- Email: [email protected]
Evaluation of Current Treatment of Prostatic Cancer
THE JOURNAL OF UROLOGY
Vol, 68, No. 4, October 1952 Printed in U.S.A.
EVALUATION OF CURRENT TREATMENT OF PROSTATIC CANCER HERBERT BRENDLER From the Department of Urology and Urology Research Laboratory, New York University Post-Graduate Medical School, New York University-Bellevue Medical Center, New York
Prostatic cancer is a problem of increasing importance. Fifty years ago Richard Wolff was able to collect only 83 cases from the world literature. Today we know from routine autopsy studies that at least 14 per cent of men over 50 harbor this disease in one form or another. 1 Using this figure, Hinman has calculated that there are :in this country today 3,000,000 men over 50 with prostatic cancer,2 which makes it the most common malignancy in the aging male. 3 Among all men dying 0£ cancer, Smith4 found it to be exceeded only by cancer of the stomach and bowel. By careful study of a series of 50 consecutive prostates obtained from men over 50, Baron and Angrist 5 found carcinoma in 23, or 46 per cent. Although this figure relates to occult cancer, its potential significance cannot be ignored. ·with life expectancy improving, the percentage of men eligible for clinical prostatic cancer is steadily increasing. Early diagnosis is difficult. The disease is insidious, causing few symptoms until late in its course. At the time of the first examination in 90-95 per cent of patients, the malignant process is too advanced for surgically curative measures. In most cases where the growth is deemed potentially curable by radical surgery, the disease has been asymptomatic preoperatively, having been discovered quite by accident on routine rectal examination. Progress has been made in the palliative treatment of patients with advanced, incurable disease. Largely as the result of the original contributions of Huggins and those working with him, most prostatic cancer patients now live more comfortably, and possibly longer, than their predecessors did in the pre-endocrine era. Today, with research in prostatic cancer proceeding at clinical and experimental levels in a number of institutions, the outlook for the future is hopeful. The ultimate yardstick of the effectiveness of any form of therapy is its ability to cure the disease. In prostatic cancer, where the percentage of act~al cures has been so low, it has been convenient to use comparative studies based on the ability of different methods of treatment to prolong life beyond the expectancy of untreated cases. Such studies have approached the problem in several ways: 1) number of survivors, apparently without disease, after a specified period, usually 5 years; Read before the Second National Cancer Conference, Cincinnati, 0., March 4, 1952. This work was made possible by a Grant-in-Aid from the American Cancer Society upon recommendation of the Committee on Growth of the National Research Council, and by a research grant from the Division of Research Grants and Fellowships of the National Institutes of Health, United States Public Health Service. Damon Runyon Cancer Research Fellow. 1 Rich, A. R.: J. Urol., 33: 215-23, 1935. 2 Hinman, F.: J. A. M.A., 135: 136-41, 1947. 3 Hinman, F.: Calif. Med., 68: 338-43, 1948. 4 Smith, G. G.: J. Urol., 64: 671-80, 1950. 5 Baron, E. and Angrist, A.: Arch. Path., 32: 787-93, 1941. 734
PROSTATIC CANCER
735
2) number of patients dead of the disease after a specified period, usually 5 years; 3) the average duration of life after diagnosis or institution of therapy. The comparative merits of these methods need not be discussed at this time. It is pertinent, however, to point out that such studies, while ofvalueinindicating trends, can be misleading, unless coupled with a thorough knowledge of the natural history of prostatic cancer. Unfortunately, this knowledge is only partially within our grasp today. The tendency to draw specious conclusions regarding absolute curability from analysis of a 5-year series is all too common today, and certainly to be deplored. Before treating patients with prostatic cancer, it has been customary to classify them as either early or advanced, according to certain simple clinical criteria (table 1). In those cases where rectal examination is inconclusive, biopsy of the prostate must be resorted to. Sternal aspiration biopsy may also be of aid in doubtful cases. 8 TABLE
I. Classification of prostatic cancer
I. Rectal examination a. Early-i.e. limited to the gland proper b. Advanced-i.e. beyond the gland proper II. Bone x-rays a. Without metastases b. With metastases III. Serum acid phosphatase a. Normal b. Elevated EARLY PROSTATIC CANCER
It is generally agreed that radical perineal excision of the prostate, seminal vesicles and adjacent bladder neck is the treatment of choice when the cancer is confined to the prostate itself. This operation, first carried out by Young in 1904, was not hastily improvised, but was based on a thorough understanding of the pathogenesis of the disease. Modifications which ignore the fascial planes along which prostatic cancer spreads, and which do not remove intact the seminal vesicles and their fascia, the bladder neck and apex of the gland, fail in their purpose. Jewett7 has reviewed 222 radical perineal prostatectomies done at the Brady Urological Institute from 1904 to 1948 (table 2). Of 78 patients with cancer con1,in~d to the i;:ir0~tt1te Q1l n:,tt11l ';)'l.\ll)'l.\t\1Jn. 1 51.~ l)eT 1;e11.t lived. 5 -years o-r longer, without evidence of the disease. Of 43 with cancer confined to the prostate on rectal palpation, 28 per cent lived 10 years or longer, the maximum sur,vival being 27 years. No patient who lived 10 years subsequently showed evidence of cancer. This is as close to an absolute cure as one can hope for. . Although Jewett found that the perineural lymphatics were frequently m6
Alyea, E. P., and Rundles, R. W.: J. UroL, 62: 332-39, 1949.
1
Jewett, H.. J,: J, UroL, 61: 277-80, 1949.
736
HERBERT BRENDLER
volved histologjcally, the 10 year figures show that distant metastases should not be inferred from this finding, as some have stated. This confirms Moore's statement in 19358 that, although perineural lymphatic infiltration occurs early in prostatic cancer, distant lymphatic invasion is a late phenomenon of the disease. Of great significance is the fact that the actual prostatic disease in Jewett's cases almost always exceeded the impression gained from rectal palpation. This finding points up the necessity for carrying out the operation as radically as possible, according to the principles described by Young. It also provides a rationale for the institution of endocrine treatment in all patients undergoing radical prostatectomy. 9 • 10 The applicability of the radical operation is, unfortunately, low. Patients must be good surgical risks, although the operative trauma is little more than that of a simple enucleation. It is doubtful whether patients over 70 should be subjected to the operation, in view of the limited life expectancy in older men. However, each case must be individualized. Jewett found the operation applicable in 11.2 TABLE
2. Radical perinea,l prostatectomies, 1904 to 1948
(From Jewett) Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microscopically-proved prostatic cancer.......................... Cancer limited to prostate on rectal examination . . . . . . . . . . . . . . . . . 5 year closed series ............................. .
222 190 78
Lived 5 years or longer .................... .
78 40 (51.3%)
10 year closed series ............................................ . Lived 10 years or longer. . . . . . ................................. .
43 12 (28%)
per cent of all patients admitted with prostatic cancer to the Brady Urological Institute. This is higher than in most clinics, where figures run about 3-5 per cent. Operative mortality is low, about 3 per cent. Impotence follows radical prostatectomy in most, if not all, patients. The incidence of other postoperative complications is comparatively low, the most common one being urinary incontinence, which occurs in 12 per cent of patients. OCCULT PROSTATIC CANCER
The treatment of clinically unsuspected, or occult, prostatic cancer discovered on subsequent histological examination after simple prostatectomy for apparently benign enlargement of the gland, has been the subject of debate recently. Hinman Jr. and Hinman11 have reported a closed series of 14 patients discovered to have occult prostatic cancer after transurethral resection, and who were followed for at least 5 years (table 3). Five of these patients subsequently had radical Moore, R. A.: J. Urol., 33: 224-34, 1935. Colston, J. A. C. and Brendler, H.: J. A. M.A., 134: 845-53, 1947. 10 Harrison, J. H. and Poutasse, E. F.: Am. J. Med., 11: 55-66, 1951. 11 Hinman, F., Jr. and Hinman, F.: J. Urol., 62: 723-29, 1949.
8 1
737
PROSTATIC CANCER
perineal prostatectomies as well; their average survival was 67.8 months The comparable 5 year figure for the other 9, treated only with transurethral resection, was 36.8 months. On the basis of these data, these authors have recommended radical surgery as the treatment of choice for occult prostatic cancer. Nesbit and Baum 12 have recently questioned this opinion. They have reported an analysis of 42 patients with occult prostatic cancer treated conservatively, i.e. by transurethral resection. Fourteen patients died of causes other than prostatic cancer. Two of the remaining 28 died of the disease, but the rest were alive and apparently well up to 12 years after the original diagnosis. Because of these figures, as well as the advanced ages of their patients, Nesbit and Baum doubt the necessity for radical surgery in patients with occult prostatic cancer. As further evidence for their stand, Nesbit and Baum have drawn on a report by Thompson in 1942 ;13 they state that he "reported a 60.9 per cent 5 year survival in 112 patients in whom clinically unsuspected adenocarcinoma was discovered following transurethral prostatectomy." A careful review of Thompson's article discloses that: 1) none of the patients in his series (887 in all) were considered as occult. In fact Thompson states clearly that all were diagnosed preTABLE
3. Occult prostatic cancer; 5 year closed series (From Hinman Jr. and Hinman)
Number discovered after transurethral prostatectomy. . . . . . . .
14
Treated with transurethral prostatectomy alone. Average survival........ . .................. .
36.8 months
Treated with radical perinea! prostatectomy ......... . Average survival. ................................ .
5 67.8 months
9
operatively as prostatic carcinoma. 2) The 112 cases cited by Nesbit and Baum from Thompson's report do not represent patients with occult cancer, but rather the number classified histologically as grade 1 (Broders). The term "occult" simply refers to cancer not suspected preoperatively; its histological grade of malignancy according to Broders (or any other method) may vary widely from :relatively benign to extremely malignant. 3) The 60.9 per cent survival figure quoted by Nesbit and Baum alludes, not to the foregoing 1.12 patients, but only to 23 with grade 1 malignancies who were followed by Thompson for 5 years. Of these, 14, or 60.9 per cent were alive at the end of that time. Neither the Hinmans, nor Nesbit and Baum have presented convincing evidence in support of their arguments, primarily because neither series is large enough for statistical purposes. Although further data bearing on this question are extremely necessary before reaching a decision, it is possible at this time to approach the problem from certain logical considerations. As stated previously, occult prostatic cancer may range widely in its degree of malignancy, as judged histologically. Similarly, there may be considerable variation in its inherent ability to grow and metastasize; unfortunately, we have 12
1a
Nesbit, R. M. and Baum, W. C.: J. Urol., 66: 890--94, 1951. Thompson, G. J.: J. A. M.A., 120: 1105--09, 1942.
738
HERBERT BRENDLER
no way of measuring this biological potential at present. Finally, despite its comparatively small size, as judged from our inability to diagnose it on rectal palpation, occult prostatic cancer may be early or late from the temporal standpoint. We are, therefore, obliged to consider occult prostatic cancer simply as a form of carcinoma which is limited to the gland proper, and to treat it as such. Thus, it becomes mandatory at this time, and until convincing evidence to the contrary be submitted, that the patient with occult prostatic cancer be given the benefit of radical prostatectomy, providing, of course, that he be a suitable candidate from the standpoint of physical condition and life expectancy. The frequency of occult prostatic carcinoma, with subsequent development of clinical cancer after simple prostatectomy, has led Smith and Woodruff 14 to recommend the use of total prostatectomy (without removing the seminal vesicles or a cuff of bladder) in selected cases with apparently benign enlargement of the gland. These observers advise it in those individuals who, because of symptoms, require an open operation, and in whom general condition, age and sexual habits offer no contra-indications. Further reports on the use of this procedure will be awaited with interest. The main objection to its adoption as standard practice is of course, the postoperative occurrence of impotence and urinary incontinence. The use of the retropubic approach for radical prostatectomy has been reported.15 The greatest disadvantage of this method is that the posterior aspect of the gland is inaccessible for biopsy under direct vision. Also, f ascial planes cannot be identified as carefully as they can be from the perineal aspect. Finally, most observers agree that it is technically more difficult than the perinea! operation. ADVANCED PROSTATIC CANCER
The treatment of the patient with prostatic cancer which has spread beyond the immediate boundaries of the gland is no longer directed toward a cure, but, instead, is concerned with a limited, twofold objective: 1) relief of urinary symptoms, and 2) endocrine control of the tumor. Transurethral resection has been the most widely used surgical method for dealing with the problem of bladder neck obstruction due to prostatic cancer. In the great majority of cases it has proved of great benefit A certain number require multiple resections to cope with continued grmvth of the neoplasm. In a few patients marked irritability of the bladder and posterior urethra develops following transurethral resection. These people are-better treated with permanent suprapubic cystostomy. 16 The question has often been asked whether transurethral resection stimulates growth in the residual cancer. Many of us have seen occasional cases where the clinical course has suddenly taken a rapid turn for the worse after transurethral resection. Possibly this is post hoc reasoning. Flocks16 has found no evidence to Smith, G. G. and Woodruff, L. M.: J. Urol., 63: 1077-80, 1950. Memmelaar, J.: J. Urol., 62: 340-48, 1949. 16 Flocks, R.H., Harness, W. N., Tudor, J.M. and Prendergast, L.: J. Urol., 66: 393-407, 1951. 14
16
PROSTATIC CANCER
739
substantiate it. Nevertheless, because of such experiences, some individuals, notably Slaughter, 17 have completely abandoned transurethral resection in favor of cystostomy in those patients in whom the obstructive symptoms are not relieved by endocrine therapy. For the treatment of the very large advanced cancer, open perineal or suprapubic resection of obstructing tissue has been favored by some. The results are said to compare favorably with those resected transurethrally, and the necessity for repeated operations is said to be obviated. Endocrine measures alone are effective in certain instances in relieving the obstructive symptoms. Such cases, however, are in the minority, although there is some difference of opinion concerning this. Some workers have attempted to widen the scope of the radical operation to include selected, nonmetastatic cases in which, on initial rectal palpation, the malignant process seems not to have extended very far beyond the immediate confines of the prostate. A certain number of these borderline advanced cases have responded so satisfactorily to endocrine therapy with respect to prostatic size, induration and degree of fixation, that radical prostatectomy has subsequently been undertaken in order to afford these patients the chance for a complete cure. It has also been stated that the operation is rendered easier technically by preliminary estrogen administration. 9 Scott and Parlow18 have recently reported the use of this procedure in 22 patients, 13 of whom were followed for at least 3 years, all 13 being alive at the end of that time. Preoperative estrogens were given for an average of 15.6 months. One of the early explanations for the seemingly beneficial effect of estrogen treatment in such cases was that it induced the prostatic neoplasm to recede from the marginal areas by depriving the more actively growing peripheral cells of necessary androgen, thus destroying thern. 9 In the light of subsequent evidence this reasoning seems fallacious. Pathological examination of specimens removed by radical excision after estrogen administration has disclosed persistence of adenocarcinoma in extraprostatic structures. 9 , 16 Furthermore, careful histological study has shown no tendency for increased cell destruction in peripheral areas as compared with the center of the neoplasm. In view of the foregoing, grave doubts arise as to the value of preoperative endocrine therapy in these advanced cases. To begin with, as Jewett has shown,7 it is quite likely that the malignant process will prove even more extensive histologically than pictured from rectal palpation. If we couple this knowledge with the histological proof that endocrine therapy does not completely destroy malignant cells situated in the extraprostatic tissues, there seems little reason to hope that we can transform an advanced cancer into one which is surgically curable, that is, capable of complete removal by Young's operation. Perhaps future studies will demonstrate the value of combined endocrine and surgical therapy in these borderline advanced cases. At this time, however, statistics are too meager to permit conclusions. Slaughter, G. W.: Personal communication. rn Scott, W.W. and Parlow, A. L.: J. Urol., !iii: 1093-1107, 195L
17
740
HERBERT BRENDLER
The recent trend toward extensive pelvic surgery for the eradication of bladder cancer has prompted some workers to advocate complete prostato-vesiculocystectomy with pelvic lymph node dissection for selected cases of advanced prostatic cancer as well. In this connection the findings of Arnheim in 1948 are of interest. 19 In studying lymph node metastases from prostatic cancer in 176 autopsy cases, this investigator found the peri-aortic nodes most frequently involved, in about 49 per cent, and the iliacs in only about 34 per cent. Surprisingly, the tracheobronchial nodes were invaded almost as frequently as the iliacs, in about 27 per cent. These findings seem to contravene the desirability of pelvic node dissections in advanced cases. ENDOCRINE TREATMENT
The palliative treatment of inoperable prostatic cancer by methods based on androgen control has proved one of the milestones in the continuing struggle to conquer this disease. Although no actual cures are on record, the recent survey by Nesbit and Baum20 of the results of endocrine treatment of 1818 cases has shown an apparent increase in the percentage of 3 and 5 year survivors among treated cases, as compared with a series of untreated controls reported by Nesbit and Plumb in 1946. 21 This apparent improvement in longevity has been found in patients with or without metastases. The combination of castration and diethylstilbestrol has seemed to be most effective in the nonmetastatic group. In those with metastases, castration alone appears to have been as effective as combined therapy, so that it seems that estrogen administration has added little in the treatment of these cases. Further evidence of this is found in the metastatic patients treated with stilbestrol alone; their 5-year survivals have been only slightly more than the untreated controls. In a careful analysis of these statistics, it is troublesome to note that, whereas all of the controls died of prostatic cancer, a considerable number of the treated cases (up to 33 per cent) died of other causes. It is not clear whether the latter were excluded from the actual survival statistics, as they certainly should have been.If, as it appears, they were included, then the results of the study are meaningless. A few remarks are also in order concerning the validity of the control series employed in the above comparative study. These cases consisted of 795 patients seen prior to the advent of endocrine therapy; of th.is group 605 died of prostatic cancer. Those without evident metastases totaled 273; 90 per cent of this group were dead in 5 years. There were 231 with metastases, of whom 94 per cent were dead in 5 years. Of significance is the fact that 239, or about 40 per cent, of the 605 who died of prostatic cancer, received no treatment whatsoever. In view of the fact that patients receiving endocrine treatment today are also afforded· the benefit of modern surgery, antibiotics and improved medical care, the validity of the above series for control purposes in a comparative study of endocrine methods of treatment may be seriously challenged. At present, therefore, it may be stated that, although there is no question as rn Arnheim, F. K. : J. U rol., 60: 599-603, 1948: Nesbit, R. M. and Baum, W. C.: J. A. M.A., 143: 1317-20, 1950. Nesbit, R. M. and Plumb, R. T.: Surgery, 20: 263-72, 1946.
20 21
PROSTATIC CANCER
741
to the palliative value of existing endocrine measures in advanced prostatic cancer, no convincing proof is at hand that such measures will actually arrest the inexorable course of the disease. The need for adequate controls and treated cases, selected without bias, becomes a matter of incalculable importance in any attempt to evaluate the ultimate effectiveness of endocrine therapy. TREATMENT OF RELAPSE
Despite initial improvement on endocrine treatment, the patient ·with advanced prostatic cancer inevitably suffers recurrence or reactivation of the malignant process. Whether the tumor has become "androgen-independent," or else insensitive to estrogens, is debatable. 22 Increasing the estrogen dosage to 1000 mg. daily or more may be of symptomatic benefit. Sometimes changing to another estrogen is helpful. TACE (tri-p-anisylchloroethylene), a synthetic estrogen, is currently being investigated in this regard. The possibility that increased amounts of adrenal androgens are responsible for the relapse has led to the use of cortisone in an effort to inhibit the production of such androgens. Although cortisone does, in fact, suppress androgen secretion in female pseudohermaphroditism, 23 Thorn and Harrison have found that in patients adrenalectomized for hypertension, cortisone administration leads to an increase in urinary 17-ketosteroids, although not over preoperative levels. The use of bilateral adrenalectomy in androgen control has recently been described by Huggins and Bergenstal.2 4 Pituitary radiation has been reported to be of some benefit. Recently, however, Kelly and others 25 administered a pituitary tissue dose of 8,100-10,000 r to each of 3 female patients with advanced cancer. Autopsy studies disclosed no demonstrable changes in the tumors, metastases, pituitaries, or other endocrine glands. The use of hypophysectomy has recently been reported by Scott. 26 It seems evident at this time that the endocrine treatment of prostatic cancer is more complicated than the anti-androgenic concept implies. Some patients with metastases actually benefit subjectively from testosterone, 27 although many develop a very prompt and severe relapse. Trunnell and Duffy28 have obtained similar variable responses in patients with progesterone. The use of other "nonandrogenic androgens" may yield valuable information. Some work has been done with urethane, the nitrogen mustards and certain folic-acid derivatives. The results are not impressive. Radiation therapy has not been as widely used as in the past. However, recent work with intraprostatic injections of radioactive gold seems quite promising, 29 but is too early to evaluate. Deming, C. L.: J. Urol., 61: 281-90, 1949. Wilkins, L., Lewis, R. A., Klein, R., and Rosemberg, E.: Bull. Johns Hopkins Hosp. 86: 249-52, 1950. 24 Huggins, C. and Bergenstal, D. JVI.: J. A. M.A., 147: 101-06, 1951. 25 Kelly, K. H., Feldsted, E. T., Brown, R. F., Ortega, P., Bierman, H. R., Low-Beer, B. V. A. and Shimkin, M. B.: J. Nat. Cancer Inst., 11: 967-83, 1951. 26 Scott, W.W.: Address given before the Halsted Society, the Johns Hopkins Hospital, February 7, 1952. 27 Brendler, H., Chase, W. E. and Scott, W.W.: Arch. Surg., 61: 433-40, 1950. 28 Trunnell, J. B. and Duffy, B. J.: Tr. N. Y. Academy of Sciences, series 2, 12: 238-41, 1950. 29 Flocks, R. H.: Personal communication. 22
23
742
HERBERT BRENDLER THE EVALUATION OF BIOLOGICAL POTENTIAL
For a fair comparison of different methods of treating prostatic cancer, it is essential that the disease be properly classified. It has been apparent to many observers that morphological criteria alone will not suffice, either gross or microscopic, whether based on extent of local spread, histological pattern, or degree of cellular differentiation. In most cases there is no correlation between the morphological appearance of the tumor and its behavior. Thus, we cannot predict the therapeutic response of a particular prostatic cancer from its histopathological characteristics. It follows that a need exists for methods by which the biological potential, or inherent malignancy, of individual prostatic cancers may be accurately determined. Park and Lees, in a recent article on the absolute curability of breast cancer, based on current survival statistics, make the following statement, which is, perhaps, applicable to prostatic cancer as well: "From an analysis of the evidence it has been shown that the apparent curability of cancer of the breast can be explained entirely in terms of the variability of growth rate." 30 It is their feeling that, when most observers discuss results of different methods of treatment, they TABLE
4. Recornrnended plan of treatment for prostatic cancer
I. Early-i.e. limited to the gland proper, including occult variety a. Radical perineal prostatectomy, and b. Endocrine therapy II. Advanced-i.e. beyond the gland proper, with or without metastases a. Surgical relief of urinary obstruction, and b. Endocrine therapy
are in reality only measuring differences in the growth rates of biologically different tumors. Unfortunately, there is no satisfactory method at present for evaluating the growth potential of the individual prostatic cancer. The increased acid phosphatase titer of malignant prostatic tissue, which is reflected in elevated serum levels in most patients with metastatic involvement, is, however, a biological property worthy of further exploration. Nesbit and Baum31 have analyzed the serum acid and alkaline phosphatase findings in patients with prostatic cancer. They have found that elevation of the serum acid phosphatase level in patients without demonstrable metastases is indicative of a worsened prognosis. Also, they have been able to show that, in patients with metastases, a normal acid phosphatase level is not a sign of low bodily resistance to the disease, and hence does not signify a poor prognosis. The elevation in serum alkaline phosphatase in many patients in response to endocrine treatment is also an interesting and frequent observation, which merits further study. CONCLUSIONS
At the present time, no satisfactory methods exist for classifying cases of prostatic cancer according to their biological properties. It is apparent, there30 31
Park, W.W. and Lees, J.C.: Surg., Gynec. & Obst., 93: 129-52, 1951. :N"esbit, R. M. and Baum, W. C.: J. A. M.A., 145: 1321-24, 1951.
PROSTATIC CANCER
743
fore, that we must devote ourselves in increasing measure to basic research in prostatic physiology. Current studies in the intermediary metabolism of phosphorylated compounds, and in certain nutritional aspects of prostatic growth, seem promising. Investigation of growth potentials of heterologously-transplanted human cancers and experimental prostatic tumors, as influenced by hormonal manipulations, may lead to an answer. The present stalemate which exists in the treatment of prostatic cancer cannot be resolved until we gain a clearer understanding of the nature of the malignant process. Until then, our methods of treatment will of necessity be determined empirically, and we must continue to use the best that combined surgical and endocrine measures can offer (table 4). SUMMARY
Prostatic cancer presents a formidable challenge today because of its frequency and the difficulty in early diagnosis. The latter factor is largely responsible for the low cure rate in this disease. Patients with cancer limited to the prostate, including the occult variety, should receive the combined benefit of radical perinea! prostatectomy and endocrine therapy, until it can be shown that 10 year survival figures are better in comparable patients treated with endocrine measures alone. The advanced case, whether or not associated with metastases, is best treated by surgical relief of urinary obstruction and hormonal therapy. The use of radical prostatectomy for borderline cases of advanced prostatic cancer is not recommended. The validity of current survival statistics for endocrine-treated cases is questioned because of 1) unsatisfactory controls, and 2) the inclusion of patients not dead of prostatic cancer. The treatment of relapse is discussed briefly. Emphasis is placed on the necessity of classifying cases according to their biological properties before drawing conclusions as to the effectiveness of different modes of therapy. The author wishes to express his appreciation to Dr. Robert S. Hotchkiss, Professor and Chairman of the Department of Urology, New York University Post-Graduate Medical School, for his helpful criticism during the preparation of this paper.
Vol, 68, No. 4, October 1952 Printed in U.S.A.
EVALUATION OF CURRENT TREATMENT OF PROSTATIC CANCER HERBERT BRENDLER From the Department of Urology and Urology Research Laboratory, New York University Post-Graduate Medical School, New York University-Bellevue Medical Center, New York
Prostatic cancer is a problem of increasing importance. Fifty years ago Richard Wolff was able to collect only 83 cases from the world literature. Today we know from routine autopsy studies that at least 14 per cent of men over 50 harbor this disease in one form or another. 1 Using this figure, Hinman has calculated that there are :in this country today 3,000,000 men over 50 with prostatic cancer,2 which makes it the most common malignancy in the aging male. 3 Among all men dying 0£ cancer, Smith4 found it to be exceeded only by cancer of the stomach and bowel. By careful study of a series of 50 consecutive prostates obtained from men over 50, Baron and Angrist 5 found carcinoma in 23, or 46 per cent. Although this figure relates to occult cancer, its potential significance cannot be ignored. ·with life expectancy improving, the percentage of men eligible for clinical prostatic cancer is steadily increasing. Early diagnosis is difficult. The disease is insidious, causing few symptoms until late in its course. At the time of the first examination in 90-95 per cent of patients, the malignant process is too advanced for surgically curative measures. In most cases where the growth is deemed potentially curable by radical surgery, the disease has been asymptomatic preoperatively, having been discovered quite by accident on routine rectal examination. Progress has been made in the palliative treatment of patients with advanced, incurable disease. Largely as the result of the original contributions of Huggins and those working with him, most prostatic cancer patients now live more comfortably, and possibly longer, than their predecessors did in the pre-endocrine era. Today, with research in prostatic cancer proceeding at clinical and experimental levels in a number of institutions, the outlook for the future is hopeful. The ultimate yardstick of the effectiveness of any form of therapy is its ability to cure the disease. In prostatic cancer, where the percentage of act~al cures has been so low, it has been convenient to use comparative studies based on the ability of different methods of treatment to prolong life beyond the expectancy of untreated cases. Such studies have approached the problem in several ways: 1) number of survivors, apparently without disease, after a specified period, usually 5 years; Read before the Second National Cancer Conference, Cincinnati, 0., March 4, 1952. This work was made possible by a Grant-in-Aid from the American Cancer Society upon recommendation of the Committee on Growth of the National Research Council, and by a research grant from the Division of Research Grants and Fellowships of the National Institutes of Health, United States Public Health Service. Damon Runyon Cancer Research Fellow. 1 Rich, A. R.: J. Urol., 33: 215-23, 1935. 2 Hinman, F.: J. A. M.A., 135: 136-41, 1947. 3 Hinman, F.: Calif. Med., 68: 338-43, 1948. 4 Smith, G. G.: J. Urol., 64: 671-80, 1950. 5 Baron, E. and Angrist, A.: Arch. Path., 32: 787-93, 1941. 734
PROSTATIC CANCER
735
2) number of patients dead of the disease after a specified period, usually 5 years; 3) the average duration of life after diagnosis or institution of therapy. The comparative merits of these methods need not be discussed at this time. It is pertinent, however, to point out that such studies, while ofvalueinindicating trends, can be misleading, unless coupled with a thorough knowledge of the natural history of prostatic cancer. Unfortunately, this knowledge is only partially within our grasp today. The tendency to draw specious conclusions regarding absolute curability from analysis of a 5-year series is all too common today, and certainly to be deplored. Before treating patients with prostatic cancer, it has been customary to classify them as either early or advanced, according to certain simple clinical criteria (table 1). In those cases where rectal examination is inconclusive, biopsy of the prostate must be resorted to. Sternal aspiration biopsy may also be of aid in doubtful cases. 8 TABLE
I. Classification of prostatic cancer
I. Rectal examination a. Early-i.e. limited to the gland proper b. Advanced-i.e. beyond the gland proper II. Bone x-rays a. Without metastases b. With metastases III. Serum acid phosphatase a. Normal b. Elevated EARLY PROSTATIC CANCER
It is generally agreed that radical perineal excision of the prostate, seminal vesicles and adjacent bladder neck is the treatment of choice when the cancer is confined to the prostate itself. This operation, first carried out by Young in 1904, was not hastily improvised, but was based on a thorough understanding of the pathogenesis of the disease. Modifications which ignore the fascial planes along which prostatic cancer spreads, and which do not remove intact the seminal vesicles and their fascia, the bladder neck and apex of the gland, fail in their purpose. Jewett7 has reviewed 222 radical perineal prostatectomies done at the Brady Urological Institute from 1904 to 1948 (table 2). Of 78 patients with cancer con1,in~d to the i;:ir0~tt1te Q1l n:,tt11l ';)'l.\ll)'l.\t\1Jn. 1 51.~ l)eT 1;e11.t lived. 5 -years o-r longer, without evidence of the disease. Of 43 with cancer confined to the prostate on rectal palpation, 28 per cent lived 10 years or longer, the maximum sur,vival being 27 years. No patient who lived 10 years subsequently showed evidence of cancer. This is as close to an absolute cure as one can hope for. . Although Jewett found that the perineural lymphatics were frequently m6
Alyea, E. P., and Rundles, R. W.: J. UroL, 62: 332-39, 1949.
1
Jewett, H.. J,: J, UroL, 61: 277-80, 1949.
736
HERBERT BRENDLER
volved histologjcally, the 10 year figures show that distant metastases should not be inferred from this finding, as some have stated. This confirms Moore's statement in 19358 that, although perineural lymphatic infiltration occurs early in prostatic cancer, distant lymphatic invasion is a late phenomenon of the disease. Of great significance is the fact that the actual prostatic disease in Jewett's cases almost always exceeded the impression gained from rectal palpation. This finding points up the necessity for carrying out the operation as radically as possible, according to the principles described by Young. It also provides a rationale for the institution of endocrine treatment in all patients undergoing radical prostatectomy. 9 • 10 The applicability of the radical operation is, unfortunately, low. Patients must be good surgical risks, although the operative trauma is little more than that of a simple enucleation. It is doubtful whether patients over 70 should be subjected to the operation, in view of the limited life expectancy in older men. However, each case must be individualized. Jewett found the operation applicable in 11.2 TABLE
2. Radical perinea,l prostatectomies, 1904 to 1948
(From Jewett) Total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Microscopically-proved prostatic cancer.......................... Cancer limited to prostate on rectal examination . . . . . . . . . . . . . . . . . 5 year closed series ............................. .
222 190 78
Lived 5 years or longer .................... .
78 40 (51.3%)
10 year closed series ............................................ . Lived 10 years or longer. . . . . . ................................. .
43 12 (28%)
per cent of all patients admitted with prostatic cancer to the Brady Urological Institute. This is higher than in most clinics, where figures run about 3-5 per cent. Operative mortality is low, about 3 per cent. Impotence follows radical prostatectomy in most, if not all, patients. The incidence of other postoperative complications is comparatively low, the most common one being urinary incontinence, which occurs in 12 per cent of patients. OCCULT PROSTATIC CANCER
The treatment of clinically unsuspected, or occult, prostatic cancer discovered on subsequent histological examination after simple prostatectomy for apparently benign enlargement of the gland, has been the subject of debate recently. Hinman Jr. and Hinman11 have reported a closed series of 14 patients discovered to have occult prostatic cancer after transurethral resection, and who were followed for at least 5 years (table 3). Five of these patients subsequently had radical Moore, R. A.: J. Urol., 33: 224-34, 1935. Colston, J. A. C. and Brendler, H.: J. A. M.A., 134: 845-53, 1947. 10 Harrison, J. H. and Poutasse, E. F.: Am. J. Med., 11: 55-66, 1951. 11 Hinman, F., Jr. and Hinman, F.: J. Urol., 62: 723-29, 1949.
8 1
737
PROSTATIC CANCER
perineal prostatectomies as well; their average survival was 67.8 months The comparable 5 year figure for the other 9, treated only with transurethral resection, was 36.8 months. On the basis of these data, these authors have recommended radical surgery as the treatment of choice for occult prostatic cancer. Nesbit and Baum 12 have recently questioned this opinion. They have reported an analysis of 42 patients with occult prostatic cancer treated conservatively, i.e. by transurethral resection. Fourteen patients died of causes other than prostatic cancer. Two of the remaining 28 died of the disease, but the rest were alive and apparently well up to 12 years after the original diagnosis. Because of these figures, as well as the advanced ages of their patients, Nesbit and Baum doubt the necessity for radical surgery in patients with occult prostatic cancer. As further evidence for their stand, Nesbit and Baum have drawn on a report by Thompson in 1942 ;13 they state that he "reported a 60.9 per cent 5 year survival in 112 patients in whom clinically unsuspected adenocarcinoma was discovered following transurethral prostatectomy." A careful review of Thompson's article discloses that: 1) none of the patients in his series (887 in all) were considered as occult. In fact Thompson states clearly that all were diagnosed preTABLE
3. Occult prostatic cancer; 5 year closed series (From Hinman Jr. and Hinman)
Number discovered after transurethral prostatectomy. . . . . . . .
14
Treated with transurethral prostatectomy alone. Average survival........ . .................. .
36.8 months
Treated with radical perinea! prostatectomy ......... . Average survival. ................................ .
5 67.8 months
9
operatively as prostatic carcinoma. 2) The 112 cases cited by Nesbit and Baum from Thompson's report do not represent patients with occult cancer, but rather the number classified histologically as grade 1 (Broders). The term "occult" simply refers to cancer not suspected preoperatively; its histological grade of malignancy according to Broders (or any other method) may vary widely from :relatively benign to extremely malignant. 3) The 60.9 per cent survival figure quoted by Nesbit and Baum alludes, not to the foregoing 1.12 patients, but only to 23 with grade 1 malignancies who were followed by Thompson for 5 years. Of these, 14, or 60.9 per cent were alive at the end of that time. Neither the Hinmans, nor Nesbit and Baum have presented convincing evidence in support of their arguments, primarily because neither series is large enough for statistical purposes. Although further data bearing on this question are extremely necessary before reaching a decision, it is possible at this time to approach the problem from certain logical considerations. As stated previously, occult prostatic cancer may range widely in its degree of malignancy, as judged histologically. Similarly, there may be considerable variation in its inherent ability to grow and metastasize; unfortunately, we have 12
1a
Nesbit, R. M. and Baum, W. C.: J. Urol., 66: 890--94, 1951. Thompson, G. J.: J. A. M.A., 120: 1105--09, 1942.
738
HERBERT BRENDLER
no way of measuring this biological potential at present. Finally, despite its comparatively small size, as judged from our inability to diagnose it on rectal palpation, occult prostatic cancer may be early or late from the temporal standpoint. We are, therefore, obliged to consider occult prostatic cancer simply as a form of carcinoma which is limited to the gland proper, and to treat it as such. Thus, it becomes mandatory at this time, and until convincing evidence to the contrary be submitted, that the patient with occult prostatic cancer be given the benefit of radical prostatectomy, providing, of course, that he be a suitable candidate from the standpoint of physical condition and life expectancy. The frequency of occult prostatic carcinoma, with subsequent development of clinical cancer after simple prostatectomy, has led Smith and Woodruff 14 to recommend the use of total prostatectomy (without removing the seminal vesicles or a cuff of bladder) in selected cases with apparently benign enlargement of the gland. These observers advise it in those individuals who, because of symptoms, require an open operation, and in whom general condition, age and sexual habits offer no contra-indications. Further reports on the use of this procedure will be awaited with interest. The main objection to its adoption as standard practice is of course, the postoperative occurrence of impotence and urinary incontinence. The use of the retropubic approach for radical prostatectomy has been reported.15 The greatest disadvantage of this method is that the posterior aspect of the gland is inaccessible for biopsy under direct vision. Also, f ascial planes cannot be identified as carefully as they can be from the perineal aspect. Finally, most observers agree that it is technically more difficult than the perinea! operation. ADVANCED PROSTATIC CANCER
The treatment of the patient with prostatic cancer which has spread beyond the immediate boundaries of the gland is no longer directed toward a cure, but, instead, is concerned with a limited, twofold objective: 1) relief of urinary symptoms, and 2) endocrine control of the tumor. Transurethral resection has been the most widely used surgical method for dealing with the problem of bladder neck obstruction due to prostatic cancer. In the great majority of cases it has proved of great benefit A certain number require multiple resections to cope with continued grmvth of the neoplasm. In a few patients marked irritability of the bladder and posterior urethra develops following transurethral resection. These people are-better treated with permanent suprapubic cystostomy. 16 The question has often been asked whether transurethral resection stimulates growth in the residual cancer. Many of us have seen occasional cases where the clinical course has suddenly taken a rapid turn for the worse after transurethral resection. Possibly this is post hoc reasoning. Flocks16 has found no evidence to Smith, G. G. and Woodruff, L. M.: J. Urol., 63: 1077-80, 1950. Memmelaar, J.: J. Urol., 62: 340-48, 1949. 16 Flocks, R.H., Harness, W. N., Tudor, J.M. and Prendergast, L.: J. Urol., 66: 393-407, 1951. 14
16
PROSTATIC CANCER
739
substantiate it. Nevertheless, because of such experiences, some individuals, notably Slaughter, 17 have completely abandoned transurethral resection in favor of cystostomy in those patients in whom the obstructive symptoms are not relieved by endocrine therapy. For the treatment of the very large advanced cancer, open perineal or suprapubic resection of obstructing tissue has been favored by some. The results are said to compare favorably with those resected transurethrally, and the necessity for repeated operations is said to be obviated. Endocrine measures alone are effective in certain instances in relieving the obstructive symptoms. Such cases, however, are in the minority, although there is some difference of opinion concerning this. Some workers have attempted to widen the scope of the radical operation to include selected, nonmetastatic cases in which, on initial rectal palpation, the malignant process seems not to have extended very far beyond the immediate confines of the prostate. A certain number of these borderline advanced cases have responded so satisfactorily to endocrine therapy with respect to prostatic size, induration and degree of fixation, that radical prostatectomy has subsequently been undertaken in order to afford these patients the chance for a complete cure. It has also been stated that the operation is rendered easier technically by preliminary estrogen administration. 9 Scott and Parlow18 have recently reported the use of this procedure in 22 patients, 13 of whom were followed for at least 3 years, all 13 being alive at the end of that time. Preoperative estrogens were given for an average of 15.6 months. One of the early explanations for the seemingly beneficial effect of estrogen treatment in such cases was that it induced the prostatic neoplasm to recede from the marginal areas by depriving the more actively growing peripheral cells of necessary androgen, thus destroying thern. 9 In the light of subsequent evidence this reasoning seems fallacious. Pathological examination of specimens removed by radical excision after estrogen administration has disclosed persistence of adenocarcinoma in extraprostatic structures. 9 , 16 Furthermore, careful histological study has shown no tendency for increased cell destruction in peripheral areas as compared with the center of the neoplasm. In view of the foregoing, grave doubts arise as to the value of preoperative endocrine therapy in these advanced cases. To begin with, as Jewett has shown,7 it is quite likely that the malignant process will prove even more extensive histologically than pictured from rectal palpation. If we couple this knowledge with the histological proof that endocrine therapy does not completely destroy malignant cells situated in the extraprostatic tissues, there seems little reason to hope that we can transform an advanced cancer into one which is surgically curable, that is, capable of complete removal by Young's operation. Perhaps future studies will demonstrate the value of combined endocrine and surgical therapy in these borderline advanced cases. At this time, however, statistics are too meager to permit conclusions. Slaughter, G. W.: Personal communication. rn Scott, W.W. and Parlow, A. L.: J. Urol., !iii: 1093-1107, 195L
17
740
HERBERT BRENDLER
The recent trend toward extensive pelvic surgery for the eradication of bladder cancer has prompted some workers to advocate complete prostato-vesiculocystectomy with pelvic lymph node dissection for selected cases of advanced prostatic cancer as well. In this connection the findings of Arnheim in 1948 are of interest. 19 In studying lymph node metastases from prostatic cancer in 176 autopsy cases, this investigator found the peri-aortic nodes most frequently involved, in about 49 per cent, and the iliacs in only about 34 per cent. Surprisingly, the tracheobronchial nodes were invaded almost as frequently as the iliacs, in about 27 per cent. These findings seem to contravene the desirability of pelvic node dissections in advanced cases. ENDOCRINE TREATMENT
The palliative treatment of inoperable prostatic cancer by methods based on androgen control has proved one of the milestones in the continuing struggle to conquer this disease. Although no actual cures are on record, the recent survey by Nesbit and Baum20 of the results of endocrine treatment of 1818 cases has shown an apparent increase in the percentage of 3 and 5 year survivors among treated cases, as compared with a series of untreated controls reported by Nesbit and Plumb in 1946. 21 This apparent improvement in longevity has been found in patients with or without metastases. The combination of castration and diethylstilbestrol has seemed to be most effective in the nonmetastatic group. In those with metastases, castration alone appears to have been as effective as combined therapy, so that it seems that estrogen administration has added little in the treatment of these cases. Further evidence of this is found in the metastatic patients treated with stilbestrol alone; their 5-year survivals have been only slightly more than the untreated controls. In a careful analysis of these statistics, it is troublesome to note that, whereas all of the controls died of prostatic cancer, a considerable number of the treated cases (up to 33 per cent) died of other causes. It is not clear whether the latter were excluded from the actual survival statistics, as they certainly should have been.If, as it appears, they were included, then the results of the study are meaningless. A few remarks are also in order concerning the validity of the control series employed in the above comparative study. These cases consisted of 795 patients seen prior to the advent of endocrine therapy; of th.is group 605 died of prostatic cancer. Those without evident metastases totaled 273; 90 per cent of this group were dead in 5 years. There were 231 with metastases, of whom 94 per cent were dead in 5 years. Of significance is the fact that 239, or about 40 per cent, of the 605 who died of prostatic cancer, received no treatment whatsoever. In view of the fact that patients receiving endocrine treatment today are also afforded· the benefit of modern surgery, antibiotics and improved medical care, the validity of the above series for control purposes in a comparative study of endocrine methods of treatment may be seriously challenged. At present, therefore, it may be stated that, although there is no question as rn Arnheim, F. K. : J. U rol., 60: 599-603, 1948: Nesbit, R. M. and Baum, W. C.: J. A. M.A., 143: 1317-20, 1950. Nesbit, R. M. and Plumb, R. T.: Surgery, 20: 263-72, 1946.
20 21
PROSTATIC CANCER
741
to the palliative value of existing endocrine measures in advanced prostatic cancer, no convincing proof is at hand that such measures will actually arrest the inexorable course of the disease. The need for adequate controls and treated cases, selected without bias, becomes a matter of incalculable importance in any attempt to evaluate the ultimate effectiveness of endocrine therapy. TREATMENT OF RELAPSE
Despite initial improvement on endocrine treatment, the patient ·with advanced prostatic cancer inevitably suffers recurrence or reactivation of the malignant process. Whether the tumor has become "androgen-independent," or else insensitive to estrogens, is debatable. 22 Increasing the estrogen dosage to 1000 mg. daily or more may be of symptomatic benefit. Sometimes changing to another estrogen is helpful. TACE (tri-p-anisylchloroethylene), a synthetic estrogen, is currently being investigated in this regard. The possibility that increased amounts of adrenal androgens are responsible for the relapse has led to the use of cortisone in an effort to inhibit the production of such androgens. Although cortisone does, in fact, suppress androgen secretion in female pseudohermaphroditism, 23 Thorn and Harrison have found that in patients adrenalectomized for hypertension, cortisone administration leads to an increase in urinary 17-ketosteroids, although not over preoperative levels. The use of bilateral adrenalectomy in androgen control has recently been described by Huggins and Bergenstal.2 4 Pituitary radiation has been reported to be of some benefit. Recently, however, Kelly and others 25 administered a pituitary tissue dose of 8,100-10,000 r to each of 3 female patients with advanced cancer. Autopsy studies disclosed no demonstrable changes in the tumors, metastases, pituitaries, or other endocrine glands. The use of hypophysectomy has recently been reported by Scott. 26 It seems evident at this time that the endocrine treatment of prostatic cancer is more complicated than the anti-androgenic concept implies. Some patients with metastases actually benefit subjectively from testosterone, 27 although many develop a very prompt and severe relapse. Trunnell and Duffy28 have obtained similar variable responses in patients with progesterone. The use of other "nonandrogenic androgens" may yield valuable information. Some work has been done with urethane, the nitrogen mustards and certain folic-acid derivatives. The results are not impressive. Radiation therapy has not been as widely used as in the past. However, recent work with intraprostatic injections of radioactive gold seems quite promising, 29 but is too early to evaluate. Deming, C. L.: J. Urol., 61: 281-90, 1949. Wilkins, L., Lewis, R. A., Klein, R., and Rosemberg, E.: Bull. Johns Hopkins Hosp. 86: 249-52, 1950. 24 Huggins, C. and Bergenstal, D. JVI.: J. A. M.A., 147: 101-06, 1951. 25 Kelly, K. H., Feldsted, E. T., Brown, R. F., Ortega, P., Bierman, H. R., Low-Beer, B. V. A. and Shimkin, M. B.: J. Nat. Cancer Inst., 11: 967-83, 1951. 26 Scott, W.W.: Address given before the Halsted Society, the Johns Hopkins Hospital, February 7, 1952. 27 Brendler, H., Chase, W. E. and Scott, W.W.: Arch. Surg., 61: 433-40, 1950. 28 Trunnell, J. B. and Duffy, B. J.: Tr. N. Y. Academy of Sciences, series 2, 12: 238-41, 1950. 29 Flocks, R. H.: Personal communication. 22
23
742
HERBERT BRENDLER THE EVALUATION OF BIOLOGICAL POTENTIAL
For a fair comparison of different methods of treating prostatic cancer, it is essential that the disease be properly classified. It has been apparent to many observers that morphological criteria alone will not suffice, either gross or microscopic, whether based on extent of local spread, histological pattern, or degree of cellular differentiation. In most cases there is no correlation between the morphological appearance of the tumor and its behavior. Thus, we cannot predict the therapeutic response of a particular prostatic cancer from its histopathological characteristics. It follows that a need exists for methods by which the biological potential, or inherent malignancy, of individual prostatic cancers may be accurately determined. Park and Lees, in a recent article on the absolute curability of breast cancer, based on current survival statistics, make the following statement, which is, perhaps, applicable to prostatic cancer as well: "From an analysis of the evidence it has been shown that the apparent curability of cancer of the breast can be explained entirely in terms of the variability of growth rate." 30 It is their feeling that, when most observers discuss results of different methods of treatment, they TABLE
4. Recornrnended plan of treatment for prostatic cancer
I. Early-i.e. limited to the gland proper, including occult variety a. Radical perineal prostatectomy, and b. Endocrine therapy II. Advanced-i.e. beyond the gland proper, with or without metastases a. Surgical relief of urinary obstruction, and b. Endocrine therapy
are in reality only measuring differences in the growth rates of biologically different tumors. Unfortunately, there is no satisfactory method at present for evaluating the growth potential of the individual prostatic cancer. The increased acid phosphatase titer of malignant prostatic tissue, which is reflected in elevated serum levels in most patients with metastatic involvement, is, however, a biological property worthy of further exploration. Nesbit and Baum31 have analyzed the serum acid and alkaline phosphatase findings in patients with prostatic cancer. They have found that elevation of the serum acid phosphatase level in patients without demonstrable metastases is indicative of a worsened prognosis. Also, they have been able to show that, in patients with metastases, a normal acid phosphatase level is not a sign of low bodily resistance to the disease, and hence does not signify a poor prognosis. The elevation in serum alkaline phosphatase in many patients in response to endocrine treatment is also an interesting and frequent observation, which merits further study. CONCLUSIONS
At the present time, no satisfactory methods exist for classifying cases of prostatic cancer according to their biological properties. It is apparent, there30 31
Park, W.W. and Lees, J.C.: Surg., Gynec. & Obst., 93: 129-52, 1951. :N"esbit, R. M. and Baum, W. C.: J. A. M.A., 145: 1321-24, 1951.
PROSTATIC CANCER
743
fore, that we must devote ourselves in increasing measure to basic research in prostatic physiology. Current studies in the intermediary metabolism of phosphorylated compounds, and in certain nutritional aspects of prostatic growth, seem promising. Investigation of growth potentials of heterologously-transplanted human cancers and experimental prostatic tumors, as influenced by hormonal manipulations, may lead to an answer. The present stalemate which exists in the treatment of prostatic cancer cannot be resolved until we gain a clearer understanding of the nature of the malignant process. Until then, our methods of treatment will of necessity be determined empirically, and we must continue to use the best that combined surgical and endocrine measures can offer (table 4). SUMMARY
Prostatic cancer presents a formidable challenge today because of its frequency and the difficulty in early diagnosis. The latter factor is largely responsible for the low cure rate in this disease. Patients with cancer limited to the prostate, including the occult variety, should receive the combined benefit of radical perinea! prostatectomy and endocrine therapy, until it can be shown that 10 year survival figures are better in comparable patients treated with endocrine measures alone. The advanced case, whether or not associated with metastases, is best treated by surgical relief of urinary obstruction and hormonal therapy. The use of radical prostatectomy for borderline cases of advanced prostatic cancer is not recommended. The validity of current survival statistics for endocrine-treated cases is questioned because of 1) unsatisfactory controls, and 2) the inclusion of patients not dead of prostatic cancer. The treatment of relapse is discussed briefly. Emphasis is placed on the necessity of classifying cases according to their biological properties before drawing conclusions as to the effectiveness of different modes of therapy. The author wishes to express his appreciation to Dr. Robert S. Hotchkiss, Professor and Chairman of the Department of Urology, New York University Post-Graduate Medical School, for his helpful criticism during the preparation of this paper.