|Year : 2001 | Volume
| Issue : 1 | Page : 49-51
Combination of finasteride and flutamide as potency-sparing hormone ablation therapy in management of advanced carcinoma of prostate
NK Mohanty, RP Arora, AK Jha, Sujeet Kumar
Department of Urology Safdarjang Hospital, New Delhi, India
N K Mohanty
D-II/87, West Kidwai Nagar, New Delhi - 110 023.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Complete androgen blockade by LHRH agonist /Orchiectomy plus antiandrogen results in androgen deficiency amongst males (ADAM). We treated advanced cancer prostate with finasteride and flutamide with an aim of potency sparing in relatively younger males with the disease.
45 sexually active males between the age of 48 to 65 having advanced cancer of prostate were treated, for 1 year with Flutamide (750mg) and Finasteride (5mg) daily and followed up for 18 months. Results showed 89% having low PSA and 80% maintained their sexual potency. Side effects were mild: 20% of patients developing diarrhoea, gynaecomastia and hot flushes with good drug compliance.
This combination is ideal as potency sparing androgen ablation therapy for advanced cancer of prostate among young & sexually active males.
Keywords: α-Reductase Inhibitor, Potency: Hormone: Flutamide; Finasteride.
|How to cite this article:|
Mohanty N K, Arora R P, Jha A K, Kumar S. Combination of finasteride and flutamide as potency-sparing hormone ablation therapy in management of advanced carcinoma of prostate. Indian J Urol 2001;18:49-51
|How to cite this URL:|
Mohanty N K, Arora R P, Jha A K, Kumar S. Combination of finasteride and flutamide as potency-sparing hormone ablation therapy in management of advanced carcinoma of prostate. Indian J Urol [serial online] 2001 [cited 2022 May 26];18:49-51. Available from: https://www.indianjurol.com/text.asp?2001/18/1/49/37417
| Introduction|| |
Prostate malignancy is the most common malignancy among males , and second leading cause of cancer deaths among elderly men. At the time of presentation, nearly 2/311 of these patients have extraprostatic spread. Total hormone ablative therapy though remains the mainstay in the treatment of advanced stage but it is not without its complications, particularly among sexually active patients. Recent thought has been directed towards limiting the side effects of such androgen ablation therapy. The main side effects of total androgen ablation are low serum testosterone level which includes loss of sexual libido. sexual impotency, psychological impairment, anaemia, muscle wasting, osteoporosis and andropause. In order to minimise these side effects of androgen deficiency among these aged males (ADAM), maximise quality of life and simultaneously provide androgen ablative therapy among these patients, the possibility of selectively blocking effect of Dihydrosterone (DHT) is thought of. Animal studies have shown that a combination of antiandrogen and 5α-reductase inhibitor in rats suppresses their ventral prostate equivalently to that of the combination of LHRH agonist/Orchiectomy plus an antiandrogen. The addition of Finasteride to Flutamide monotherapy has the theoretical advantage of proving more complete intraprostatic androgen blockade while preserving serum testosterone level. Since this combination does not lower serum testosterone levels it should be possible to treat advanced prostate cancer effectively with minimum side effects, particularly in sexually active young males suffering from advanced malignancy of prostate.
| Materials and Methods|| |
A total number of 45 patients between age group of 48 to 65 years (mean age 58 years) having advanced prostate malignancy (stage C, DI & DII) were included in this study. All these men were sexually active in their lie. A baseline estimation of serum PSA, DHT, Total Testosterone, LFT, LH, Renal function and complete haemogram count was done. Radiological investigations like X-ray chest, ultrasound of prostate, skeletal surgery, isotope bone scan and CT abdomen was performed to accurately stage the disease. All the patients had histological evidence of prostate malignancy with tumor grade and gleason score.
After obtaining the consent, all these patients were administered Flutamide (Drogenil) 250 mg thrice a day orally for one week. The serum PSA estimation was then done which showed a mean fall in its value. Thereafter Finasteride (Fincar) 5mg orally daily was added to Flutamide therapy and the combination was continued for one year.
All these patients were followedup every third month during one year of therapy and thereafter every 6 months for the next 18 months. During the follow-up estimation of serum PSA, serum testosterone, DHT, X-ray chest was done apart from detailed PR exam and detailed history of their sexual activity was recorded. Any side effects noted were recorded. At the end of one year of therapy and thereafter isotope bone scan, skeletal survey and CT abdomen was done annually.
| Result|| |
Estimation of serum PSA was the best parameter available for measuring the disease status and response to their therapy. The normal range of PSA (total) in our laboratory is 0-4ng/ml.
The initial mean PSA level was 58.2ng/ml (ranging from 10 to 128ng/ml). At the end of 3" month of therapy, the mean PSA fell to 4.8ng/ml and at the end of 12'" month the mean PSA was 2.8ng/ml. During the 18 months' follow-up period the low PSA values remained unaltered in the responders only (89%). .
Serum Testosterone. The initial serum testosterone was 6.5n-/ml (normal 3-10ng/ml) and the level remained in the higher range 10-20ng/ml at the end of 3th and 12th month estimation. Routine serum testosterone level was estimated following one year of therapy which remained well above normal, during follow-up.
DHT. The initial baseline DHT was 3±2µg/ml (normal 1.0-4.2µg/m1) but at the end of 31" month of therapy it fell by 48% from baseline and remained there till the end of therapy.; At the end of 18 months' follow-up DHT was lower than baseline among the responders (89%).
Sexual Activity. All men were sexually active before the therapy and remained so till the end of the therapy. At the end of 18 months' follow-up after therapy 35 patients (80%) maintained their sexual potency while the remaining 9 patients (20%) observed either diminished libido or had lost their sexual desire, though most of them gave a history of having morning erections.
Though majority of these patients enjoyed their sex life most of them noticed decrease in the volume of ejaculate.
Side Effects. The blood counts, the renal and hepatic functions remained unchanged throughout the therapy & follow-up. Side effects in the form of diarrhoea was noticed in 12 patients (27%), gynaecomastia 9 patients (20%), hot flushes in 10 patients (22%) but none of these patients discontinued the drug therapy because of these side effects.
Prostate Size. The mean decrease in prostate size was observed in 66% of patients at the end of the therapy & 38% at the end of 18 months' follow-up.
Failure to Respond. All 45 patients responded very well to the therapy till the end showing good compliance, sexual potency, decreased serum PSA, DHT, increased serum testosterone. At the end of 18 months' follow-up, 5 patients (11 %) showed a rise in their serum PSA. These 5 patients in all probability had developed hormone resistance and were hence termed as non responders.
| Discussion|| |
Though the benefits from total hormone ablation therapy in term of palliation is unquestionable in advanced stage of prostate malignancy but it is not without side effect of ADAM.,
Because most men treated with CAD become impotent, it is highly desirable to identify a form of therapy that does not have this side effect as monotherapy with Flutamide is inferior to surgical castration., Addition of Finasteride to antiandrogen monotherapy has the theoretical advantage of providing more complete intraprostatic blockade while preserving serum testosterone level.
The use of a combination of an antiandrogen alongwith 5α-reductase inhibitor does not result in these side effects of ADAM, since this combination maintains normal or high serum testosterone level. Flutamide, a non-steroidal antiandrogen has shown itself as a single agent to be very effective in management of advanced carcinoma prostate but it alone is not a sufficient androgen blockade because it causes reflex increase in LH and testosterone levels and furthermore invitro data suggests that testosterone itself at high concentration can interact with DHT receptors. Hence there is a need to add Finasteride, 5α-reductase inhibitor which selectively decreases DHT level without reducing testosterone level.
Human prostate cancer can synthesise 15% to 40% of its available DHT from circulating adrenal androgenic precursors. Finasteride monotherapy can reduce intraprostatic DHT,, as well as induce regression of normal human prostatic epithelium, furthermore it also has been shown to delay local and distant recurrences after radical prostatectomy.
Recent studies have shown that there is an additive effect of these two drugs when used in combination because withdrawal of one drug from the combination showed increase in PSA level and PSA level decreased with the resumption of the withdrawn drug. This only suggests that both the agents act in an additive fashion and their therapy is superior to monotherapy with either of the drugs. Finasteride limits the availability of DHT at its receptor, thus augmenting the inhibitory effects of Flutamide. It was observed that PSA level fell approximately 80% of baseline with Flutamide alone but with addition of Finasteride it further fell by another 10% below the baseline value which was significant. Similar combination in patients having raised PSA after radical prostatectomy have shown decrease in PSA level proving the efficacy of this regime.
Selection for such kind of therapy is challenging and best suited for patients of younger age group or patients enjoying active sex life but having advanced disease. The majority of the patients (36-80%) enjoyed their sex life having erection sufficient for sexual intercourse and retained their potency in our study. Our results are similar to those of Fleshner & Trachtenberg.
Our study has shown that a combination of Flutamide and Finasteride therapy for stage C & D disease are very beneficial as the side effects of ADAM is minimal, sexual potency is retained, serum PSA & DHT levels decreases resulting in longer survival period. It is important to realise the limitation of this study as it was conducted in highly selective group of young patients having active sex life and longer survival age period.
| Conclusion|| |
We conclude that a combination of Flutamide and Finasteride is the ideal drug therapy for potency sparing androgen ablation in advanced carcinoma prostate particularly for younger sexually active patients. A long term follow-up and data is still required to establish this therapy in future.
| References|| |
|1.||Dhom G. Epidemiologic aspects of latent and clinically manifest carcinoma of the prostate. J Cancer Res Clin Oncol 1983; 106: 210. |
|2.||Parker SL. Lang T, Bolden S. Cancer Statistics 1997. Cancer J Clin 1997; 47: 5-27. |
|3.||American Cancer Society Facts & Figures 1994, Atlanta. American Cancer Society Inc 1994. |
|4.||Stamey TA, McNeal JE. Adenocarcinoma of the prostate. In: Campbell's Urology. 6" ed PC Walsh ed. 1992: 1159-1221. |
|5.||Tyrrell CJ. Altwein JE, Klippel F et al. A multicenter randomised trial comparing the LHRH analogue goserelin acetate alone with flutamide in the treatment of advanced prostate cancer. I J Urol 1991; 146: 1321-1326. |
|6.||Fleshner NE. Trachtenberg J. Sequential androgen blockade: a biological study in the inhibition of prostatic growth. J Urol 1992: 148: 1928-1931. |
|7.||Partin AW. Osterling JE. The clinical usefulness of prostate specific antigen: Update 1994. J Urol 1994: 152: 1358-1368. |
|8.||Fleshner NE, Trachtenberg J. Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results. Eur Urol 1993: 24 (Suppl. 2): 106-112. |
|9.||Karling P. Hammar M, Varenhorst E. Prevalence and duration of hot flushes after surgical and medical castration in men with prostatic carcinoma. J Urol 1994; 152: 1170-1173. |
|10.||Sogani PC. Whitmore WF Jr. Experience with flutamide in patients with advanced prostate cancer without prior endocrine therapy. Cancer 1984; 54: 744. |
|11.||Grino PB. Griffix JE. Wilson JD. Treatment at high concentration intervals with human androgen receptor similar to dihydrotestosterone . Endocrinology 1995: 126: 1105. |
|12.||Geller J, Albert JD. Nachtsheim DA. Loza D. Comparison of prostatic cancer tissue dihydrotestosterone levels at the time of relapse following orchiectomy or estrogen therapy. J Urol 1984; 132: 693-696. |
|13.||Geller J. Effects of finasteride. 5a-reductase inhibitor on prostate tissue androgen & prostate specific antigen. J Clin Endocrinol Metab 1990; 71: 1552-1559. |
|14.||McConnell JD. Wilson JD, George FW. Finasteride - an inhibitor of 5a-reductase suppresses prostatic dihydrotestosterone in men with BPH. J Clin Endocrinol Metab 1992: 74: 505-508. |
|15.||Rittmash RS, Norman RW et al. Evidence for atrophy and apoptosis with prostate of men given finasteride. J Clin Endocrinol Metab 1996; 81: 814-819. |
|16.||Andriole G. Lieber M. Smith J et al. Treatment with finasteride following radical prostatectomy for prostate cancer. Urology 1995: 45: 491-497. |
|17.||Crawford ED. Changing concepts in the management of advanced prostate cancer. Urol (Symposium) 1994: 44 (6A): 67-74. |
|18.||Fleshner NE. Trachtenberg J. Combination finasteride and flutamide in advanced carcinoma of the prostate: effective therapy with minimal side effects. J Urol 1995; 154: 1642-1646. |