The Prostate 28:205-208 (I 996)

Carcinoma of Prostate: Case Against Immediate Hormonal Therapy

Philip H. Smith Department of Urology, St jarnes's University NHS Trust, Leeds, United Kingdom

BACKGROUND

The introduction of hormonal therapy for patients disabled with prostatic cancer in the early 1940s led to such dramatic effects that hormone treatment, usu- ally of diethylstilbestrol (DES), rapidly became wide- spread and general. If response failed to occur, or upon relapse, the dose was raised and up to 100 mg/ day were being given in the 1960s [l]. At that time, patients in whom incidental tumors were found at prostatectomy for benign disease were also com- monly given hormonal treatment, irrespective of age.

The first study of the Veterans Administration Co- operative Urological Research Group [2] drew atten- tion to the cardiovascular effects of female hormones administered to male patients and led to the search for alternative treatments. Since that time, alternative estrogens, including Estracyt, the steroidal and non- steroidal anti-androgens, and the LHRH analogues, have all been introduced and evaluated alone or in combination.

During the first years of this decade the concept of total androgen ablation (an anti-gonadrotrophic agent plus an anti-androgen) became very popular. The statistical basis for this popularity has recently been questioned [3].

Over the past decade, those not committed to the general use of total androgen ablation as the "best" treatment required immediately upon diagnosis and given in perpetuity have thought again about the pal- liative nature of hormonal treatment, the fact that 20% of patients do not respond and the way in which some patients survive for prolonged periods with minimal treatment or on deferred therapy. As a con- sequence, alternative concepts, including intermit- tent therapy, have started to emerge.

tion is focused on the 5% of patients in whom dis- tressing pain may arise from progression of the pri- mary tumor if it is not removed. For the patient with metastases, relief of pain is again the prime benefit of therapy, with the added hope of some prolongation of life.

In the hope of curing the disease, and in the desire to avoid those pelvic problems that affect the minor- ity, it is increasingly common to suggest annual dig- ital rectal examination (DRE) and other forms of screening, including serial estimations of prostate- specific antigen (PSA), undertaking transrectal ultra- sound (TRUS) with multiple biopsies where suspi- cion of a tumor arises.

Sakr et al. [4] have drawn the attention of the pro- fession to the presence of changes consistent with carcinoma in the prostates of 30% of men dying in road accidents between 40 and 50 years of age. It is now generally accepted that approximately 30% of men over age 50 also have changes consistent with prostatic cancer, the condition being asymptomatic or "latent." Coffey [5] noted that males in this age group had a chance of approximately 10% of developing clinical evidence of carcinoma of the prostate and a 1:4 chance of subsequently dying of the condition. This suggests, but does not prove, that an active ap- proach in which early diagnosis is sought by public- ity, education, and the encouragement of screening is likely to lead to overtreatment in many patients, since only 10% of those with the histological changes are likely to die of the condition.

For the patient with metastases, the demand has been for total androgen ablation on the basis that this prolongs life by approximately 7 months, raising the

PROSTATIC CANCER AS A DISEASE PROCESS

The Urologist is anxious to cure patients where possible and to minimize the impact of the disease where treatment is palliative. Within the pelvis atten-

Received for publication October 13, 1995; accepted November 9, 1995. Address reprint requests to Dr. Philip H. Smith, Department of Urology, St. James's University NHS Trust, Leeds, United King- dom.

0 1996 Wiley-Liss, Inc.

206 Smith

survival for the patient with metastatic disease from something over 2 years to approximately 3 years. It does not prevent death from prostatic cancer, and the terminal stages of the disease are likely to be just as distressing as after monotherapy. If the patient has no symptoms from his metastases at diagnosis, such treatment will impact adversely on his quality of life without dramatically improving his survival.

Such an active, and expensive, approach to pa- tients with and without metastases is clearly justified if the individual patient and the community at large benefit. The evidence in favor of such benefit is how- ever limited, since the clinical debate usually ignores the real possibility of over- or premature treatment. This has led some to question whether the disease- free (asymptomatic) interval might be longer if treat- ment were given only when required to relieve symp- toms. From this view has stemmed the concept of watchful waiting and of intermittent therapy in which treatment is interrupted once the PSA returns to normal. It is still too soon to determine the value, if any, of intermittent therapy, but it is expected that information will shortly become available from the Medical Research Council’s trial of immediate or de- ferred orchidectomy (or LHRH therapy) in patients with nonmetastatic disease or with asymptomatic metastases.

HORMONE THERAPY

Patients With Localized Disease

Surgeons are increasingly advocating screening, early diagnosis and “radical” (total) prostatectomy. This revival of an operation introduced in the earlier part of the century followed the description of the nerve-sparing operation by Walsh and Mostwin in 1984 [6]. Since then the introduction of routine PSA determinations and (TRUS) has increased the capac- ity of the profession to make a very early diagnosis, sometimes when the tumour is impalpable and occa- sionally when the PSA is normal.

This capacity for earlier diagnosis has coincided with the recognition that a gradually rising, but nor- mal PSA will still take the better part of a decade in most patients before its curve rises steeply predicting that progression which will soon thereafter lead to the presence of metastatic disease detectable by a bone scan [7].

Increasingly, early diagnosis must, in the absence of postoperative death, improve the survival in pa- tients following total prostatectomy. Such improve- ment will be seen even if the early diagnosis in some way can be restricted to those patients whose condi- tion would subsequently become clinically apparent (the minority). If the early diagnosis discovers the

condition in those in whom it would normally have remained latent the “benefits” of surgery will be per- ceived to be even greater. Given that PSA screening detects cancer in 10% of cases [8], it may be that this technique does detect the active tumours.

The improved survival will, of course, be bought at the price of any side effects, including postoperative death, incontinence of urine, and impotence. Most people accept that a 5% chance of incontinence is not uncommon and that at least 40% of patients will be impotent from the time of their operation. The quality of life of such patients and their partners must there- fore be considerably impaired.

The results of total prostatectomy so far published suggest that the disease will not be controlled in at least 20% of patients [9] and two studies reported at the start of this decade showed a 20% mortality after 10 years [10,11].

Because of the failure to cure all patients and the difficulties associated with total prostatectomy in those with extracapsular disease, surgeons are con- sidering the use of neoadjuvant hormonal treatment or of prostatectomy with added hormone therapy [ll]. There is also a trial of the Urological Group of the EORTC coordinated by Professor Schroder of Rot- terdam (EORTC Protocol 30846), in which patients in whom total prostatectomy appears inappropriate at the time of operation are randomized to receive im- mediate or delayed hormonal treatment. This study now contains almost 250 patients, but the rate of pro- gression and life expectancy in these patients is such that it is still too early to expect any published infor- mation. The historical evidence in favor of such an approach is limited but worthy of consideration.

A second EORTC study (Protocol 30891, Coordi- nation Professor Studer, Bern) compares immediate versus delayed anti-gonadotrophic effect in patients with nonmetastatic cancer unsuitable for radical pros- tatectomy. More than 300 patients have so far been recruited to this study, but again no information is yet available as sufficient time has not passed to come to any judgment.

In the studies of the VACURG the addition of hor- monal treatment to total prostatectomy in a small number of patients was not shown to be beneficial [12]. Statistical evaluation of such small numbers was not possible.

The National Prostatic Cancer Project considered this issue in their protocols 900 and 1000 reported by Schmidt et al. in 1993 [13]. This paper draws attention to the great differences between patients selected for total prostatectomy and for radiotherapy, the disease being more extensive in patients allocated to radio- therapy.

In the patients undergoing total prostatectomy

Carcinoma of Prostate: Case Against Immediate Hormonal Therapy 207

(protocol 900) they were subsequently randomized to receive no further treatment, cyclophosphamide or estramustine. Neither estramustine nor cyclophos- phamide reduced the incidence of recurrent disease. In terms of survival, those randomized to observation only showed a 10% death rate at 10 years, while those receiving adjuvant estramustine had a 15% death rate at the same time. Cancer-specific death rates are not given in this paper.

In protocol 1000, where the primary treatment was radiotherapy, the rate of recurrence was lower in the group receiving estramustine than in the other two groups, while overall survival for the three groups showed no significant difference. It must be con- cluded either that estramustine is beneficial in those whose disease is more advanced or that radiotherapy in some way impacts adversely on the outcome in terms of the time to development of recurrent disease.

Neither the figures from the VACURG, which are small and statistically insignificant, nor the figures from the NPCP protocols 900 or 1000 support the use of hormonal treatment at the time of primary inter- vention, if such intervention is by total prostatectomy or by radiotherapy. Also, the studies do not give any guidance as to whether hormonal therapy alone or deferred therapy is preferable.

These studies do emphasise the importance of ran- domized trials to compare the two major forms of primary treatment. The difference in survival be- tween them is still unknown although the Medical Research Council in London is now attempting such a study in which patients are randomized to total prostatectomy, radiotherapy, or watchful waiting. No data are yet available.

Patient With Extracapsular Disease

In patients with disease clinically extending be- yond the prostatic capsule (stage C, T3, Veterans Stage HI), the incidence of involved pelvic nodes (ap- proximately 60%) precludes total prostatectomy as an option for cure, although the operation may limit the possibility of distressing pelvic disease as a conse- quence of progression of a primary tumor that re- mains in situ. In these patients, Zincke [ l l ] has com- pared survival with and without additional hormonal treatment following total prostatectomy. He reported a reduction in death rate at 10 years from 25% to 20%.

The literature from the VACURG did not show any benefit for immediate hormonal treatment as com- pared to deferred therapy in those with extracapsular but nonmetastatic disease. The rate of progression (development of metastases) was reduced from 50% to 20% at 8 years, but the overall death rates were very similar in those randomized to immediate or de- ferred hormonal treatment.

Similarly, the studies of Adolfsson et al. [14] and Johansson [15] and the reviews of Chodak [16] and of Warner and Whitman [17] of nonmetastatic prostatic cancer treated by watchful waiting with hormonal therapy on progression do not suggest that immedi- ate treatment is mandatory-at least over the period of 10 years from diagnosis. These studies support the concept of watchful waiting for any man of 70 years or over and allow one to consider the concept of in- termittent therapy once progression (rise in PSA, en- largement of the primary, development of metastases or symptoms) demands it. This concept was first con- sidered by Eisen and Vock [18] and recently re-intro- duced by Akakura et al. [19]. A randomized clinical trial of this concept was launched in 1994 by Dr. Ca- lais da Silva in Lisbon, Portugal.

Patients With Metastatic Disease

Once the condition is metastatic, the argument for immediate hormonal treatment is more compelling, since the surgeon is aware that his patient is unlikely to survive more than 3 years. Certainly all patients with symptoms should be treated, since hormonal therapy will almost certainly relieve their pain, at least for a period of time. In the absence of symp- toms, the situation is less clear since the original VA- CURG study demonstrated no increase in survival for immediate therapy.

As far as I am aware, there has been no further trial of immediate versus deferred therapy restricted to patients with asymptomatic metastatic disease. How- ever, the Medical Research Council study, which re- cruited more than 900 patients, does include some patients with asymptomatic metastatic disease who have been randomized between immediate and de- ferred anti-gonadotrophic treatment. The preliminary results of this study are expected shortly and may shed further light on this topic. Consideration must, however, be given to the contributions of the NCI Intergroup study and of the EORTC Urological Group study, both dealing with total androgen abla- tion [20,21]. In these studies, the early use of total androgen blockade using an anti-gonadotrophic agent with an anti-androgen offered the potential of an additional 7-8 months survival for patients newly diagnosed and untreated with metastatic disease. This argument is slightly different from that of early versus deferred hormone therapy, but these two studies have been used in an attempt to demonstrate the superiority of combination therapy which in the American study showed very prolonged benefit for those with metastatic disease limited to the axial skel- eton in whom the performance status was good. The limitations of these studies have been considered

208 Smith

[221, and these and all other studies comparing monotherapy versus total androgen ablation that could be made available have been considered by the meta-analysis of the Prostate Cancer Collaborative Trialists Collaborative Group [3]. That group has con- cluded that the case for immediate total androgen ablation requires further consideration. In such cir- cumstances it is almost certainly ethical still to con- sider the concept of immediate versus deferred ther- apy for those without symptoms who wish to preserve their sexual function and of intermittent therapy for those who show response to treatment in the hope of preserving a better quality of life. If im- mediate treatment is not given, close monitoring for progression and complications is required.

CONCLUSIONS

In a condition as complex and slowly progressive as prostatic cancer, valid information can come only from clinical trials. Insofar as information is available from clinical trials the present situation is as follows:

1. There is no evidence that the addition of hor- monal therapy to primary treatment by total pros- tatectomy or radical radiotherapy improves survival.

2. For patients with extracapsular disease, there is no information to justify the use of hormonal therapy upon diagnosis rather than upon progression.

3. In patients with metastatic disease there is still no evidence to show that immediate as distinct from deferred treatment is mandatory in those patients who have no symptoms.

4. All forms of treatment carry side effects, and the patient who is free from symptoms, mobile, and sexually active may still, if he wishes, be followed at intervals by clinical examination and repeat PSA de- termination, choosing to accept treatment when his PSA rises or when symptoms occur.

ACKNOWLEDGMENT

I thank Mrs. S. Cordingley for her kindness in pre- paring this manuscript.

1.

2.

3.

4.

REFERENCES

Ferguson JD: Cancer of the prostate 11. BMJ 4:512-514, 1970. Veterans Administration Cooperative Urological Re- search Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 124:lOll- 1017, 1967. Prostate Cancer Trialists Collaborative Group: Maxi- mum androgen blockade in advanced prostate cancer: An overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet 346:265-269, 1995. Sakr WA, Haas GP, Cassin BF, Pontes JE, Crissman JD:

The frequency of carcinoma and intraepithelial neopla- sia of the prostate in young male patients. J Urol 150: 379-385, 1993.

5. Coffey DS: Prostate cancer. An overview of an increas- ing dilemma. Cancer 71(suppl):880-886, 1993.

6. Walsh PC, Mostwin IL: Radical prostatectomv and

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

cysto-prostatectomy with preserva6on of potency: Re- sults of a new nerve sparing technique. Br J Urol 56: 694-697, 1984. Pearson JD, Carter HB: Natural history of changes in prostate specific antigen in early stage prostate cancer. J Urol 152:1743-1748, 1994. Andriole GL, Catalona WJ: Using PSA to screen for prostate cancer. Urol Clin North Am 20:647-651, 1993. Partin AW, Pound CR, Clemens JQ: Serum PSA after anatomic radical prostatectomy. Urol Clin North Am 20:713-725, 1993. Smith JA: Management in localized prostate cancer. In Proceedings of International Workshop on Prostate Cancer and Benign Hypertrophy, October 26-30, 1991, Sea Island, Georgia. Zincke H: Combined surgery and immediate adjuvant hormonal treatment for stage D1 adenocarcinoma of the prostate. Mayo Clinic experience. Semin Urol 8:175-183, 1990. Madsen PO, Graversen PH, Gasser TC, Corle DK: Treatment of localized prostatic cancer. Radical pros- tatectomy versus placebo. A 15-year follow up. Scand J Urol Nephrol Suppl 110:95-100, 1988. Schmidt JD, Gibbons RP, Murphy GP, Bartolucci A: Adjuvant therapy for localized prostate cancer. Cancer 71 (suppl):l005-1013, 1993. Adolfsson J, Riinstrom L, Lowhagen T, Carstensen J, Hedlund PO: Deferred treatment of clinically low grade prostate cancer: The experience from a prospective se- ries at the Karolinska Hospital. J Urol 152:1757-1760, 1994. Johansson JE: Expectant management of early stage prostatic cancer: Swedish experience. J Urol 152:1753- 1756, 1994. Chodak GW: The role of watchful waiting in the man- agement of localized prostate cancer. J Urol 152:1766- 1768, 1994. Warner J, Whitmore WF Jr: Expectant management of clinically localized prostate cancer. J Urol 1521761- 1765, 1994. Eisen M, Nappe HE, Vock R: Thombocytere-aggrega- tionshemming bei oestrogen-behadelten prosta ta-carci- noma-patients. Urologe A14:132-136, 1974. Akakura K, Bruchovwky N, Goldenberg SC, Rennie PS, Buckley AR, Sullivan LD: Effects of intermittent androgen suppression on androgen-dependent tu- mours. Cancer 71:2782-2789, 1993. Crawford ED, Eisenberger MA, McLeod DG, et al: A comparison of leuprolide with and without flutamide in previously untreated patients with disseminated prostate carcinoma: a placebo controlled study. N Engl J Med 321:419-424, 1989. Denis LJ, Whelan P, Carneiro De Moura JL, et al: Gos- erelin acetate and flutamide versus bilateral orchidec- tomy: A phase 111 EORTC trial (30853). Urology 42:119- 129, 1993. Smith PH: Hormone therapy: An overview. Cancer Surv 23:171-181, 1995.