuvant therapy. Solid line indicates that all 9 patients were at risk for 6 years. Broken line indicates patients at risk for 7 to 10 years.
vesicle invasion and 1 of 6 (17 per cent) with capsular penetration only had recurrent disease. The survival rates free of recurrence in pathological stage C cancer patients followed beyond 6 years also are shown in figure 1. Of those at risk for 8 years approximately two-thirds remained free of recurrence. Thereafter, there was an apparent decrease in survival, although the sample size included only 3 eligible patients at 10 years. The further decrease in survival free of tumor was owing to recurrence in all patients, since none of these long-term patients died of unrelated causes. Figure 2 depicts the survival free of recurrence in the 12 pathological stage Dl cancer patients. Of the patients 75 per cent were free of recurrence at 5 years and 58 per cent at 7 years. One patient died of unrelated causes after recurrence. All 5 patients with recurrence suffered distant metastases, including 3 who had local recurrence (palpable mass that was
3
4
5
5
7
9
10
YEARS AFTER OPERATION
FIG. 2. Direct survival free of recurrence in 12 clinically understaged patients with pathological stage Dl prostatic cancer after radical prostatectomy without adjuvant therapy. Solid line indicates that al! 12 patients were at risk for at least 7 years. Broken line indicates patients at risk for 8 to 10 years.
not biopsied) as well. The mean interval to recurrent disease was 4.9 years. One patient with 2 positive nodes had recurrence at 5.5 years, 1 with 2 positive nodes is free of recurrence at 9.5 years and 1 with 4 positive nodes had recurrence at 7.5 years. The survival free of recurrence in the pathological stage Dl cancer patients followed beyond 7 years also is shown in figure 2. By 8 years the survival decreased to 36 per cent and remained near that level throughout 10 years of followup. This decrease in survival was owing to the late tumor recurrence, since none of the long-term patients died of unrelated causes. DISCUSSION
Despite the use of current staging techniques, clinical understaging remains a common problem in patients with clinically localized prostate cancer. The optimal subsequent management of these patients has not been defined clearly. Some investigators have recommended the use of adjunctive radiation or
542
CATALONA, MILLER AND KAVOUSSI
hormonal therapy but there are no compelling data to document the therapeutic benefits of such therapy. In our study we examined the subsequent courses of 21 clinically understaged cancer patients who were followed for a minimum of 6 years with no adjunctive therapy before tumor recurrence. It should be emphasized that these patients represent the earliest stages of extracapsular prostatic cancer. The majority (67 per cent with stage C and 75 per cent with stage Dl disease) fared well for at least 6 years without adjunctive therapy. These patients were followed with routine interval acid phosphatase determinations. Bone scans were performed only if there was an elevation of acid phosphatase or bone pain. It is possible that the use of routine followup bone scans and/ or the use of prostate specific antigen levels may have detected treatment failure earlier. Limited data are available on the natural history of clinically understaged prostate cancer patients after radical prostatectomy. Few previously reported series are strictly comparable to our series. This information is important in view of the current controversy surrounding adjuvant therapy protocols for understaged cancer patients. Jewett reported that capsular penetration without seminal vesicle invasion was not necessarily a dire prognostic finding. 3 In an update of the Johns Hopkins series of patients with clinical stage B2 tumors, Elder and associates reported that of 32 patients with histological evidence of extracapsular tumor extension the survival free of tumor without hormonal therapy (except for 7 patients who received 1 to 3 mg. diethylstilbestrol daily for 3 months postoperatively) was approximately 75 per cent at 5 years but it decreased to about 40 per cent at 10 years and it was only 13 per cent at 15 years. 4 In our series the survival free of recurrence was remarkably good at 5 years but it appeared to decrease appreciably by 10 years, although the number of patients at risk for 10 years was small. Our results in patients with pathological stage C disease are similar to those of Middleton and associates, who reported a 71 per cent 5-year survival free of tumor in comparably staged patients. 5 Among 18 of their patients with microscopic capsular invasion 12 (67 per cent) were free of recurrence at 5 years without adjuvant therapy. They also observed a higher recurrence rate among patients with seminal vesicle invasion and found that no patient failed with local recurrence only. Among their 10 patients with seminal vesicle invasion 5 (50 per cent) died of prostatic cancer or had osseous metastases within 5 years after radical prostatectomy. Adjunctive radiation or hormonal therapy has been advocated in patients with pathological stage C disease after radical prostatectomy. However, to date no convincing evidence has been presented to indicate that any form of adjuvant therapy significantly increases the cure rate. Gibbons and associates reported that adjunctive radiation therapy significantly reduced the local recurrence rate from 30 per cent in nonirradiated patients to 5 per cent in patients receiving adjunctive radiation therapy. 6 However, adjunctive irradiation did not significantly decrease the ultimate incidence of distant metastases. In our experience, as in that of Middleton and associates,5 distant metastases is the major cause of treatment failure in clinically understaged cancer patients after radical prostatectomy. Bahnson and associates also reported on the use of adjunctive radiation therapy in clinically understaged cancer patients. 7 In their series of 14 patients with stage C disease who received adjunctive radiation the 5-year survival rate free of tumor was 75 per cent, which is comparable to our results in nonirradiated patients. The Veterans Administration Urological Research Study Group 2 demonstrated that adjuvant hormonal therapy delayed the progression from stage C to stage D disease but it had no significant effect on over-all survival. 8 Zincke and associates examined the effects of adjuvant endocrine therapy in 49 patients treated with radical prostatectomy who had limited clin-
ical stage C disease without nodal involvement. 9 Although the followup in this study was limited, among 12 patients treated with adjuvant orchiectomy the projected survival free of progression at 6 years was approximately 50 per cent for those treated with orchiectomy compared to 45 per cent for those who did not receive adjuvant orchiectomy. The authors concluded that adjuvant hormonal therapy conferred no survival advantage on men with limited stage C disease treated with radical prostatectomy. This survival free of progression is less in both groups than was observed among our pathological stage C cancer patients treated without adjuvant therapy, which may be explained by the more advanced clinical stage of disease in the series of Zincke and associates. The failure of hormonal therapy to delay progression may be explained by the limited followup in both groups. Lange and associates reported on 45 pathological stage C or Dl cancer patients with seminal vesicle invasion, positive anastomotic margins, marked capsular penetration associated with a Gleason grade of more than 7, or 6 or fewer microscopically positive nodes. 10 Patients with stage C tumors were treated with 6,000 rad external beam radiation therapy to the prostatic bed. In patients with positive nodes 4,500 rad were delivered to the pelvis and 6,000 rad were delivered to the prostatic bed. The median followup for stage C cancer patients was 62 months and for stage Dl cancer patients it was 48 months. There were no local recurrences. Bone metastases developed in 3 of 24 patients (13 per cent) with stage C disease and 3 of 21 (14 per cent) with stage Dl tumor. The actuarial survival projections free of recurrence at 5 years were 79 per cent for patients with stage C and 72 per cent for those with stage Dl disease. Lange and associates presented a review of the literature comparing their results 10 with other reported studies, 11- 15 and tentatively concluded that their results with adjuvant radiation therapy may be better than previous results obtained without adjuvant radiation therapy. However, their actuarial projections are comparable to our direct survival results free of tumor in patients who did not receive ad_iuvant radiation therapy. Skinner and associates reported that 16 of 18 patients (89 per cent) with clinical stages B2 and C and pathological stage C disease after radical prostatectomy who were treated with 4,000 to 5,000 rad adjuvant radiation therapy were free of recurrence, with a mean followup of 60 months (range 36 to 120 months). 16 All patients who failed therapy had distant metastases; 1 also had a synchronous local recurrence. Our 5-year survival free of recurrence of 75 per cent in patients with pathological stage Dl disease is comparable to the excellent survival free of tumor reported by deKernion and associates in their subgroup of patients treated with radical prostatectomy who did not receive adjunctive hormonal or radiation therapy. 17 Bahnson and associates reported a 5-year survival free of recurrence of 41 per cent among 6 pathological stage Dl cancer patients treated with adjuvant radiation therapy. 7 This survival rate is less than that observed in our patients who were not treated with adjuvant therapy. In the Mayo Clinic series the 6-year survival rate without recurrence in clinical stage C but pathological stage Dl cancer patients who did not receive adjuvant orchiectomy was 11 per cent compared to approximately 80 per cent in patients treated with adjuvant orchiectomy. 11 Although these results suggest that hormonal therapy may significantly delay tumor progression in stage Dl cancer patients, the reason for the low survival free of progression in the patients not receiving adjuvant orchiectomy is unclear but it may be related to the more advanced clinical stage of the disease. In conclusion, our results indicate that the intermediateterm survival results free of recurrence in clinically understaged A or B prostate cancer patients are remarkably good without adjuvant therapy. However, survival appears to decrease appreciably after 7 years owing primarily to late distant
SURVIVAL IN CLINICALLY UNDERSTAGED PROSTATE CANCER PATIENTS
metastases. These findings may be important when considering the adjuvant therapy protocols that have been reported for understaged prostatic cancer patients and they clearly indicate the need for future prospective randomized trials with adequate followup to resolve this issue. REFERENCES
1. Catalona, W. J. and Stein, A. J.: Staging errors in clinically localized prostatic cancer. J. Urol., 127: 452, 1982. 2. Donohue, R. E., Fauver, H. E., Whitesel, J. A., Augspurger, R. R. and Pfister, R.R.: Prostatic carcinoma: influence of tumor grade on results of pelvic lymphadenectomy. Urology, 17: 435, 1981. 3. Jewett, H.J.: The case for radical perinea! prostatectomy. J. Urol., 103: 195, 1970. 4. Elder, J. S., Jewett, H. J. and Walsh, P. C.: Radical perinea! prostatectomy for clinical stage B2 carcinoma of the prostate. J. Urol., 127: 704, 1982. 5. Middleton, R. G., Smith, J. A., Jr., Melzer, R. B. and Hamilton, P. B.: Patient survival and local recurrence rate following radical prostatectomy for prostatic carcinoma. J. Urol., 136: 422, 1986. 6. 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. 7. Bahnson, R. R., Garnett, J. E. and Grayhack, J. T.: Adjuvant radiation therapy in stages C and Dl prostatic adenocarcinoma: preliminacy results. Urology, 27: 403, 1986. 8. Byar, D. P.: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer, 32:
543
1126, 1973. 9. Zincke, H., Utz, D. C. and Taylor, W. F.: Bilateral pelvic lymphadenectomy and radical prostatectomy for clinical stage C prostatic cancer: role of adjuvant treatment for residual cancer and in disease progression. J. Urol., 135: 1199, 1986. 10. Lange, P. H., Moon, T. D., Narayan, P. and Medini, E.: Radiation therapy as adjuvant treatment after radical prostatectomy: patient tolerance and preliminacy results. J. Urol., 136: 45, 1986. 11. Zincke, H. and Utz, D. C.: Observations on surgical management of carcinoma of the prostate with limited nodal metastases. Urology, 24: 137, 1984. 12. Paulson, D. F. and Uro-Oncology Research Group: Radical surgecy for the management of prostatic carcinoma. World J. Urol., 1: 29, 1983. 13. Smith, J. A., Jr. and Middleton, R. G.: Implications of volume of nodal metastases in patients with adenocarcinoma of the prostate. J. Urol., 133: 617, 1985. 14. Bagshaw, M. A.: Radiation therapy of prostatic carcinoma. In: Genitourinacy Cancer Surgecy. Edited by E. D. Crawford and T. A. Borden. Philadelphia: Lea & Febiger, sect. XI, chapt. 47, p. 405, 1982. 15. Rosenberg, S. J., Loening, S. A., Hawtrey, C. E., Narayana, A. S. and Culp, D. A.: Radical prostatectomy with adjuvant radioactive gold for prostatic cancer: a preliminacy report. J. Urol., 133: 225, 1985. 16. Skinner, D. G., Lieskovsky, G. and Carter, G. E.: Management of locally extensive cancer of the prostate without evidence of metastatic disease. Prob!. Urol., 1: 99, 1987. 17. deKernion, J. B., Huang, M. Y., Kaufman, J. J. and Smith, R. B.: Result of treatment of patients with stage Dl prostatic carcinoma. Urology, 26: 446, 1985.
THE JOURNAL OF UROLOGY
Copyright © 1988 by The Williams & Wilkins Co.
INTERMEDIATE-TERM SURVIVAL RESULTS IN CLINICALLY UNDERSTAGED PROSTATE CANCER PATIENTS FOLLOWING RADICAL PROSTATECTOMY WILLIAM J. CATALONA,* DONALD R. MILLER
AND
LOUIS R. KAVOUSSI
From the Division of Urologic Surgery, Washington University School of Medicine, St. Louis, Missouri
ABSTRACT
To determine the natural history of clinically understaged prostatic cancer patients who were followed without adjuvant therapy for at least 6 years after radical prostatectomy we reviewed the clinical courses of 21 patients (1 with clinical stage A and 20 with clinical stage B disease). All patients underwent radical retropubic prostatectomy and 9 had pathological stage C disease (6 with capsular penetration only and 3 with seminal vesicle invasion). A total of 12 patients had pathological stage Dl disease by virtue of positive nodes on permanent sections after frozen sections were read as negative. Among the patients with pathological stage C disease 67 per cent were free of recurrence 6 years after radical prostatectomy. Of the patients with seminal vesicle invasion 33 per cent had recurrence compared to 17 per cent of those with capsular penetration only. Among the 12 stage Dl cancer patients 75 per cent were free of recurrence at 6 years. In both groups patients who were followed beyond 7 years had a diminished survival free of tumor owing to late tumor recurrences. The results indicate that the intermediate survival rates free of tumor in patients with clinically understaged A or B prostatic cancer are remarkably good without adjuvant therapy. However, survival without recurrence appears to decrease after 7 years. All patients who failed treatment did so distantly; no patient failed with local recurrence alone. These results may be important in the evaluation of adjuvant therapy protocols currently under investigation for patients with clinically understaged prostate cancer. (J. Ural., 140: 540-543, 1988) Radical prostatectomy frequently is used in the treatment of patients with clinically localized carcinoma of the prostate. Approximately 20 per cent of the patients with clinical stage A2, 15 per cent with clinical stage Bl and 40 per cent with clinical stage B2 disease have histological evidence of local extracapsular tumor extension and/or seminal vesicle invasion in the surgical specimen. 1 In addition, 18 to 35 per cent of the patients with stages A and B disease have unsuspected pelvic lymph node metastases. 2 The management of patients with clinically localized carcinoma of the prostate and pathological stage C or Dl disease after radical prostatectomy is controversial. Some investigators have recommended treatment with adjunctive hormonal or radiation therapy. Others have advised expectant management, treating only those patients who have clinical evidence of tumor recurrence. Many studies have reported only short-term (5year) projected survival results. We examine the courses of clinically understaged cancer patients followed without adjuvant therapy for a minimum of 6 years (range 6 to 10 years or until death) after radical prostatectomy. We refer to this followup interval as intermediate-term for prostate cancer patients. MATERIALS AND METHODS
The study group included 21 patients between 56 and 73 years old, of whom 1 had clinical stage A2 and 20 had stage B prostate cancer (see table). All patients were treated with staging pelvic lymphadenectomy and radical retropubic prostatectomy and the disease had been clinically understaged. All patients were operated on between 1976 and 1980. The closing Accepted for publication January 12, 1988. Read at annual meeting of American Urological Association, Anaheim, California, May 17-21, 1987. * Requests for reprints: Division of Urologic Surgery, Washington University School of Medicine, 4960 Audubon Ave., St. Louis, Missouri 63110.
date for followup was March 1987. Specimens were examined in the routine fashion by the surgical pathology staff at Barnes Hospital. Specimens were graded as either well, moderately or poorly differentiated adenocarcinoma according to the grading system used at Barnes Hospital. All of the stage C cancer patients were followed for at least 6 years, with a range of 6 to 10 years or until death. All of the stage Dl cancer patients were followed for at least 7 years, with a range of 7 to 10 years or until death. No patient received any form of adjuvant therapy before tumor recurrence. Followup included digital rectal examination, serum acid phosphatase (thymolphthalein monophosphate) determinations and bone scans when clinically indicated (acid phosphatase elevation or bone pain). Acid phosphatase elevation was considered to be evidence of treatment failure. Followup intervals were 3 to 6 months for the first 4 postoperative years, then annually. RESULTS
Five patients had well, 10 moderately and 6 poorly differentiated tumors. Of 9 patients with pathological stage C disease 6 had capsular penetration only and 3 had seminal vesicle invasion. Twelve patients had lymph node metastases on permanent sections after frozen sections were read as negative and, thus, the disease was upstaged to stage DL Nine patients had 1, 2 had 2 and 1 had 4 positive nodes. Of the 12 stage Dl cancer patients 6 (50 per cent) also had capsular penetration and 2 (17 per cent) also had seminal vesicle involvement. The survival data are expressed in terms of direct survival free of recurrence. Figure 1 depicts the survival rates in the 9 pathological stage C cancer patients. At 6 years 67 per cent of the patients were free of recurrence, 1 died of unrelated causes without evidence of tumor and 2 had recurrence at a mean of 3.25 years postoperatively. The latter 2 patients had distant metastases with 1 failing locally (palpable mass that was not biopsied) as well. One of 3 patients (33 per cent) with seminal
540
541
SURVIVAL IN CLII¾HCALL'Y Ui'JDERSTAGED PROSTATE CANCER PArfIENTS
Ciinicopathological data on patients Pt. Yr. of Clinical No.-Age Operation Stage
No. Pos. Seminal Local Yrs. to Margins Metastases Nodes Recurrence Vesicle Recurrence
Grade
Pathological stage C Ca Pos. Neg. Neg.
Neg.
1980
B2
Well differentiated
2-70 3-69
1976 1978
A2 Bl
Poorly differentiated Moderately differentiated
Pos. Pos.
Pos. Neg.
Pos. Neg.
Pos. Neg.
3
4-64 5-58
1976 1980
B2 Bl
Moderately differentiated Moderately differentiated
Pos. Pos.
Pos. Neg.
Neg. Neg.
Pos. Neg.
4
6-66
1978
B2
Poorly differentiated
Pos.
Neg.
Neg.
Neg.
7-56 8-56
1975 1976
B2 B2
Well differentiated Moderately differentiated
Pos. Pos.
Neg. Neg.
Neg. Neg.
Pos. Neg.
9-73
1980
B2
Well differentiated
Pos.
Pos.
Neg.
Neg.
1-61
1976
Bl
Well differentiated
1/25
Pathological stage D Ca Pos. Pos. Neg.
Neg.
2-57 3-65 4-63 5-61
1976 1977 1977 1977
Bl Bl Bl A2
Moderately differentiated Poorly differentiated Poorly differentiated Well differentiated
4/16 1/17 1/31 2/46
Pos. Neg. Neg. Neg.
Neg. Pos. Pos. Neg.
Neg. Pos. Pos. Neg.
Pos. Pos. Pos. Neg.
7.5 2 3
6-57 7-58
1977 1978
Bl B2
Moderately differentiated Moderately differentiated
1/12 1/23
Neg. Neg.
Neg. Neg.
Neg. Neg.
Pos. Neg.
8
8-69
1978
Bl
Moderately differentiated
1/36
Pos.
Neg.
Neg.
Neg.
9-55 10-68 11-56 12-72
1978 1978 1979 1980
Bl B2 B2 B2
Poorly differentiated Moderately differentiated Poorly differentiated Moderately differentiated
1/14 1/40 1/25 1/10
Pos. Neg. Pos. Pos.
Neg. Neg. Neg. Neg.
Neg. Pos. Neg. Neg.
Pos. Pos. Pos. Neg.
%
STAGE C RECURRENCE-FREE SURVIVAL (n=9)
Foilowup (yrs.)
No evidence of disease Death of Ca No evidence of disease Death of Ca No evidence of disease Death of intercurrent disease Lost to followup No evidence of disease No evidence of disease
1-65
%
Current Status
9
1.5 7 5
7 3 9 6 6 2 9 10
7
No evidence of disease Alive with Ca Death of Ca Death of Ca No evidence of disease Alive with Ca No evidence of disease No evidence of disease Death of Ca Death of Ca Death with Ca No evidence of disease
10 10 4
6 9 9 9 9 4
7 6 7
STAGE D1 RECURRENCE-FREE SURVIVAL (n=12)
10/12
80 7/9
9/12
70
70
60
60
50
50
40
40
30
30
20 -
20
10
10
2 2
4
5
7
a
10
YEARS AFTER OPERATION
Fm. l. Direct survival free of recurrence in 9 clinically understaged patients with pathological stage C prostatic cancer after radical prostatectomy without adjuvant therapy. Solid line indicates that all 9 patients were at risk for 6 years. Broken line indicates patients at risk for 7 to 10 years.
vesicle invasion and 1 of 6 (17 per cent) with capsular penetration only had recurrent disease. The survival rates free of recurrence in pathological stage C cancer patients followed beyond 6 years also are shown in figure 1. Of those at risk for 8 years approximately two-thirds remained free of recurrence. Thereafter, there was an apparent decrease in survival, although the sample size included only 3 eligible patients at 10 years. The further decrease in survival free of tumor was owing to recurrence in all patients, since none of these long-term patients died of unrelated causes. Figure 2 depicts the survival free of recurrence in the 12 pathological stage Dl cancer patients. Of the patients 75 per cent were free of recurrence at 5 years and 58 per cent at 7 years. One patient died of unrelated causes after recurrence. All 5 patients with recurrence suffered distant metastases, including 3 who had local recurrence (palpable mass that was
3
4
5
5
7
9
10
YEARS AFTER OPERATION
FIG. 2. Direct survival free of recurrence in 12 clinically understaged patients with pathological stage Dl prostatic cancer after radical prostatectomy without adjuvant therapy. Solid line indicates that al! 12 patients were at risk for at least 7 years. Broken line indicates patients at risk for 8 to 10 years.
not biopsied) as well. The mean interval to recurrent disease was 4.9 years. One patient with 2 positive nodes had recurrence at 5.5 years, 1 with 2 positive nodes is free of recurrence at 9.5 years and 1 with 4 positive nodes had recurrence at 7.5 years. The survival free of recurrence in the pathological stage Dl cancer patients followed beyond 7 years also is shown in figure 2. By 8 years the survival decreased to 36 per cent and remained near that level throughout 10 years of followup. This decrease in survival was owing to the late tumor recurrence, since none of the long-term patients died of unrelated causes. DISCUSSION
Despite the use of current staging techniques, clinical understaging remains a common problem in patients with clinically localized prostate cancer. The optimal subsequent management of these patients has not been defined clearly. Some investigators have recommended the use of adjunctive radiation or
542
CATALONA, MILLER AND KAVOUSSI
hormonal therapy but there are no compelling data to document the therapeutic benefits of such therapy. In our study we examined the subsequent courses of 21 clinically understaged cancer patients who were followed for a minimum of 6 years with no adjunctive therapy before tumor recurrence. It should be emphasized that these patients represent the earliest stages of extracapsular prostatic cancer. The majority (67 per cent with stage C and 75 per cent with stage Dl disease) fared well for at least 6 years without adjunctive therapy. These patients were followed with routine interval acid phosphatase determinations. Bone scans were performed only if there was an elevation of acid phosphatase or bone pain. It is possible that the use of routine followup bone scans and/ or the use of prostate specific antigen levels may have detected treatment failure earlier. Limited data are available on the natural history of clinically understaged prostate cancer patients after radical prostatectomy. Few previously reported series are strictly comparable to our series. This information is important in view of the current controversy surrounding adjuvant therapy protocols for understaged cancer patients. Jewett reported that capsular penetration without seminal vesicle invasion was not necessarily a dire prognostic finding. 3 In an update of the Johns Hopkins series of patients with clinical stage B2 tumors, Elder and associates reported that of 32 patients with histological evidence of extracapsular tumor extension the survival free of tumor without hormonal therapy (except for 7 patients who received 1 to 3 mg. diethylstilbestrol daily for 3 months postoperatively) was approximately 75 per cent at 5 years but it decreased to about 40 per cent at 10 years and it was only 13 per cent at 15 years. 4 In our series the survival free of recurrence was remarkably good at 5 years but it appeared to decrease appreciably by 10 years, although the number of patients at risk for 10 years was small. Our results in patients with pathological stage C disease are similar to those of Middleton and associates, who reported a 71 per cent 5-year survival free of tumor in comparably staged patients. 5 Among 18 of their patients with microscopic capsular invasion 12 (67 per cent) were free of recurrence at 5 years without adjuvant therapy. They also observed a higher recurrence rate among patients with seminal vesicle invasion and found that no patient failed with local recurrence only. Among their 10 patients with seminal vesicle invasion 5 (50 per cent) died of prostatic cancer or had osseous metastases within 5 years after radical prostatectomy. Adjunctive radiation or hormonal therapy has been advocated in patients with pathological stage C disease after radical prostatectomy. However, to date no convincing evidence has been presented to indicate that any form of adjuvant therapy significantly increases the cure rate. Gibbons and associates reported that adjunctive radiation therapy significantly reduced the local recurrence rate from 30 per cent in nonirradiated patients to 5 per cent in patients receiving adjunctive radiation therapy. 6 However, adjunctive irradiation did not significantly decrease the ultimate incidence of distant metastases. In our experience, as in that of Middleton and associates,5 distant metastases is the major cause of treatment failure in clinically understaged cancer patients after radical prostatectomy. Bahnson and associates also reported on the use of adjunctive radiation therapy in clinically understaged cancer patients. 7 In their series of 14 patients with stage C disease who received adjunctive radiation the 5-year survival rate free of tumor was 75 per cent, which is comparable to our results in nonirradiated patients. The Veterans Administration Urological Research Study Group 2 demonstrated that adjuvant hormonal therapy delayed the progression from stage C to stage D disease but it had no significant effect on over-all survival. 8 Zincke and associates examined the effects of adjuvant endocrine therapy in 49 patients treated with radical prostatectomy who had limited clin-
ical stage C disease without nodal involvement. 9 Although the followup in this study was limited, among 12 patients treated with adjuvant orchiectomy the projected survival free of progression at 6 years was approximately 50 per cent for those treated with orchiectomy compared to 45 per cent for those who did not receive adjuvant orchiectomy. The authors concluded that adjuvant hormonal therapy conferred no survival advantage on men with limited stage C disease treated with radical prostatectomy. This survival free of progression is less in both groups than was observed among our pathological stage C cancer patients treated without adjuvant therapy, which may be explained by the more advanced clinical stage of disease in the series of Zincke and associates. The failure of hormonal therapy to delay progression may be explained by the limited followup in both groups. Lange and associates reported on 45 pathological stage C or Dl cancer patients with seminal vesicle invasion, positive anastomotic margins, marked capsular penetration associated with a Gleason grade of more than 7, or 6 or fewer microscopically positive nodes. 10 Patients with stage C tumors were treated with 6,000 rad external beam radiation therapy to the prostatic bed. In patients with positive nodes 4,500 rad were delivered to the pelvis and 6,000 rad were delivered to the prostatic bed. The median followup for stage C cancer patients was 62 months and for stage Dl cancer patients it was 48 months. There were no local recurrences. Bone metastases developed in 3 of 24 patients (13 per cent) with stage C disease and 3 of 21 (14 per cent) with stage Dl tumor. The actuarial survival projections free of recurrence at 5 years were 79 per cent for patients with stage C and 72 per cent for those with stage Dl disease. Lange and associates presented a review of the literature comparing their results 10 with other reported studies, 11- 15 and tentatively concluded that their results with adjuvant radiation therapy may be better than previous results obtained without adjuvant radiation therapy. However, their actuarial projections are comparable to our direct survival results free of tumor in patients who did not receive ad_iuvant radiation therapy. Skinner and associates reported that 16 of 18 patients (89 per cent) with clinical stages B2 and C and pathological stage C disease after radical prostatectomy who were treated with 4,000 to 5,000 rad adjuvant radiation therapy were free of recurrence, with a mean followup of 60 months (range 36 to 120 months). 16 All patients who failed therapy had distant metastases; 1 also had a synchronous local recurrence. Our 5-year survival free of recurrence of 75 per cent in patients with pathological stage Dl disease is comparable to the excellent survival free of tumor reported by deKernion and associates in their subgroup of patients treated with radical prostatectomy who did not receive adjunctive hormonal or radiation therapy. 17 Bahnson and associates reported a 5-year survival free of recurrence of 41 per cent among 6 pathological stage Dl cancer patients treated with adjuvant radiation therapy. 7 This survival rate is less than that observed in our patients who were not treated with adjuvant therapy. In the Mayo Clinic series the 6-year survival rate without recurrence in clinical stage C but pathological stage Dl cancer patients who did not receive adjuvant orchiectomy was 11 per cent compared to approximately 80 per cent in patients treated with adjuvant orchiectomy. 11 Although these results suggest that hormonal therapy may significantly delay tumor progression in stage Dl cancer patients, the reason for the low survival free of progression in the patients not receiving adjuvant orchiectomy is unclear but it may be related to the more advanced clinical stage of the disease. In conclusion, our results indicate that the intermediateterm survival results free of recurrence in clinically understaged A or B prostate cancer patients are remarkably good without adjuvant therapy. However, survival appears to decrease appreciably after 7 years owing primarily to late distant
SURVIVAL IN CLINICALLY UNDERSTAGED PROSTATE CANCER PATIENTS
metastases. These findings may be important when considering the adjuvant therapy protocols that have been reported for understaged prostatic cancer patients and they clearly indicate the need for future prospective randomized trials with adequate followup to resolve this issue. REFERENCES
1. Catalona, W. J. and Stein, A. J.: Staging errors in clinically localized prostatic cancer. J. Urol., 127: 452, 1982. 2. Donohue, R. E., Fauver, H. E., Whitesel, J. A., Augspurger, R. R. and Pfister, R.R.: Prostatic carcinoma: influence of tumor grade on results of pelvic lymphadenectomy. Urology, 17: 435, 1981. 3. Jewett, H.J.: The case for radical perinea! prostatectomy. J. Urol., 103: 195, 1970. 4. Elder, J. S., Jewett, H. J. and Walsh, P. C.: Radical perinea! prostatectomy for clinical stage B2 carcinoma of the prostate. J. Urol., 127: 704, 1982. 5. Middleton, R. G., Smith, J. A., Jr., Melzer, R. B. and Hamilton, P. B.: Patient survival and local recurrence rate following radical prostatectomy for prostatic carcinoma. J. Urol., 136: 422, 1986. 6. 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. 7. Bahnson, R. R., Garnett, J. E. and Grayhack, J. T.: Adjuvant radiation therapy in stages C and Dl prostatic adenocarcinoma: preliminacy results. Urology, 27: 403, 1986. 8. Byar, D. P.: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer, 32:
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1126, 1973. 9. Zincke, H., Utz, D. C. and Taylor, W. F.: Bilateral pelvic lymphadenectomy and radical prostatectomy for clinical stage C prostatic cancer: role of adjuvant treatment for residual cancer and in disease progression. J. Urol., 135: 1199, 1986. 10. Lange, P. H., Moon, T. D., Narayan, P. and Medini, E.: Radiation therapy as adjuvant treatment after radical prostatectomy: patient tolerance and preliminacy results. J. Urol., 136: 45, 1986. 11. Zincke, H. and Utz, D. C.: Observations on surgical management of carcinoma of the prostate with limited nodal metastases. Urology, 24: 137, 1984. 12. Paulson, D. F. and Uro-Oncology Research Group: Radical surgecy for the management of prostatic carcinoma. World J. Urol., 1: 29, 1983. 13. Smith, J. A., Jr. and Middleton, R. G.: Implications of volume of nodal metastases in patients with adenocarcinoma of the prostate. J. Urol., 133: 617, 1985. 14. Bagshaw, M. A.: Radiation therapy of prostatic carcinoma. In: Genitourinacy Cancer Surgecy. Edited by E. D. Crawford and T. A. Borden. Philadelphia: Lea & Febiger, sect. XI, chapt. 47, p. 405, 1982. 15. Rosenberg, S. J., Loening, S. A., Hawtrey, C. E., Narayana, A. S. and Culp, D. A.: Radical prostatectomy with adjuvant radioactive gold for prostatic cancer: a preliminacy report. J. Urol., 133: 225, 1985. 16. Skinner, D. G., Lieskovsky, G. and Carter, G. E.: Management of locally extensive cancer of the prostate without evidence of metastatic disease. Prob!. Urol., 1: 99, 1987. 17. deKernion, J. B., Huang, M. Y., Kaufman, J. J. and Smith, R. B.: Result of treatment of patients with stage Dl prostatic carcinoma. Urology, 26: 446, 1985.