Treatment of Stage 1 Carcinoma of the Prostate: A Preliminary Report

Vol. 106, November Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1971 by The Williams & Wilkins Co.

TREATJ\IE;\;T OF STAGE 1 CARCINOMA OF THE PROSTATE: A PRELIMINARY REPORT CLYDE E. BLACKARD, GEORGE T. MELLINGER

A.ND

DONALD F. GLEASON

From the Departments of Surgery (Urology) ancl Pathology, Veterans Administration Hospital and Universily of JVlinnesota School of !Vleclicine, Minneapolis, :vlinnesota, and the Veterans Administration Hospital, Kansas City, IVIissouri

Stage 1 prostatic carcinoma is a microscopic cancer arising in a gland which is not indurated on rectal examination and is not accompanied by evidence of metastases. Diagnosis usually is made by finding a small focus of carcinoma in an enucleated adenoma or in chips of prostatic tissue removed transurethrally for benign hyperplasia. The incidence of microscopic carcinoma in prostatic tissue removed for benign hyperplasia has varied from 3.5 to 21 per cent. 1 - 2 Recommended treatment has varied from no treatment in addition to transurethral resection or open prostatectorny, to total prostatoserninal vesiculectomy with or without supplementary estrogcn. 3-14_ A

preliminary report of our experience with this type of prostatic cancer is described herein. MATERIAL A"fD METHODS

Between January 1, 1960 and December 31, 1968 diagnosis of stage 1 prostatic carcinoma was made in 91 patients at the Minneapolis Veterans Administration Hospital, using the criteria mentioned previously. Metastases were considered to be absent if the prostatic acid phosphatase was normal and if there were no skeletal lesions. Followup in all 91 patients was from the time of diagnosis until their death or until January 1, 1970. There were no losses to followup. Diagnosis was made by transurethral prostatic resection in 82 patients, by open prostatectomy in 8 and by random needle biopsy in 1. After transurethral resection at least 12 prostatic chips were processed and examined, while following enucleation random sections were taken from the adenoma and from any suspicious areas. Histological examination of the tissue was made by 1 of 2 referee pathologists (Drs. F. K. :VIostofi or D. F. Gleason). According to Dr. Gleason, carcinoma was well differentiated in 40 per cent of patients, moderately differentiated in 54 per cent and poorly differentiated in 6 per cent. Therapy was not randomized (table 1). Either no additional treatment or hormonal therapy was assigned to patients who were thought to be in poor health or whom the investigator did not expect to live 5 years. General health and age were

Accepted for publication December 1970. The authors acknowledge the support of the Veternns Administration Cooperative Urological Research Group but statements and conclusions made in this paper are not necessarily those of the entire group. 1 Bergman, H. T., Turner, H., Barnes, R. W. a.nd Ha.dley, H. L.: Compa.rative ana.lysis of one thousand consecutive cases of transurethral pros(atic resection. J. Urol., 74: 533, 1955. 2 Denton, S. K, Choy, 8. H. and Valk, W. L.: Occult prostatic carcinoma diagnosed by the stepsection technique of the Rnrgical specimen. J. Urol., 93: 296, 1965. 3 Hinman, F., Jr. and Hinman, F.: Occult prostatic carcinoma. diagnosed upon transurethral resection. J. Urol., 62: 723, 1949. 4 Nesbit, R. M. and Baum, W. C.: Management of occult prostatic carcinoma.. J. Urol., 65: 890, 1951. 5 Goodwin, W. E.: Radical prostatectomy after previous prostatic surgery: technical problems encountered in treatment of occult prostatic carcinoma. J.A.M.A., 148: 799, 1952. 6 Labess, M.: Occult carcinoma in clinically benign hypertrophy of the prostate: a pathological and clinical study. J. Urol., 68: 893, 1952. 7 Hudson, P. B., Finkle, A. L., Hopkins, J. A., Sproul, E. E. and Stout, A. P.: Prost a tic cancer: XI. Early prostatic cancer diagnosed by arbitrary open perinea! biopsy among 300 unselected patients. Cancer, 7: 690, 1954. 8 Greene, L. F. and Simon, H. B.: Occult carcinoma of the prostate: clinical and therapeutic study of 83 cases. J.A.M.A., 158: 1494, 1955. 9 Barnes, R. W. and Emery, D.S.: Management of early prostatic carcinoma. Calif. Med., 91: 57, 1959. 10 Bauer, W. C., McGavran, M. H. and Carlin, M. R.: Unsuspected carcinoma of the prostate

in suprapubic prostatectomy specimens. Cancer, 13: 370, 1960. 11 Montgomery, T. R., Whitlock, G. F., Nohlgren, J. E. and Lewis, A. M.: What becomes of the patient with latent or occnlt carcinoma of the prostate. J. Urol., 86: 655, 1961. 12 Fergusson, .J. D.: The doubtfully malignant prosta1e. Brit. J. Surg., 52: 746, 1965. 13 Meli cow, M. M.: Cancer of the prostate· concepts and guide lines in histological diagnosis. J. Urol., 95: 791, 1966. 14 Lehma.n, T. H., Kirchheim, D., Braun, E. and Moore, R.: An evaluation of radical prostatectomy for incidentally diagnosed carcinoma of the prostate. J. Urol., 99: 646, 1968.

729

730

BLACKARD, MELLINGER AND GLEASON

the major factors in deciding whether to perform a total prostatoseminal vesiculectomy. If a patient was considered a suitable candidate, radical prostatectomy with or without supplementary estrogen was performed. Pelvic lymphadenectomy was not performed. Patients were examined by one of the investigators at least every 6 months. Rectal examination of the prostate, hemoglobin, acid phosphatase level (total and prostatic fraction), roentgenogram of the chest and skeletal survey were obtained at each examination. An excretory urogram was performed at least once a year. Five of 91 patients required a change in the primary therapy because of clinical carcinoma of the prostate with or without metastases. Three patients in the untreated group and two in the surgical group were changed to hormonal therapy because of recurrence. In the hormonal group, no patient's treatment was changed. The median age of the 45 untreated patients was 71 years (range 55 to 80 years), of the 22 hormonal patients it was 72 years (range 64 to 77 years) and of the 24 surgical patients it was 68 years (range 61 to 78 years). The 30 living untreated patients have been followed for 12 to llO months with a median duration of 62 months. The 12 living hormonal patients have been folTABLE

1. Primary

treatment of patients stage 1 carcinoma of the prostate

with

No. Pts. No treatment other than TUR or open prostatectomy. Hormonal. . . Diethylstilbestrol (DES) 5.0 mg. daily, 13 Orchiectomy, 5 DES 5.0 mg. daily plus orchiectomy, 4 Surgical.. Radical prostatectomy, 16 Radical prostatectomy plus DES 5.0 mg. daily, 8

45 22

Total

91

24

2. Pre-treatment cardiovascular and electrocardiographic status of stage 1 patients according to primary treatment

TABLE

No. Pts.

No PreTreatment History of C-V Disease No.(%)

Normal PreTreatment EKG No.(%)

45

23 (51)

22 24

10 (46) 18 (75)

21 (47) 11 (50) 15 (63)

lowed for 24 to 79 months with a median duration of 42 months, while the 14 living surgical patients have been followed for 12 to 108 months with a median duration of 78 months. PRE-'l'REATMENT CARDIOVASCULAR STATUS

A method for rating the pre-treatment and post-treatment cardiovascular status and electrocardiographic findings of study patients has been described in a previous report (table 2).15 Patients who underwent radical prostatectomy had the best pre-treatment cardiovascular and electrocardiographic status. Men assigned to no additional treatment and those assigned to hormonal therapy had similar pre-treatment cardiovascular and electrocardiographic statuses. RESULTS

Survival rates. Survival rates were determined for stage 1 patients using the actuarial or lifetable method described by Cutler. 16 Analysis of survival data was done in terms of the primary treatment to which patients were assigned. Untreated patients had the best survival rate, although there was no significant difference among the 3 major treatment groups at any followup period (see figure). Causes of death. Fifteen untreated, 10 surgical and 10 hormonal patients have died (table 3). The method of determining the cause of death in study patients has been described previously. 15 Necropsy was performed in a third of the cases. There were only 2 deaths due to cancer of the prostate: 1 in the untreated group and 1 in the surgical group. There were 22 cardiovascular deaths. Fourteen of these 22 patients (64 per cent) had been treated daily with 5.0 mg. diethylstilbestrol. The increased incidence of cardiovascular deaths in patients receiving estrogen in this study was highyl significant (p < 0.001). Status of patients following total prostatoseminal vesiculectomy. Twenty-four of 91 patients had a radical prostatectomy. The operation was performed by the perineal route in 16 patients and by the retropubic approach in 8. There were no 15 Blackard, C. E., Doe, R. P., Mellinger, G. T. and Byar, D. P.: Incidence of cardiovascular disease and death in patients receiving diethylstilbestrol for carc>inoma of the prostate. Cancer,

26: 249, 1970. No additional treatment Hormonal Surgical

16 Cutler, S. J.: International symposium on end results of cancer therapy. Computation of survival rates. Nat. Cancer Inst. Monogr., 15:

381, 1964.

731

TREATMENT OF STAGE l PROSTATIC CARCINOMA

postoperative deaths or permanent fistulas. Six of 24 patients (25 per cent) were incontinent of urine at 1 year or later following radical prostatectomy. Residual tumor was found in 21 of 24 radical prostatectomy specimens, while no residual tumor could be found in 3 of 24 totally removed prostates. Two of these 3 patients previously had had transurethral resection and one an open prostatectomy. Status of the prostatic cancer. Seventeen patients had evidence of clinical carcinoma sometime following admission to the study (table 4). This included 13 patients in the untreated group, 2 in the hormonal group and 2 in the surgical group. Six of the 17 patients had metastases: 4 in the untreated and 2 in the surgical groups. Only 4 of 17 patients who had clinical carcinoma were disabled from their cancer. These 4 men had bone pain and other symptoms due to metastatic disease, and 3 received excellent palliation following initiation of estrogen therapy. Pre-study histological slides on the 17 patients who had clinical cancer showed well-differentiated carcinoma in 4 slides, moderately-differentiated carcinoma in 11 slides and poorly-differentiated carcinoma in 2 slides. When compared to the group without clinical carcinoma, those with recurrence showed a tendency toward more anaplastic stage 1 tumors but the difference between the 2 groups was not significant (p > 0.20). DISCUSSIOJ\i

Although this was a prospective study therapy was not randomized since many patients were in poor health and probably could not have withstood radical prostatectorny. Approximately three-fourths of patients originally were ihought to be unsuitable candidates for radical prostatectomy and, consequently, received no additional therapy or hormonal therapy alone. The median age of stage 1 patients was 71 years and all but 2 patients were 60 years or older. The median age, pre-treatment cardiovascular status and electrocardiogram of untreated patients were similar to those of the hormonal group but patients who underwent radical prostatectomy were younger on the average and had the best pre-treatment cardiovascular status and electrocardiogram. ·while it was recognized that the patients who underwent radical prostatectomy were not comparable to the untreated and hormonal patients, surgical patients were ex-

Survival Curves, Sta.911, I Carcinoma of the Pros"tate, by Primary Tr(l,atme,nt

90 -

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70

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(,0

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"0"'"'"'""-0

50

+-

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40

r:f_

30

w

0 ------ 0

No Additional Tre,atme-nt Su r.9ical Tr,z,atmint

,_ _, Hormonal Tr11,atm,z,nt

10

0

'2

3

4

(,

5

7

Years T.,BLJc

3. Causes of death in stage 1 patients according to primary treatment No SurAddi- Horgical tional monal TreatTreatTreatment ment rnent

Number of patients Total dead

45 15

22 10

24 10

Cancer of the prostate Arteriosclerotic heart disease Cerebrovascu1ar Pulmonary embolism Other causes

pected to show the best survival. However, there has been no significant difference in survival among the 3 groups. There have been only 2 deaths owing to carcinoma of the prostate: 1 in the untreated and 1 in the surgical groups. This suggests that in most patients with stage 1 carcinoma, either the tumor has a low biological potential or there is increased host resistance. vVith our present knowledge, we cannot predict which stage 1 carcinomas are destined to metastasize. vVe are studying histological methods using light and electron microscopy for predicting the biological potential of prostatic carcinoma. Nearly two-thirds of patients dying of cardiovascular disease in this study had been taking sup-

732

BLACKARD, MELLINGER AND GLEASON TABLE 4.

Age

PreTreatment Degree

of Differen-

Appearance of clinical carcinoma in stage 1 patients

Inter- Indura- Posi- Elevated Skelval to tion on tive Prostatic eta! Primary RecurAcid MetasTreatment rence Rectal Needle Exam. Biopsy P-tase tases (mos.)

Secondary Treatment

Alive or Dead

PostTreat-

Dead Dead Dead Alive Alive Dead

38 50 96 12 54 56

Dead

82

Alive Alive Alive Alive Alive Alive Alive Alive Dead Dead

67 102 48 66 108 110 36 48 32 89

ment

Cause of Death

(mos.)

tiation

73 74 68 78 69 72

Mod. Good Mod. Mod. Mod. Poor

None None None None None None

4 6 12 12 12 18

Yes Yes Yes Yes Yes No

Yes No No No No No

No No Yes No No Yes

No No Yes No No Yes

67

Mod.

None

36

Yes

Yes

No

No

70 55 69 72 72 72 69 67 61 64

Mod. Good Mod. Mod. Mod. Good Good Mod. Mod. Poor

None None None None None

40 42 42 54

Yes Yes Yes Yes Yes No Yes Yes Yes Yes

No Yes No No Yes No No No Yes No

No Yes No No No Yes No No Yes Yes

No No No No No No No No Yes Yes

None DES DES Radical Radical

72 104 18 24 12 60

plementary diethylstilbestrol or estrogen alone. The Veterans Administration Cooperative Urological Research Group has shown previously that supplementary estrogen decreased survival following radical prostatectomy. 11- 18 This decreased urvival in estrogen-treated patients was due to an increase in cardiovascular deaths. Radical prostatectomy was technically more difficult following previous prostatic operations. Also, the incidence of urinary incontinence following radical prostatectomy for stage 1 carcinoma was 25 per cent in our hands. In other reports the incidence of urinary incontinence following radical prostatectomy has been as low as 3 per cent. 19 It was difficult to determine what we did that was different from other surgeons to account for our higher incidence of urinary incontinence. We did not leave a small button of apical prostatic tissue because of a fear of leaving 17 Veterans Administration Cooperative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 18 Veterans Administration Cooperative Urological Research Group: Carcinoma of the prostate: treatment comparisons. J. Urol., 98: 516, 1967. 19 Colston, J. A. C.: Perinea! prostatectomy. In: Urology, 2nd ed. Edited by M. F. Campbell. Philadelphia: W. B. Saunders Co., vol. 3, p. 2606, 1963.

Orch. None

DES None None None

Orch. & DES None None None None None

None None None

DES DES

Pulm. embolism Cerebrovascular Ca prostate

Chr. brain syndrome Myocardial infarction

Ca prostate Arteriosclerotic heart disease

malignant tissue. Mostofi recently noted in 210 total prostatectomy specimens on which he cut serial sections, that 75 per cent contained carcinoma in the distal 1 cm. of the apex. 20 This is a valid argument against leaving a button of distal prostatic tissue in order to insure a higher incidence of continent patients postoperatively. Patients rece1vmg no additional therapy technically cannot be called untreated. Transurethral resection or open prostatectomy may completely eradicate the cancer. No residual carcinoma was observed in 3 of 24 totally excised prostates in our study (12.5 per cent). Total specimens were examined by making transverse step-sections every 3 to 4 mm. throughout the entire prostate. Lehman and associates reported on 25 patients with stage 1 cancer who underwent radical prostatectomy. In 10 cases (40 per cent) they found no residual tumor in the totally excised specimen. 14 The percentage of patients with later evidence of clinical carcinoma was highest in untreated patients. In our study, recurrence appeared in 13 of 45 untreated patients (29 per cent). However, only 4 of 45 untreated men (9 per cent) had distant metastases. Patients who had prostatic and extra-prostatic induration alone were 20

Mostofi, F. K.: Personal communication.

TREATMENT OF STAGE 1 PROSTATIC CARCINOMA

asymptomatic except for an occasional case of prostatic obstruction. The only patients who had cancer symptoms were those with skeletal metastases and then symptoms usually abated with the institution of estrogen therapy. The pre-treatment histological slides did not seem to predict in all cases which patients were going to have local recurrence or metastases. Gleason described a system of classifying prostatic cancer according to the primary and secondary histological patterns of the tumor. 21 These patterns have been useful in determining prognosis. Currently, Gleason has been applying this more detailed classification to a large number of stage 1 patients. 21 Gleason, D. F.: Classification of prostatic carcinomas. Cancer Chemother. Rep., 50: 125,

1966.

733

SUMMARY

A preliminary report on 91 patients with stage 1 carcinoma of the prostate has been presented. The patients have undergone no additional therapy, hormonal therapy or an operation. There has been no significant difference in survival among the 3 groups and there have been only 2 deaths owing to prostatic carcinoma. The use of 5.0 mg. diethylstilbestrol daily increased the incidence of cardiovascular deaths. Incontinence occurred in 25 per cent of the patients who underwent radical prostatectomy. Because of the usually low biological potential of stage 1 carcinoma and the aforementioned complications of therapy, it has been hoped that no additional therapy would be satisfactory. However, clinical carcinoma developed in 13 of 45 untreated patients and 4 of these 13 cancers metastasized.