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Combination Finasteride and Flutamide in Advanced Carcinoma of the Prostate: Effective Therapy with Minimal Side Effects
00!22-634719vl545-1642$03.W0
Val. 154, 1642-1646, November 1995 Printed in U.S A.
kJOURNAL OF UROLOGY C0p-t 8 1996 by WCAN U~01lxjic.u.ASS~CIAT~ON, hc.
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CARCINOMA OF THE PROSTATE: EFFECTIVE THERAPY WITH MINIMAL SIDE EFFECTS NEIL E. FLESHNER AND JOHN TRACHTENBERG From the Division of Urology, University of Toronto, Toronto, Canada
ABSTRACT
Purpose: The efficacy of the combination of finasteride and flutamide in select patients with advanced prostatic cancer is determined. Materials and Methods: A total of 22 sexually active patients with stages C and D1 carcinoma of the prostate was treated with finasteride plus flutamide. Mean followup was 22 months. Results: Initial mean prostate specific antigen level was 42.9 ng./ml. At 3 and 6 months, the mean prostate specific antigen level was 3.6 ng./ml. and 2.9 ng./ml., respectively. The results appear durable at 24 months. Side effects were minimal, with 86%of the men maintaining sexual function. Conclusions: Finasteride plus flutamide should be considered in sexually active patients with minimal volume advanced prostate cancer. KEY WORDS:prostatic neoplasms, flutamide, chemotherapy, drug therapy
Prostate cancer is the most common cancer in humans' and the second leading cause of cancer deaths in men in North America.2 Despite recent advances in the detection and treatment of localized disease, 75% of the patients are potential candidates for androgen deprivation therapy.3 Although not curative, androgen deprivation therapy provides excellent palliation of painfid bone metastasis and obstructive urinary tract symptoms. Recent advances in androgen deprivation therapy have been directed towards limiting the side effects of treatment or eliminating the need for surgical extirpation of the testes. The major side effects of androgen deprivation therapy are a result of castrate levels of serum testosterone, including loss of libido, psychological impairment, loss of potency, anemia, malaise and muscle ~ a s t i n g . 4 - ~ In an effort to maximize quality of life and provide adequate androgen deprivation therapy, we have been exploring the possibility of selectively blocking dihydrotestosterone, the major effector hormone of prostatic tissue. Animal data from our laboratory suggest that the combination of flutamide and finasteride suppresses the rat ventral prostate equivalently to the combination of a luteinizing hormonereleasing hormone agonist plus flutamide.7 Because these 2 drugs do not lower serum testosterone levels it should be possible to treat prostate cancer effectivelywith minimal side effeds. We report the results of this combination in the first 22 patients treated at our institution with a minimum of 18 months of followup. Our results suggest that this combination successfully causes disease regression while still maintaining sexual libido and potency. In addition, the antiandrogenic effects appear to be maintained a t 2 years.
4 in 2 patients, 5 to 7 in 17 and 8 to 10 in 3. Followup ranged
bom 18 to 24 months (mean 22). AU men were sexually active and consented to participate in the study. Baseline serum evaluation consisted of measurements of serum prostate specific antigen (PSA, Hybritech assay), acid phosphatase (enzymatic), testosterone and luteinizing hormone levels, liver function tests (alkaline phosphatase, total bilirubin and transaminases) and a complete blood count. Patients also underwent radionuclide bone scintigraphy to rule out bony metastases. Serial transrectal ultrasonography of the prostate was performed on 8 patients. Drug dosages. Our initial 10 patients were started on 375 mg. flutamide daily. If serum PSA levels were not within the normal range (less than 4 ng.lml.1 by 8 weeks the dosage was increased to 750 mg. daily. Of the initial 15 patients 7 required 750 mg. flutamide. Since the higher dose was well tolerated, all subsequent patients received 750 mg. daily. All patients were treated with 5 mg. finasteride daily. Followup. Patients were followed twice monthly for 1 month, monthly for the next 2 months and every 3 to 6 months thereafter. At each visit a history was obtained and physical examination was performed. A detailed inquiry into the potential side effects of the treatment regimen was made. PSA levels were determined at each visit. For the initial 12 months of therapy, all blood work was repeated. If it was believed that a patient had a suboptimal response to treatment, he was taken off the study regimen and started on a standard form of androgen deprivation therapy. Treatment was begun in August 1992. Followup of 18 months was available on all patients and 24-month followup was available on 15. RESULTS
MATERIALS AND METHODS
Patients. Patient age ranged from 55 to 71 years (mean 63, median 62). AU patients had histologically proved carcinoma of the prostate: 16 had stage N+ and 6 had bulky stage T3NO disease. Of the patients with positive nodes 11 had abandoned radical prostatectomies and 5 had biopsy proved lymph node metastases. Tumor grade was classified as Gleason scores 2 to Accepted for publication June 9, 1995. Supported in part by the American Foundation for Urologic Disease.
Serum PSA. Serum PSA is the best method available for measuring disease status8 and response to therapy. The changes in the distribution and mean PSA levels are shown in table 1. One patient had a suboptimal response and was changed to standard therapy at week 12. The clinical course was eliminated from the analysis after week 12. Initial mean PSA level was 42.9 ng./ml. (range 16 to 109).At 3 months the PSA values had successfully decreased to a mean of 3.6 ng./ml. Longer term followup revealed that these low PSA values appear to be durable at 24 months.
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COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER OF PROSTATE
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TABLE1. PSA followup in patients treated with finasteride plus flutamide MOB.Therapy
Mean ng./ml. (median) No. pts. at PSA level (ng./ml.): Less than 4 4-10 10-50 50-250
Total No. pts.
Initial
3
6
9
12
18
24
42.9 (25.7)
3.6 (1.3)
2.9 (1.1)
2.8 (1.4)
3.1 (1.6)
2.9 (1.9)
3.1 (1.8)
0
20
0 17 5 22
1
21 0 0 0 21
21 0 0 0 21
20 1 0 0 21
20 1 0 0 21
15 0
1 0 22
Testosterone. The initial and serial serum testosterone levels as well as the percentage change from baseline are shown in table 2. Initial mean testosterone level was 19.4 nmo1.A. (normal 10 to 40, range 13.9to 27.9). At month 3 there was an increase in mean testosterone to 27.1 nm01.A. Three patients had testosterone increases into the abnormal region. These elevated levels were maintained at 1 year. We did not routinely perform testosterone measurements following 1year of therapy. Luteznizing hormone. The initial and serial serum luteinizing hormone levels as well as the percentage change from baseline are shown in table 3. The initial mean luteinizing hormone level was 7.2 IUA. (normal 2 to 12, range 4.8 to 11.7). The percent changes in luteinizing hormone levels with time mirrors the testosterone data. At 3 months the mean luteinizing hormone level was 12.3 IUA., which represents a 71% increase. No further increases have been noted past 3 months. We routinely stopped collecting data on luteinizing hormone levels after 1year of therapy. Unlike testosterone, 18 to 23% of patients had increases outside of the normal range of luteinizing hormone values. Failure to respond. One patient was believed to have had a suboptimal response to therapy. The clinical course is depicted in figure 1. This 62-year-old man was diagnosed with Gleason score 8, stage T3N+ carcinoma of the prostate. The initial PSA level was 24.7 ngJml. and he was started on finasteride (5 mg. daily) and flutamide (375 mg. daily). At week 8 the PSA level had decreased to 17.4 nglml. and the flutamide level was increased to 750 mg. daily. By week 12 the PSA value had decreased to 12.2 ngJml. We believed that this response was suboptimal and changed the drug to a luteinizing hormone-releasing hormone analogue (goserelin acetate) plus flutamide. The PSA level decreased to 1.2 ng./ ml. by week 24 but at month 18 it had reached 3.9 ngJml. Whether he would have reached this nadir on finasbride and flutamide is unclear. Sexual function. AU men were sexually active before the initiation of therapy. At month 18,86% of the patients maintained sexual function. The remaining 3 patients noticed either diminished libido but maintenance of morning erections (2) or total loss of morning erections and libido (1).One of these 3 patients had a history of hypertension and was taking antihypertensive medications. The major complaint regarding sexual function was dry ejaculation (71%). Side effects. Liver h c t i o n , renal function and complete blood counts were unchanged. Diarrhea was reported as a side effect in 7 patients (33%). The diarrhea was actually a mild loosening of bowel movements in 6 patients and
-
0
0 15
TABLE3. Serial luteinizing hormone levels in patients treated with finasteride plus flutamide Mos. Therapy
No. pts.
Initial
3
6
12
22
22 12.3 f 2.1 +71 18 (6122)
21 11.9% 1.6 +65 23 (5/22)
21 12.1 2 1.9 +68 18 (6122)
Mean 2 SD 7.2 z 1.8 % Change fmm baseline 0 (0/22) IAbnormal (NoJtotaI No. pts.) Normal lutehizing hormone range 2 to 12 IUO.
St
\
0 Initial
0 ymh
ymh
ymh
ymh
ymh
ymh
ymh
1
2
3
6
9
12
18
TIME (months)
FIG.1. Serial PSA values in suboptimal responder. LHRH, luteinizing hormone-releasing hormone.
was moderate in 1, which responded to treatment with loperamide. Gynecomastia was reported in 4 patients (19%). Mild mastodynia not requiring analgesia was noted in 2 patients. Interestingly, both patients had elevations of testosterone into the abnormal range (40.4 nmo1.A. and 41.7 nmolfl., respectively). No patient withdrew from the study because of side effects. Prostate volume change. Serial transrectal ultrasonograms were available for 8 patients, including serial ultrasound couplets of 0 and 3 months in 4,O and 6 months in 3, and 0 and 18 months in 1. The mean decrease in prostate volume was 26% and 31% at 3 and 6 months, respectively. The patient who underwent ultrasound determined prostate volume measurements at months 0 and 18 had a 29% decrease in volume. Thus, it appears that the maximal hormonal effect is at 3 to 6 months. Normal prostatic tissue and hypoechoic lesions underwent involution.
TABLE2. S e d testosterone values in patients treated with finasterid0 plus flutarnide Mos. Therapy
No. pts. Mean mos. 2 SD (median) IChange from baseline IElevated ( N o h t n l No. pta.) Normal testaaterune level 10 to 40 nmo1.h.
Initial
3
6
22
22 27.1 2 6.9 (25.8)
21 28.4 2 8.1 (29.3) +46 14 (322)
19.4 2 7.7 (17.6)
-
0 (0/22)
+40 14 (3/22)
12 26.9
?
21 7.9 (24.7)
+39 14 (3/22)
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COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER O F PROSTATE DISCUSSION
Despite advances in the early detection and treatment of localized disease, androgen deprivation therapy remains the most effective for patients with incurable cancer. The benefits of hormonal therapy in terms of palliation are unquestioned. However, there is some debate as to whether overall survival is improved by early versus delayed androgen deprivation therapy.3 A major argument against starting androgen deprivation therapy early relates to the side effects associated with this form of treatment. All currently approved modalities of hormonal therapy cause castrate levels of serum testosterone, which produces side effects such as malaise, psychological impairment, anemia, decreased muscle mass, impotence and decreased libido.4-6 Using a combination of finasteride and flutamide, we demonstrated that effective anticancer therapy can be administered without the side effects associated with castrate levels of serum testosterone. Flutamide, a nonsteroidal antiandrogen, acts at the dihydrotestosterone receptor. As a single agent it has been shown to be effective in the treatment of advanced prostate cancer.9 Nevertheless, there is a sense in the urological community, not founded in clinical trials, that flutamide alone is not a sufficient androgen blockade because it causes a reflex increase in luteinizing hormone and testosterone levels. Furthermore, in vitro data suggest that testosterone itself, a t high concentrations, can interact with the dihydrotestosterone receptor.10 F'inasteride, a 5a-reductase inhibitor, is used in the medical management of benign prostatic hyperplasia. Because it selectively decreases dihydrotestosterone levels without reducing testosterone levels, patients are not rendered impotent from its consumption. Finasteride has been studied in advanced prostatic carcinoma as a single agent. The results from that trial suggested that tumor burden was reduced (decreased PSA levels) but that the effectiveness was not equivalent to conventional modes of therapy." In theory, a combination of flutamide and finasteride in patients with advanced prostate cancer should provide tumor control while maintaining serum testosterone levels. The finasteride should limit the availability of dihydrotestosterone at its receptor, thus augmenting the inhibitory effects of the flutamide. Laboratory data have shown that the combination of finasteride and flutamide in the rat ventral prostate model caused significant decreases in prostate size compared to either drug alone and equivalent suppression compared to luteinizing hormone-releasing hormone agonist plus flutamide.7 Is there evidence for an additive effect of the 2 drugs in humans? Two patients have had "drug holidays" from flutamide and finasteride, respectively (fig. 2). Interim PSA values increased during these holidays and decreased with the resumption of the withdrawn drug. This finding provides strong evidence that both agents are working and that this therapy is superior to monotherapy with flutamide or finasteride. One patient had what we considered a suboptimal response to therapy. The rate of PSA level decrease was less rapid than previously treated patients. Whether he would have ultimately reached the appropriate nadir or if the disease was intrinsically less sensitive to this therapy is unclear. Alternatively, he may have relatively hormone refractory disease (Gleason score 8),since it is too early to know when he will fail on standard androgen deprivation therapy. At the most recent measurement of serum PSA, there appeared to be a premature increase. Longer followup of this patient is necessary. Selecting the ideal patients for this form of therapy is challenging. We believe that patients with stages C (T3)and D1 (N+)cancer are the best candidates. The inherent biology of prostate cancer often affords these patients a long natural
30 T
2s 20
A I
0 4 Initial Y m f h l Umth
2
Umlh Ymth Ymlh Y m t h 4 6 8 10
Ymth 12
Ymth 14
Umth H n i h
16
18
TIME ON THERAPY
(months)
FIG. 2. Serial PSA values in 2 patients on drug holidays
history making quality of life issues important. The 10-year survival rates for both subsets ranged from 25 to 60%.12.'3 Therefore, they would have a relatively long disease-free survival. Another group of individuals in whom quality of life issues may be important are patients with biochemical failure following radical therapy. The lead time afforded by the measurement of PSA will undoubtedly result in therapy for a longer duration than previously recognized. Our results suggest that effective anticarcinogenic therapy is being delivered with minimal side effects. Tumor volume as measured by PSA decrease is substantially diminished. In addition, sexual function, libido and anemia appear to be spared. It is important to realize the limitations of this study. It was conducted on a highly select group of patients. These men were generally younger and more active than typical prostate cancer patients. Also, long-term data are still not available. The interval to disease relapse may be shorter in patients on this therapy compared to traditional forms of androgen deprivation therapy. CONCLUSIONS
Ultimately, a randomized trial of the combination of finasteride and flutamide (for patients with stages C and D1 cancer) compared to standard forms of androgen deprivation therapy is required to determine its efficacy. Outcome measures of this trial should include psychological testing, quality of life scales and survival. Until this is performed, finasteride and flutamide in combination should be reserved for the select patient who is relatively young and sexually active. REFERENCES
1. Dhom, G.: Epidemiologic aspects of latent and clinically manifest carcinoma of the prostate. J. Cancer Res. Clin. Oncol., 106 210, 1983. 2. American Cancer Society: Cancer Facts & Figures-1994. Atlanta: American Cancer Society, Inc., 1994. 3. Stamey, T. A. and McNeal, J. E.: Adenocarcinoma of the prostate. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan, J r . Philadelphia: W. B. Saunders Co., vol. 2, chapt. 29, pp. 1159-1221, 1992. 4. Fleshner, N. E. and Trachtenberg, J.: Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results. Eur. Urol., suppl. 2, 24: 106, 1993. 5. Karling, P., Hammar, M. and Varenhorst, E.: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J. Urol., 1 5 2 1170, 1994. 6. Tyrrell, C. J., Altwein, J . E., Klippel, F., Varenhorst, E., Lunglmayr, G., Boccardo, F., Holdaway, I. M., Haefliger, J M. and Jordaan, J . P.: A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of ndvanced prostate cancer. The International Prostate Cancer Study Group. J. Urol., 1 4 6 1321, 1991. 7. Fleshner. N. and Trachtenherg, J.: Sequential androgen block-
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER OF PROSTATE
1645
ade: a biological study in the inhibition of prostatic growth. Inillion. It is time for the American Urologicd Association to estabJ. Urol., 148 1928,1992. 1ish guidelines for the use of hormonal therapy in prostate cancer. 8. Partin. A. W. and Oesterling, J. E.: The clinical usefulness of Patrick C. Walsh prostate specific antigen: update 1994. J. Urol., 162 1358, Department of Urology 1994. The Johns Hopkins Hospital 9.Sogani, P.C.,Vagaiwala, M. R. and Whitmore, W. F., Jr.: ExpeBaltimore, Maryland rience with flutamide in patients with advanced prostatic cancer without prior endocrine therapy. Cancer, 54: 744,1984. 1. Newling, D. W. W.: The use of flutamide as monotherapy in the 10. Grino. P.B..Griffin, J. E. and Wilson, J. D.: Testosterone at high treatment of advanced prostate cancer. In: Therapeutic concentrations interacts with human androgen receptor simiProgress in Urological Cancers. Edited by G. P. Murphy and S. larly to dihydrotestosterone. Endocrinology, 126: 1165,1990. Khoury. New York: Alan R. Liss, Inc., pp. 117-121, 1989. 2. Prout, G.R., Jr., Kliman, B., Daly, J. J., MacLaughlin, R. A. and 11. Presti, J. C., Jr., Fair, W. R., Andriole, G., Sogani, P. C., Griffin, P. P.: In vitro uptake of 3H testosterone and its conSeidmon, E. J.. Ferguson, D., Ng, J. and Gormley, G. J.: Mulversion to dihydrotestosterone by prostatic carcinoma and ticenter, randomized, double-blind, placebo controlled study to other tissues. J. Urol., 116 603, 1976. investigate the effect of finasteride (MK-906) on stage D pros3. Geller, J., Albert, J., Loza, D., Geller, S., Stoeltzing,W.and de la tate cancer. J. Urol., 148: 1201. 1992. Vega, D.: DHT concentrations in human prostate cancer tis12. Sayer, J., Ramirez, E. I. and von Eschenbach, A C.: Retrospecsue. J. Clin. Endow. Metab., 48:440,1978. tive review of prostate cancer patients with lymph node me4. Brooks, J. R., Berman, C., Nguyen, H.,Prahalada, S., F’rimka, tastases 11968-83).J. Urol.,part 2, 141: 45ZA,abstract 957, R. L., Rasmusson, G. H. and Slater,E. E.: Effect of castration, 1992. DES, flutamide, and the 5 alpha-redudase inhibitor, MK-906, 13.van den Ouden, D., Davidson, P. J. T., Hop, W. and Schrder, on the growth of the Dunning rat prostatic carcinoma, R-3327. F. H.: Radical prostatectomy as a monotherapy for locally Prostate, 1 8 215,1991. advanced (stage T3)prostate cancer. J. Urol., 161:646,1994. For nearly half a century, the mainstay of therapy for advanced EDITORIAL COMMENTS metastatic prostate cancer was either bilateral surgical orchiectomy or estrogen therapy. During the last 5 years, the accepted gold Bccause most men treated with hormonal therapy become impotent, standard of treatment and the definition of advanced prostate cancer it is highly desimble to identify a form of treatment that does not have have undergone metamorphosis. Regarding treatment, several large this side effect.There are 2 drugs that preserve sexual function in most clinical trials support the combination of either surgical orchiectomy men: flutamide and finasteride. The response to flutamide as mono- or a luteinizing hormone-releasing hormone agonist with the antitheriipy. however, has been shown to be inferior to diethylstilbestrol at androgen flutamide for the treatment of advanced prostate cancer. 1 rng. per day‘ and finasteride has only a muted effect when adminis- We have established that a substantial survival benefit is enjoyed by tered to men with advanced prostate cancer (reference 11 in article). In those who have minimal metastatic disease and who are trea-d with this study the authora have kated the influence of flutamide and combined androgen b1ockade.l The majority of patients diagnosed with prostate cancer before finiisteride in combination. reasoning that hasteride should lower tissue dihydrotestoatemne levels and thereby augment the ability of 1985 presented with advanced stage disease. The definition of advanced included bony metastases, or soft tissue, nodal or other organ flukimide to compete for receptor sites. 1 am disappointed by the study design selected by the authors. It involvement. However, I believe that the concept of advanced cancer is hard to imagine why they did not have a control group or did must be modified because by definition advanced is synonymous not administer the drugs sequentially. Thus, it is impossible to with incurable to patients and clinicians. Therefore, the concept of tell whether the combination of agents is synergistic or additive, or advanced cancer in 1995is not only stage D2 (M1) but also stages DO, whether there is no effect. The anecdotal information provided in 1 DUN+) or C(T3). or an increasing PSA level after radical prostatecpatient who stopped finasteride suggests that the influence was tomy or other definitive local therapy.’ Most patients presenting with a high initial Gleason score (9or 10)can be considered to have minimal. Thus, I conclude that this is basically a negative study. advanced disease. All of these stages and/or pathological findingsare The authors suggest that a randomized trial should be done with frequently the harbingers of progression and death. appropriate controls. Again, I wonder why they did not take their own The authors review a novel new therapy for advanced stage T3 advice and do this initially. Nonetheless, I believe that such a trial and/or N+ disease. The mean PSA level was 42.9 ngJml.. generally would be futile. When patients with stage C or Dl prustate cancer are reflective of a reasonably significant tumor burden. The initial dose treated with effective hormonal therapy (a luteinizing hormone-releas- of flutamide chosen was 375 mg. a day. It appears that this dosage ing hormone agonist or castration1, PSA levels are usually suppressed was not able to decrease the PSA level consistently to less than 4 to the undetectable range. Clearly, the combination of agents did not ngJm1. by 8 weeks and, therefore, a dose of 750 mg. was chosen for exhibit a similar effect in this study. Indeed, serum PSA levels were the remainder of the clinical trial. All patients then experienced a maintained at an average of 3 nglml. Although finasteride may be substantial decrease in PSA level. However, the nadir does not synergistic with flutamide when tested in the rat model (reference 7 in approach the level of less than 0.1 or even 0.2 that would be expected article), this does not appear to be the ease in human pmstate cancer. with such disease treated with a luteinizing hormone-releasing horThere am several reasons why one might anticipate that a Ba-reductase mone agonist and an antiandrogen. In 34 patients with clinical stage inhibitor, such as fiwteride, would not be active in cancer: 1) 5 ~ -T3 disease whose initial PSA level was 37.4 nglml. 4 months of d u c t a s e activity is low in prostate cancers? 2) dihydrotestosterone flutamide and a luteinizing hormone-releasing hormone agonist remncentrations in human p m t a t e cancer are low? and 3)finasteride is sulted in a 98% decrease in the PSA level.* In fact, PSA may not be ineffectivewhen administered to the hormone sensitive Dunning rat the best barometer to measure true response to agents such as finasteride with flutamide. This sort of hormonal manipulation Pmstate cancer carcinoma R3327.‘ These observations coupled with the findings in this study suggest results in increased levels of testosterone, not a decrease to castrthat finasteride adds little or nothing to the effect of flutamide, ate levels as occurs with the standard forms of castration. The increased levels may stimulate PSA pruduction. and that either drug singly or in combination does not achieve the The patients in this clinical trial all appeared to have a durable degree of androgen deprivation provided by castration or treatment response during the short-term followup. One patient who did not with a luteinizing hormone-releasing hormone agonist. initially respond as predicted had a significant second response with Finally, 1 am disturbed by the suggestion that these drugs should more typical surgical castration. be !4km to patients with elevated PSA levels following radical prosThe clinical importance of this trial is that it offers a novel treatbtrctomy or men with low volume advanced prostate cancer. There ment for the increasing number of patients who now have not only is no evidence that early hormonal therapy prolongs life. Men die of stage T3 or node positive disease but also increasing PSA levels after the androgen insensitive cell population that is unaffected by hor- radical radiation therapy or prostatectomy. While the only abnormonal therapy. The only ones who will benefit from these sugges- mality in the latter patients is increasing PSA, they are subjectively tions are the pharmaceutical companies who are currently fanning symptomatic. Patients become focused on the PSA values and desire the flames of escalating health care costs. Last year, the Medicare “treatment” of this abnormal laboratory value. They become i n m a s chanees in the PSA level and doubline ...~.,RWRW - -..o .f . incremental ... bill for luteinizing hormone-releasing hormone agonists was 832CI in& ”
1
1646
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER O F PROSTATE
times, and recognize that the disease is progressing even though efficacy are demonstrated does i t then become appropriate to perthey are asymptomatic. My experience has been that these patients form a phase 3 study. In addition, the known inferiority of monogladly accept a luteinizing hormone-releasing hormone agonist and therapy finasteride or flutamide coupled with our laboratory data antiandrogen, only to start expressing concern after approximately 6 (reference 7 in article),which revealed a n additive effect of the drug to 9 months of therapy. They find the weight gain, hot flashes, cost combination, led us to conclude that it would be inappropriate to and inconvenience of monthly injections challenging, and frequently treat patients with sequential monotherapy. Furthermore, an instop the treatments. crease in PSA secondary to temporary finasteride withdrawal in 1 This combination of finasteride and flutamide may address many patient treated with this regimen lends credence to the fact that of these concerns, while delivering effective androgen ablation. We there is to some degree an additive effect of this combination (unhave now treated 27 patients with increasing PSA levels after rad- published data). However, flutamide provides the major antiandroical prostatectomy or radiation therapy with a similar regimen, genic effect. using 5 mg. finasteride plus 125 mg. flutamide twice daily. We have Although we agree that mean nadir PSA values are minimally seen similar results with decreased PSA to undetectable levels in 25 higher than with standard therapy, it is important to realize that 4 of the 27 patients. I t should be emphasized that the regimen pro- of the 15 evaluable patients had undetectable levels at 24 months. In posed by the authors or the one that we have used would likely be addition, nadir levels are well within the range that predicts good ineffective in cases of advanced prostate cancer. This study estabresponse to androgen deprivation therapy.' Nevertheless, we believe lishes the necessity of a randomized trial with interval t o progression and survival as an end point before we can conclude that this is a n that patients with long disease duration (patients with T3, nodeappropriate way to treat advanced prostate cancer. A number of positive and post-radical therapy recurrent disease) may be willing other treatment options that do not use standard castration include to sacrifice minimally less optimal therapy for improved overall single agent flutamide, bicalutamide and intermittent hormonal ab- quality of life. Surgical or medical castration can perhaps salvage lation. It is hoped that proper randomized trials will be conducted to these patients when disease progresses. We agree with Walsh that there is no proof that early hormonal address the effect on patient survival and quality of life. therapy prolongs survival but, to our knowledge, no adequately E. David Crawford powered study addressing this issue has ever been performed. FurDicrision of Urology thermore, we concur with Crawford that many patients in whom Department of Urology Uniuersity of Colorado Health Sciences Center radical treatment fails become obsessed with PSA levels and desire therapy. Therefore, these patients may be placed on total androgen Denver, Colorado blockade for long periods. However, there are concerns about longterm castrate levels of testosterone, including sexual dysfunction, 1. Crawford, E. D.: Changing concepts in the management of ad- muscle wasting, psychosocial disturbances, hot flashes and osteopovanced prostate cancer. Urology, suppl., 44:67, 1994. rosis. Finasteride and flutamide in combination may provide the 2. Pummer, K., Crawford, E. D., Daneshgari, F., Andros, B., correct balance between effective therapy and improved quality of Pfister, S.and Miller, G. J.: Hormone pretreatment does not life. This therapy is also less expensive than luteinizing hormoneaffect the final pathologic stage in locally advanced prostate releasing hormone analogues plus flutamide. Clearly a randomized cancer. Urology, suppl., 44: 38, 1994. study with time to progression, survival and overall quality of life are needed to define better the appropriate, if any, uses of this novel drug REPLY BY AUTHORS combination. 1. Cooper, E. H., Armitage, T. G., Robinson, M. R., Newling, D. W., While we welcome the comments of Walsh. we respectfully disRichards, B. R., Smith, P. H., Denis, L. and Sylvester, R.: aeree with some of his criticisms of our study. The reason for not Prostate specific antigen and prediction of prognosis in metacommencing a controlled study is because of the need for phase l and 2 testing of any new drug or drug combination. Only after safety and static prostatic cancer. Cancer, suppl., 66: 1025, 1990.
Val. 154, 1642-1646, November 1995 Printed in U.S A.
kJOURNAL OF UROLOGY C0p-t 8 1996 by WCAN U~01lxjic.u.ASS~CIAT~ON, hc.
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CARCINOMA OF THE PROSTATE: EFFECTIVE THERAPY WITH MINIMAL SIDE EFFECTS NEIL E. FLESHNER AND JOHN TRACHTENBERG From the Division of Urology, University of Toronto, Toronto, Canada
ABSTRACT
Purpose: The efficacy of the combination of finasteride and flutamide in select patients with advanced prostatic cancer is determined. Materials and Methods: A total of 22 sexually active patients with stages C and D1 carcinoma of the prostate was treated with finasteride plus flutamide. Mean followup was 22 months. Results: Initial mean prostate specific antigen level was 42.9 ng./ml. At 3 and 6 months, the mean prostate specific antigen level was 3.6 ng./ml. and 2.9 ng./ml., respectively. The results appear durable at 24 months. Side effects were minimal, with 86%of the men maintaining sexual function. Conclusions: Finasteride plus flutamide should be considered in sexually active patients with minimal volume advanced prostate cancer. KEY WORDS:prostatic neoplasms, flutamide, chemotherapy, drug therapy
Prostate cancer is the most common cancer in humans' and the second leading cause of cancer deaths in men in North America.2 Despite recent advances in the detection and treatment of localized disease, 75% of the patients are potential candidates for androgen deprivation therapy.3 Although not curative, androgen deprivation therapy provides excellent palliation of painfid bone metastasis and obstructive urinary tract symptoms. Recent advances in androgen deprivation therapy have been directed towards limiting the side effects of treatment or eliminating the need for surgical extirpation of the testes. The major side effects of androgen deprivation therapy are a result of castrate levels of serum testosterone, including loss of libido, psychological impairment, loss of potency, anemia, malaise and muscle ~ a s t i n g . 4 - ~ In an effort to maximize quality of life and provide adequate androgen deprivation therapy, we have been exploring the possibility of selectively blocking dihydrotestosterone, the major effector hormone of prostatic tissue. Animal data from our laboratory suggest that the combination of flutamide and finasteride suppresses the rat ventral prostate equivalently to the combination of a luteinizing hormonereleasing hormone agonist plus flutamide.7 Because these 2 drugs do not lower serum testosterone levels it should be possible to treat prostate cancer effectivelywith minimal side effeds. We report the results of this combination in the first 22 patients treated at our institution with a minimum of 18 months of followup. Our results suggest that this combination successfully causes disease regression while still maintaining sexual libido and potency. In addition, the antiandrogenic effects appear to be maintained a t 2 years.
4 in 2 patients, 5 to 7 in 17 and 8 to 10 in 3. Followup ranged
bom 18 to 24 months (mean 22). AU men were sexually active and consented to participate in the study. Baseline serum evaluation consisted of measurements of serum prostate specific antigen (PSA, Hybritech assay), acid phosphatase (enzymatic), testosterone and luteinizing hormone levels, liver function tests (alkaline phosphatase, total bilirubin and transaminases) and a complete blood count. Patients also underwent radionuclide bone scintigraphy to rule out bony metastases. Serial transrectal ultrasonography of the prostate was performed on 8 patients. Drug dosages. Our initial 10 patients were started on 375 mg. flutamide daily. If serum PSA levels were not within the normal range (less than 4 ng.lml.1 by 8 weeks the dosage was increased to 750 mg. daily. Of the initial 15 patients 7 required 750 mg. flutamide. Since the higher dose was well tolerated, all subsequent patients received 750 mg. daily. All patients were treated with 5 mg. finasteride daily. Followup. Patients were followed twice monthly for 1 month, monthly for the next 2 months and every 3 to 6 months thereafter. At each visit a history was obtained and physical examination was performed. A detailed inquiry into the potential side effects of the treatment regimen was made. PSA levels were determined at each visit. For the initial 12 months of therapy, all blood work was repeated. If it was believed that a patient had a suboptimal response to treatment, he was taken off the study regimen and started on a standard form of androgen deprivation therapy. Treatment was begun in August 1992. Followup of 18 months was available on all patients and 24-month followup was available on 15. RESULTS
MATERIALS AND METHODS
Patients. Patient age ranged from 55 to 71 years (mean 63, median 62). AU patients had histologically proved carcinoma of the prostate: 16 had stage N+ and 6 had bulky stage T3NO disease. Of the patients with positive nodes 11 had abandoned radical prostatectomies and 5 had biopsy proved lymph node metastases. Tumor grade was classified as Gleason scores 2 to Accepted for publication June 9, 1995. Supported in part by the American Foundation for Urologic Disease.
Serum PSA. Serum PSA is the best method available for measuring disease status8 and response to therapy. The changes in the distribution and mean PSA levels are shown in table 1. One patient had a suboptimal response and was changed to standard therapy at week 12. The clinical course was eliminated from the analysis after week 12. Initial mean PSA level was 42.9 ng./ml. (range 16 to 109).At 3 months the PSA values had successfully decreased to a mean of 3.6 ng./ml. Longer term followup revealed that these low PSA values appear to be durable at 24 months.
1642
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER OF PROSTATE
1643
TABLE1. PSA followup in patients treated with finasteride plus flutamide MOB.Therapy
Mean ng./ml. (median) No. pts. at PSA level (ng./ml.): Less than 4 4-10 10-50 50-250
Total No. pts.
Initial
3
6
9
12
18
24
42.9 (25.7)
3.6 (1.3)
2.9 (1.1)
2.8 (1.4)
3.1 (1.6)
2.9 (1.9)
3.1 (1.8)
0
20
0 17 5 22
1
21 0 0 0 21
21 0 0 0 21
20 1 0 0 21
20 1 0 0 21
15 0
1 0 22
Testosterone. The initial and serial serum testosterone levels as well as the percentage change from baseline are shown in table 2. Initial mean testosterone level was 19.4 nmo1.A. (normal 10 to 40, range 13.9to 27.9). At month 3 there was an increase in mean testosterone to 27.1 nm01.A. Three patients had testosterone increases into the abnormal region. These elevated levels were maintained at 1 year. We did not routinely perform testosterone measurements following 1year of therapy. Luteznizing hormone. The initial and serial serum luteinizing hormone levels as well as the percentage change from baseline are shown in table 3. The initial mean luteinizing hormone level was 7.2 IUA. (normal 2 to 12, range 4.8 to 11.7). The percent changes in luteinizing hormone levels with time mirrors the testosterone data. At 3 months the mean luteinizing hormone level was 12.3 IUA., which represents a 71% increase. No further increases have been noted past 3 months. We routinely stopped collecting data on luteinizing hormone levels after 1year of therapy. Unlike testosterone, 18 to 23% of patients had increases outside of the normal range of luteinizing hormone values. Failure to respond. One patient was believed to have had a suboptimal response to therapy. The clinical course is depicted in figure 1. This 62-year-old man was diagnosed with Gleason score 8, stage T3N+ carcinoma of the prostate. The initial PSA level was 24.7 ngJml. and he was started on finasteride (5 mg. daily) and flutamide (375 mg. daily). At week 8 the PSA level had decreased to 17.4 nglml. and the flutamide level was increased to 750 mg. daily. By week 12 the PSA value had decreased to 12.2 ngJml. We believed that this response was suboptimal and changed the drug to a luteinizing hormone-releasing hormone analogue (goserelin acetate) plus flutamide. The PSA level decreased to 1.2 ng./ ml. by week 24 but at month 18 it had reached 3.9 ngJml. Whether he would have reached this nadir on finasbride and flutamide is unclear. Sexual function. AU men were sexually active before the initiation of therapy. At month 18,86% of the patients maintained sexual function. The remaining 3 patients noticed either diminished libido but maintenance of morning erections (2) or total loss of morning erections and libido (1).One of these 3 patients had a history of hypertension and was taking antihypertensive medications. The major complaint regarding sexual function was dry ejaculation (71%). Side effects. Liver h c t i o n , renal function and complete blood counts were unchanged. Diarrhea was reported as a side effect in 7 patients (33%). The diarrhea was actually a mild loosening of bowel movements in 6 patients and
-
0
0 15
TABLE3. Serial luteinizing hormone levels in patients treated with finasteride plus flutamide Mos. Therapy
No. pts.
Initial
3
6
12
22
22 12.3 f 2.1 +71 18 (6122)
21 11.9% 1.6 +65 23 (5/22)
21 12.1 2 1.9 +68 18 (6122)
Mean 2 SD 7.2 z 1.8 % Change fmm baseline 0 (0/22) IAbnormal (NoJtotaI No. pts.) Normal lutehizing hormone range 2 to 12 IUO.
St
\
0 Initial
0 ymh
ymh
ymh
ymh
ymh
ymh
ymh
1
2
3
6
9
12
18
TIME (months)
FIG.1. Serial PSA values in suboptimal responder. LHRH, luteinizing hormone-releasing hormone.
was moderate in 1, which responded to treatment with loperamide. Gynecomastia was reported in 4 patients (19%). Mild mastodynia not requiring analgesia was noted in 2 patients. Interestingly, both patients had elevations of testosterone into the abnormal range (40.4 nmo1.A. and 41.7 nmolfl., respectively). No patient withdrew from the study because of side effects. Prostate volume change. Serial transrectal ultrasonograms were available for 8 patients, including serial ultrasound couplets of 0 and 3 months in 4,O and 6 months in 3, and 0 and 18 months in 1. The mean decrease in prostate volume was 26% and 31% at 3 and 6 months, respectively. The patient who underwent ultrasound determined prostate volume measurements at months 0 and 18 had a 29% decrease in volume. Thus, it appears that the maximal hormonal effect is at 3 to 6 months. Normal prostatic tissue and hypoechoic lesions underwent involution.
TABLE2. S e d testosterone values in patients treated with finasterid0 plus flutarnide Mos. Therapy
No. pts. Mean mos. 2 SD (median) IChange from baseline IElevated ( N o h t n l No. pta.) Normal testaaterune level 10 to 40 nmo1.h.
Initial
3
6
22
22 27.1 2 6.9 (25.8)
21 28.4 2 8.1 (29.3) +46 14 (322)
19.4 2 7.7 (17.6)
-
0 (0/22)
+40 14 (3/22)
12 26.9
?
21 7.9 (24.7)
+39 14 (3/22)
1644
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER O F PROSTATE DISCUSSION
Despite advances in the early detection and treatment of localized disease, androgen deprivation therapy remains the most effective for patients with incurable cancer. The benefits of hormonal therapy in terms of palliation are unquestioned. However, there is some debate as to whether overall survival is improved by early versus delayed androgen deprivation therapy.3 A major argument against starting androgen deprivation therapy early relates to the side effects associated with this form of treatment. All currently approved modalities of hormonal therapy cause castrate levels of serum testosterone, which produces side effects such as malaise, psychological impairment, anemia, decreased muscle mass, impotence and decreased libido.4-6 Using a combination of finasteride and flutamide, we demonstrated that effective anticancer therapy can be administered without the side effects associated with castrate levels of serum testosterone. Flutamide, a nonsteroidal antiandrogen, acts at the dihydrotestosterone receptor. As a single agent it has been shown to be effective in the treatment of advanced prostate cancer.9 Nevertheless, there is a sense in the urological community, not founded in clinical trials, that flutamide alone is not a sufficient androgen blockade because it causes a reflex increase in luteinizing hormone and testosterone levels. Furthermore, in vitro data suggest that testosterone itself, a t high concentrations, can interact with the dihydrotestosterone receptor.10 F'inasteride, a 5a-reductase inhibitor, is used in the medical management of benign prostatic hyperplasia. Because it selectively decreases dihydrotestosterone levels without reducing testosterone levels, patients are not rendered impotent from its consumption. Finasteride has been studied in advanced prostatic carcinoma as a single agent. The results from that trial suggested that tumor burden was reduced (decreased PSA levels) but that the effectiveness was not equivalent to conventional modes of therapy." In theory, a combination of flutamide and finasteride in patients with advanced prostate cancer should provide tumor control while maintaining serum testosterone levels. The finasteride should limit the availability of dihydrotestosterone at its receptor, thus augmenting the inhibitory effects of the flutamide. Laboratory data have shown that the combination of finasteride and flutamide in the rat ventral prostate model caused significant decreases in prostate size compared to either drug alone and equivalent suppression compared to luteinizing hormone-releasing hormone agonist plus flutamide.7 Is there evidence for an additive effect of the 2 drugs in humans? Two patients have had "drug holidays" from flutamide and finasteride, respectively (fig. 2). Interim PSA values increased during these holidays and decreased with the resumption of the withdrawn drug. This finding provides strong evidence that both agents are working and that this therapy is superior to monotherapy with flutamide or finasteride. One patient had what we considered a suboptimal response to therapy. The rate of PSA level decrease was less rapid than previously treated patients. Whether he would have ultimately reached the appropriate nadir or if the disease was intrinsically less sensitive to this therapy is unclear. Alternatively, he may have relatively hormone refractory disease (Gleason score 8),since it is too early to know when he will fail on standard androgen deprivation therapy. At the most recent measurement of serum PSA, there appeared to be a premature increase. Longer followup of this patient is necessary. Selecting the ideal patients for this form of therapy is challenging. We believe that patients with stages C (T3)and D1 (N+)cancer are the best candidates. The inherent biology of prostate cancer often affords these patients a long natural
30 T
2s 20
A I
0 4 Initial Y m f h l Umth
2
Umlh Ymth Ymlh Y m t h 4 6 8 10
Ymth 12
Ymth 14
Umth H n i h
16
18
TIME ON THERAPY
(months)
FIG. 2. Serial PSA values in 2 patients on drug holidays
history making quality of life issues important. The 10-year survival rates for both subsets ranged from 25 to 60%.12.'3 Therefore, they would have a relatively long disease-free survival. Another group of individuals in whom quality of life issues may be important are patients with biochemical failure following radical therapy. The lead time afforded by the measurement of PSA will undoubtedly result in therapy for a longer duration than previously recognized. Our results suggest that effective anticarcinogenic therapy is being delivered with minimal side effects. Tumor volume as measured by PSA decrease is substantially diminished. In addition, sexual function, libido and anemia appear to be spared. It is important to realize the limitations of this study. It was conducted on a highly select group of patients. These men were generally younger and more active than typical prostate cancer patients. Also, long-term data are still not available. The interval to disease relapse may be shorter in patients on this therapy compared to traditional forms of androgen deprivation therapy. CONCLUSIONS
Ultimately, a randomized trial of the combination of finasteride and flutamide (for patients with stages C and D1 cancer) compared to standard forms of androgen deprivation therapy is required to determine its efficacy. Outcome measures of this trial should include psychological testing, quality of life scales and survival. Until this is performed, finasteride and flutamide in combination should be reserved for the select patient who is relatively young and sexually active. REFERENCES
1. Dhom, G.: Epidemiologic aspects of latent and clinically manifest carcinoma of the prostate. J. Cancer Res. Clin. Oncol., 106 210, 1983. 2. American Cancer Society: Cancer Facts & Figures-1994. Atlanta: American Cancer Society, Inc., 1994. 3. Stamey, T. A. and McNeal, J. E.: Adenocarcinoma of the prostate. In: Campbell's Urology, 6th ed. Edited by P. C. Walsh, A. B. Retik, T. A. Stamey and E. D. Vaughan, J r . Philadelphia: W. B. Saunders Co., vol. 2, chapt. 29, pp. 1159-1221, 1992. 4. Fleshner, N. E. and Trachtenberg, J.: Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results. Eur. Urol., suppl. 2, 24: 106, 1993. 5. Karling, P., Hammar, M. and Varenhorst, E.: Prevalence and duration of hot flushes after surgical or medical castration in men with prostatic carcinoma. J. Urol., 1 5 2 1170, 1994. 6. Tyrrell, C. J., Altwein, J . E., Klippel, F., Varenhorst, E., Lunglmayr, G., Boccardo, F., Holdaway, I. M., Haefliger, J M. and Jordaan, J . P.: A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of ndvanced prostate cancer. The International Prostate Cancer Study Group. J. Urol., 1 4 6 1321, 1991. 7. Fleshner. N. and Trachtenherg, J.: Sequential androgen block-
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER OF PROSTATE
1645
ade: a biological study in the inhibition of prostatic growth. Inillion. It is time for the American Urologicd Association to estabJ. Urol., 148 1928,1992. 1ish guidelines for the use of hormonal therapy in prostate cancer. 8. Partin. A. W. and Oesterling, J. E.: The clinical usefulness of Patrick C. Walsh prostate specific antigen: update 1994. J. Urol., 162 1358, Department of Urology 1994. The Johns Hopkins Hospital 9.Sogani, P.C.,Vagaiwala, M. R. and Whitmore, W. F., Jr.: ExpeBaltimore, Maryland rience with flutamide in patients with advanced prostatic cancer without prior endocrine therapy. Cancer, 54: 744,1984. 1. Newling, D. W. W.: The use of flutamide as monotherapy in the 10. Grino. P.B..Griffin, J. E. and Wilson, J. D.: Testosterone at high treatment of advanced prostate cancer. In: Therapeutic concentrations interacts with human androgen receptor simiProgress in Urological Cancers. Edited by G. P. Murphy and S. larly to dihydrotestosterone. Endocrinology, 126: 1165,1990. Khoury. New York: Alan R. Liss, Inc., pp. 117-121, 1989. 2. Prout, G.R., Jr., Kliman, B., Daly, J. J., MacLaughlin, R. A. and 11. Presti, J. C., Jr., Fair, W. R., Andriole, G., Sogani, P. C., Griffin, P. P.: In vitro uptake of 3H testosterone and its conSeidmon, E. J.. Ferguson, D., Ng, J. and Gormley, G. J.: Mulversion to dihydrotestosterone by prostatic carcinoma and ticenter, randomized, double-blind, placebo controlled study to other tissues. J. Urol., 116 603, 1976. investigate the effect of finasteride (MK-906) on stage D pros3. Geller, J., Albert, J., Loza, D., Geller, S., Stoeltzing,W.and de la tate cancer. J. Urol., 148: 1201. 1992. Vega, D.: DHT concentrations in human prostate cancer tis12. Sayer, J., Ramirez, E. I. and von Eschenbach, A C.: Retrospecsue. J. Clin. Endow. Metab., 48:440,1978. tive review of prostate cancer patients with lymph node me4. Brooks, J. R., Berman, C., Nguyen, H.,Prahalada, S., F’rimka, tastases 11968-83).J. Urol.,part 2, 141: 45ZA,abstract 957, R. L., Rasmusson, G. H. and Slater,E. E.: Effect of castration, 1992. DES, flutamide, and the 5 alpha-redudase inhibitor, MK-906, 13.van den Ouden, D., Davidson, P. J. T., Hop, W. and Schrder, on the growth of the Dunning rat prostatic carcinoma, R-3327. F. H.: Radical prostatectomy as a monotherapy for locally Prostate, 1 8 215,1991. advanced (stage T3)prostate cancer. J. Urol., 161:646,1994. For nearly half a century, the mainstay of therapy for advanced EDITORIAL COMMENTS metastatic prostate cancer was either bilateral surgical orchiectomy or estrogen therapy. During the last 5 years, the accepted gold Bccause most men treated with hormonal therapy become impotent, standard of treatment and the definition of advanced prostate cancer it is highly desimble to identify a form of treatment that does not have have undergone metamorphosis. Regarding treatment, several large this side effect.There are 2 drugs that preserve sexual function in most clinical trials support the combination of either surgical orchiectomy men: flutamide and finasteride. The response to flutamide as mono- or a luteinizing hormone-releasing hormone agonist with the antitheriipy. however, has been shown to be inferior to diethylstilbestrol at androgen flutamide for the treatment of advanced prostate cancer. 1 rng. per day‘ and finasteride has only a muted effect when adminis- We have established that a substantial survival benefit is enjoyed by tered to men with advanced prostate cancer (reference 11 in article). In those who have minimal metastatic disease and who are trea-d with this study the authora have kated the influence of flutamide and combined androgen b1ockade.l The majority of patients diagnosed with prostate cancer before finiisteride in combination. reasoning that hasteride should lower tissue dihydrotestoatemne levels and thereby augment the ability of 1985 presented with advanced stage disease. The definition of advanced included bony metastases, or soft tissue, nodal or other organ flukimide to compete for receptor sites. 1 am disappointed by the study design selected by the authors. It involvement. However, I believe that the concept of advanced cancer is hard to imagine why they did not have a control group or did must be modified because by definition advanced is synonymous not administer the drugs sequentially. Thus, it is impossible to with incurable to patients and clinicians. Therefore, the concept of tell whether the combination of agents is synergistic or additive, or advanced cancer in 1995is not only stage D2 (M1) but also stages DO, whether there is no effect. The anecdotal information provided in 1 DUN+) or C(T3). or an increasing PSA level after radical prostatecpatient who stopped finasteride suggests that the influence was tomy or other definitive local therapy.’ Most patients presenting with a high initial Gleason score (9or 10)can be considered to have minimal. Thus, I conclude that this is basically a negative study. advanced disease. All of these stages and/or pathological findingsare The authors suggest that a randomized trial should be done with frequently the harbingers of progression and death. appropriate controls. Again, I wonder why they did not take their own The authors review a novel new therapy for advanced stage T3 advice and do this initially. Nonetheless, I believe that such a trial and/or N+ disease. The mean PSA level was 42.9 ngJml.. generally would be futile. When patients with stage C or Dl prustate cancer are reflective of a reasonably significant tumor burden. The initial dose treated with effective hormonal therapy (a luteinizing hormone-releas- of flutamide chosen was 375 mg. a day. It appears that this dosage ing hormone agonist or castration1, PSA levels are usually suppressed was not able to decrease the PSA level consistently to less than 4 to the undetectable range. Clearly, the combination of agents did not ngJm1. by 8 weeks and, therefore, a dose of 750 mg. was chosen for exhibit a similar effect in this study. Indeed, serum PSA levels were the remainder of the clinical trial. All patients then experienced a maintained at an average of 3 nglml. Although finasteride may be substantial decrease in PSA level. However, the nadir does not synergistic with flutamide when tested in the rat model (reference 7 in approach the level of less than 0.1 or even 0.2 that would be expected article), this does not appear to be the ease in human pmstate cancer. with such disease treated with a luteinizing hormone-releasing horThere am several reasons why one might anticipate that a Ba-reductase mone agonist and an antiandrogen. In 34 patients with clinical stage inhibitor, such as fiwteride, would not be active in cancer: 1) 5 ~ -T3 disease whose initial PSA level was 37.4 nglml. 4 months of d u c t a s e activity is low in prostate cancers? 2) dihydrotestosterone flutamide and a luteinizing hormone-releasing hormone agonist remncentrations in human p m t a t e cancer are low? and 3)finasteride is sulted in a 98% decrease in the PSA level.* In fact, PSA may not be ineffectivewhen administered to the hormone sensitive Dunning rat the best barometer to measure true response to agents such as finasteride with flutamide. This sort of hormonal manipulation Pmstate cancer carcinoma R3327.‘ These observations coupled with the findings in this study suggest results in increased levels of testosterone, not a decrease to castrthat finasteride adds little or nothing to the effect of flutamide, ate levels as occurs with the standard forms of castration. The increased levels may stimulate PSA pruduction. and that either drug singly or in combination does not achieve the The patients in this clinical trial all appeared to have a durable degree of androgen deprivation provided by castration or treatment response during the short-term followup. One patient who did not with a luteinizing hormone-releasing hormone agonist. initially respond as predicted had a significant second response with Finally, 1 am disturbed by the suggestion that these drugs should more typical surgical castration. be !4km to patients with elevated PSA levels following radical prosThe clinical importance of this trial is that it offers a novel treatbtrctomy or men with low volume advanced prostate cancer. There ment for the increasing number of patients who now have not only is no evidence that early hormonal therapy prolongs life. Men die of stage T3 or node positive disease but also increasing PSA levels after the androgen insensitive cell population that is unaffected by hor- radical radiation therapy or prostatectomy. While the only abnormonal therapy. The only ones who will benefit from these sugges- mality in the latter patients is increasing PSA, they are subjectively tions are the pharmaceutical companies who are currently fanning symptomatic. Patients become focused on the PSA values and desire the flames of escalating health care costs. Last year, the Medicare “treatment” of this abnormal laboratory value. They become i n m a s chanees in the PSA level and doubline ...~.,RWRW - -..o .f . incremental ... bill for luteinizing hormone-releasing hormone agonists was 832CI in& ”
1
1646
COMBINATION FINASTERIDE AND FLUTAMIDE IN ADVANCED CANCER O F PROSTATE
times, and recognize that the disease is progressing even though efficacy are demonstrated does i t then become appropriate to perthey are asymptomatic. My experience has been that these patients form a phase 3 study. In addition, the known inferiority of monogladly accept a luteinizing hormone-releasing hormone agonist and therapy finasteride or flutamide coupled with our laboratory data antiandrogen, only to start expressing concern after approximately 6 (reference 7 in article),which revealed a n additive effect of the drug to 9 months of therapy. They find the weight gain, hot flashes, cost combination, led us to conclude that it would be inappropriate to and inconvenience of monthly injections challenging, and frequently treat patients with sequential monotherapy. Furthermore, an instop the treatments. crease in PSA secondary to temporary finasteride withdrawal in 1 This combination of finasteride and flutamide may address many patient treated with this regimen lends credence to the fact that of these concerns, while delivering effective androgen ablation. We there is to some degree an additive effect of this combination (unhave now treated 27 patients with increasing PSA levels after rad- published data). However, flutamide provides the major antiandroical prostatectomy or radiation therapy with a similar regimen, genic effect. using 5 mg. finasteride plus 125 mg. flutamide twice daily. We have Although we agree that mean nadir PSA values are minimally seen similar results with decreased PSA to undetectable levels in 25 higher than with standard therapy, it is important to realize that 4 of the 27 patients. I t should be emphasized that the regimen pro- of the 15 evaluable patients had undetectable levels at 24 months. In posed by the authors or the one that we have used would likely be addition, nadir levels are well within the range that predicts good ineffective in cases of advanced prostate cancer. This study estabresponse to androgen deprivation therapy.' Nevertheless, we believe lishes the necessity of a randomized trial with interval t o progression and survival as an end point before we can conclude that this is a n that patients with long disease duration (patients with T3, nodeappropriate way to treat advanced prostate cancer. A number of positive and post-radical therapy recurrent disease) may be willing other treatment options that do not use standard castration include to sacrifice minimally less optimal therapy for improved overall single agent flutamide, bicalutamide and intermittent hormonal ab- quality of life. Surgical or medical castration can perhaps salvage lation. It is hoped that proper randomized trials will be conducted to these patients when disease progresses. We agree with Walsh that there is no proof that early hormonal address the effect on patient survival and quality of life. therapy prolongs survival but, to our knowledge, no adequately E. David Crawford powered study addressing this issue has ever been performed. FurDicrision of Urology thermore, we concur with Crawford that many patients in whom Department of Urology Uniuersity of Colorado Health Sciences Center radical treatment fails become obsessed with PSA levels and desire therapy. Therefore, these patients may be placed on total androgen Denver, Colorado blockade for long periods. However, there are concerns about longterm castrate levels of testosterone, including sexual dysfunction, 1. Crawford, E. D.: Changing concepts in the management of ad- muscle wasting, psychosocial disturbances, hot flashes and osteopovanced prostate cancer. Urology, suppl., 44:67, 1994. rosis. Finasteride and flutamide in combination may provide the 2. Pummer, K., Crawford, E. D., Daneshgari, F., Andros, B., correct balance between effective therapy and improved quality of Pfister, S.and Miller, G. J.: Hormone pretreatment does not life. This therapy is also less expensive than luteinizing hormoneaffect the final pathologic stage in locally advanced prostate releasing hormone analogues plus flutamide. Clearly a randomized cancer. Urology, suppl., 44: 38, 1994. study with time to progression, survival and overall quality of life are needed to define better the appropriate, if any, uses of this novel drug REPLY BY AUTHORS combination. 1. Cooper, E. H., Armitage, T. G., Robinson, M. R., Newling, D. W., While we welcome the comments of Walsh. we respectfully disRichards, B. R., Smith, P. H., Denis, L. and Sylvester, R.: aeree with some of his criticisms of our study. The reason for not Prostate specific antigen and prediction of prognosis in metacommencing a controlled study is because of the need for phase l and 2 testing of any new drug or drug combination. Only after safety and static prostatic cancer. Cancer, suppl., 66: 1025, 1990.