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ORIGINAL ARTICLE
Year : 2001  |  Volume : 18  |  Issue : 1  |  Page : 52-56
 

Orchiectomy versus combined androgen blockade in the management of advanced carcinoma prostate


Department of Urology, All India Institute of Medical Sciences, New Delhi., India

Correspondence Address:
N P Gupta
Department of Urology, All India Institute of Medical Sciences, New Delhi 110029
India
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Source of Support: None, Conflict of Interest: None


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Keywords: Orchiectomy; Combined Androgen Blockade; Advanced Carcinoma Prostate


How to cite this article:
Ansari M S, Gupta N P, Hemal A K, Dogra P N, Seth A. Orchiectomy versus combined androgen blockade in the management of advanced carcinoma prostate. Indian J Urol 2001;18:52-6

How to cite this URL:
Ansari M S, Gupta N P, Hemal A K, Dogra P N, Seth A. Orchiectomy versus combined androgen blockade in the management of advanced carcinoma prostate. Indian J Urol [serial online] 2001 [cited 2020 May 27];18:52-6. Available from: http://www.indianjurol.com/text.asp?2001/18/1/52/37418



   Introduction Top


Since Labrie et al[1],[2],[3] reported excellent results with CAB in non randomized studies, during the last few years the interest regarding endocrine therapy for prostate cancer has been directed at complete androgen blockade (CAB). The impressive results shown by Labrie et al exalted many urologists to use maximum androgen blockade by using additional antiandrogens to block the adrenal derived circulating androgens. But others never achieved the excellent results obtained by Labrie and the results in subsequent studies have been conflicting making CAB a vexing question. We studied the efficacy of orchiectomy alone vis-a-vis orchiectomy plus flutamide in the management of advanced carcinoma prostate.


   Objective Top


To compare the efficacy of orchiectomy alone and orchiectomy plus flutamide in treating patients with advanced carcinoma prostate.


   Materials and Methods Top


The study was initiated on 1st June, 1997 and enrolled 80 patients till 30th June, 2000. The patient characteristics are given in [Table - 1]. The inclusion criteria were histologically documented carcinoma prostate along with distant metastasis (stage D2). Patients were randomly stratified into two groups. Group I had patients treated with orchiectomy alone and Group II those treated with orchiectomy plus flutamide. Patients with other kinds of hormonal therapies like stilbesterol, honvan or ketoconazole and treatment with cytotoxics or radiotherapy were excluded from the study. Baseline PSA estimation was done in all cases before initiation of either kind of therapy. Bone scan was done in each case. After orchiectomy in both the groups first PSA estimation was obtained at first month and three monthly thereafter. The evaluation of efficacy was based primarily on findings of bone scan and the serum PSA value on followup. A complete response (CR) was defined as normalization of bone scan and serum PSA returning to normal (< 4ng/ ml). A partial response (PR) was defined as ≥50% reduction in metastasis mass as compared to the initial study or decrease in PSA level ≥50% of initial value. Progressive disease (PD) was defined as development of any new hot spot on bone scan or any increase in previously existing PSA by 25%. Percentage change in PSA value was also calculated each time as compared to the pretreatment value in both the groups in order to compare the efficacy of the two treatment arms. Statistical analysis was done by number of variables, Kruskal-Wallis tests and overall survival was calculated using Kaplan-Meier curves. A p-value of < 0.05 was considered as statistically significant.


   Results Top


A total of eighty patients were entered in the study. The characteristics of the patients is shown on [Table - 1]. The maximum percentage change in PSA was found in the first three months after orchiectomy. The mean percentage change at three years, in two groups was 70% and 75% respectively [Table - 2]. It was not statistically significant (p-value=0.95). Based on the evaluation of response as defined in the protocol, there was no significant difference in response rate between the two treatment groups [Table - 3]. The overall response rate (CR+PR) was 94.74% and 92.85% in two Groups respectively. There was no statistical difference in two groups (p-value>0.05). The overall survival measured by Kaplan-Meier method is shown in the [Figure]. The overall survival at three years, in two treatment groups was 44.74% and 47.61 % respectively. There was no significant difference in two groups (p-value>0.05). It is evident that additional flutamide therapy did not significantly improve the outcome of patients undergoing bilateral orchiectomy for metastatic carcinoma of the prostate. The usual side effects noted with flutamide were transient nausea, vomiting and diarrhea, which were managed easily.


   Discussion Top


Prostate gland is androgen dependent and controlled by circulating testosterone, which is synthesized and secreted from the testes upto 90-95%. Removal of trophic androgen by medical or surgical castration has been the standard therapy for prostate carcinoma for more than fifty years. In the normal prostate. androgen ablation induces within days profound morphological changes including apoptotic cell death[4] and the initial positive effect of castration therapy in prostate cancer is attributed to apoptotic depletion of androgen dependent tumor cells[5] Prostate tumor may respond in a variety of ways to castration therapy including apoptosis and decrease in cell proliferation. The androgens, specially those formed in the adrenal cortex, are thought to be very important when there are low levels of circulating testosterone, there is still a continuous stimulation of the prostate. whose receptors are `hungry' for androgen.[6] Orchiectomy over the decade has been the most effective tool for lowering the circulating testosterone. The procedure provides symptomatic relief for up to 70-80% of patients.[7],[8] The endocrine response of carcinoma prostate (CAP) depends upon the presence of an drogen sensitive cells. The incidence of primary androgen independent prostate carcinoma is approximately 20%.[9] It has been postulated that inactivation of oncogenes like P53 and expression of Bcl-2 can block the process of apoptosis.[12] There is no definitive way to predict which patient will respond to orchiectomy. Some experimental studies have suggested that study of apoptosis related oncoproteins like P53. Bcl-2 and C-myc might help in predicting which patient will respond to castration and which will not.[13],[14]

PSA has been used as the clinical marker to monitor the disease both in surgical as well as nonsurgical mode of treatments. In a study including rat models there was an approximately 11-19-fold increase in the apoptosis index at 3 days and 5-8-fold increase at 7 days after castration. In another study on human prostates, a 7-fold increase in apoptosis in normal human prostatic tissue at 7 days after castration. It is therefore likely that a major castration induced changes in apoptosis index in human prostate tumors would be detected at this time.[12] In the present study, we recorded the changes in PSA level after orchiectomy and it was evident that maximum percentage changes in PSA is seen in the first three months after orchiectomy. This can be explained to some extent by the degree of apoptosis, which is maximum within the initial 7 days as well as the dc.7ree of inhibition of cell proliferation.[12] PSA has got a prognostic importance in endocrine therapy in carcinoma prostate. The multinational nilutamide study and INT-0105 study provided interesting observations about the PSA changes in endocrine therapy of carcinoma prostate. In the former trial after three months of treatment serum PSA level normalized in 121 patients in both arms, which predicted a longer survival time and time to progression. The percent of patients with serum PSA less than 4ng/ml at three months was significantly higher in complete androgen blockade group. Whilst, in INT-0105 there was a difference in PSA normalization between complete androgen blockade and monotherapy (74% versus 61%). In the present study there was no statistical difference in percentage change in PSA in both the treatment groups.

Labrie et al reported a 96% response rate and long term survival in advanced carcinoma prostate[1]. But similar excellent results were never achieved in the hands of others. Several randomized studies in the early nineties demonstrated better results with combined androgen blockade.[15],[16] A multicentre study in United States (National Cancer Institute 036), compared LHRH agonist plus flutamide with a LHRH agonist and a placebo control and found that results of combined androgen blockade were better than LHRH agonist alone. The results were more evident in patients with low volume disease.[17] Till date combined androgen blockade in metastatic carcinoma prostate remains controversial. Studies done before the nineties showed minor to major advantages of CAB over orchiectomy. Further with the time, more controlled studies failed to show any substantial advantage of CAB over orchiectomy alone. In the mid nineties the concept of CAB further contracted as a few studies showed that it is only effective in patients with good performance status and a low volume disease.[18],[19] The CAB further suffered a blow when the EORTC phase three prospective trial comparing orchiectomy to orchiectomy plus cyproterone acetate and diethyl stillbestrol (DES), it was shown that there was no difference in progression and survival in all three arms.[19] In an open, multicenter, randomized study it was concluded that both short term or continuous addition of cyproterone acetate to buserline. a LHRH agonist did not improve treatment results compared to orchiectomy only,[20] Another multicentre, randomized trial comparing zoladex with zoladex plus flutamide in advanced carcinoma prostate showed no statistical differences in objective response between the two groups, 67% in zoladex group and 65% in combination group. Also there was no difference in time to treatment failure and time to progression between the two treatment groups.[21] In a recent study the Agency for Health Care Policy and Research published the results of a comprehensive meta-analysis based on all 27 published complete androgen blockade studies. The meta-analysis detected no difference in 2-year survival rates. Only 10 of the 27 studies reported 5-year survival figures, and reported only minimal survival differences in favour of combined androgen blokade.22 In a most recent review based on 27 clinical trials using various combinations of androgen deprivation data does not support routine use of antiandrogens in combination with medical or surgical castration as first line hormonal therapy in patients with metastatic prostatic carcinoma. It was also evident that quality of life-benefit resulting from orchiectomy in patients with metastatic prostate carcinoma appeared to be offset by the addition of flutamide, primarily because of an increased incidence of adverse effects.[23]


   Conclusion Top


In endocrine therapy of advanced carcinoma prostate maximum percentage change (decrease) in serum PSA is seen in first three months after orchiectomy. Addition of antiandrogen like flutamide to orchiectomy has not given any significant benefit to effect the PSA changes as well the survival in advanced carcinoma prostate. Hence, routine use of additional antiadrogen to orchiectomy is not advisable. In India, most of the patients present in advanced stage of carcinoma prostate. Large randomized trials comparing the efficacy of orchiectomy alone and CAB are urgently warranted to guide the clinician in planning the appropriate treatment in order to save both money as well as guard the patient against the unwanted effects of the antiandrogens.

 
   References Top

1.Labrie F. Dupont A. Raynaud JP et al. New hormonal therapy in prostate cancer: combined use of pure anti-androgen and an LHRH agonist. Horm Res 1983: 18: 18-27.  Back to cited text no. 1    
2.Labrie F, Dupont A. Raynaud JP, Husson JM et al. New approaches in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate 1983: 4: 579-594.  Back to cited text no. 2    
3.Labrie F. Dupont A. Cusan L. Combination therapy with flutamide and medical (LHRH agonist) or surgical castration in advanced prostate cancer: 7-year clinical experience. J Steroid Biochem Mot 1990: 37: 943-950.  Back to cited text no. 3    
4.Kerr JFR, Searle JW. Deletion of cells by apoptosis during castration induced involution of the rat prostate. Vichows Arch Cell Pathol 1973: 13: 87-102  Back to cited text no. 4    
5.Issac JT, Lundmo Pj. Berges R et al. Androgen regulation of programmed death of normal and malignant prostatic cells. J Androl 1992: 13: 457-464.  Back to cited text no. 5    
6.Davis P et al. Correlation between prostate chromatin structure and transcriptional activity and acceptor site distribution. Prostate 1986: 8: 151-166.  Back to cited text no. 6    
7.Huggins C et al. Studies on prostate cancer. The effect of castration on advanced cancer of the prostate gland. Arch Surg 1941: 43: 209-223.  Back to cited text no. 7    
8.Huggins C et al. Studies on prostate cancer. The effect of castration, of estrogen and of androgen injection on serum phosphates in metastatic cancer of the prostate. Cancer Res 1941: 1: 293-297.  Back to cited text no. 8    
9.Resnick WB. Grayhack JT. Treatment of stage IV carcinoma prostate. Urol Clin North Am 1975: 2: 141-161.  Back to cited text no. 9    
10.Westin P, Statin P. Damber JE, Berg A. Castration therapy rapidly induces apoptosis in a minority and decreases cell proliferation in a majority of human prostatic tumors. Am J Path 1995: 146: 1368-1375.  Back to cited text no. 10    
11.Westin P, Bergh A, Damber JE. Castration rapidly results in a major reduction in epithelial cell tumors in the rat prostate but not in the highly differentiated dunning R-3327 PAP prostate adenocarcinoma. Prostate 1993; 22: 65-74.  Back to cited text no. 11    
12.Wijsman J H. Jonker RR, Keizer vande De, Velde CJH et al. A new method to detect apoptosis in paraffin sections: In Situ end-labelling of fragmented DNA. J Histochem Cytochem 1993; 41: 7-12.  Back to cited text no. 12    
13.Miyashita T. Krajewsky S, Krajewski M, Wang HG, Reed JC. Tumor suppressor p 53 is a regulator of Bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994; 1799-1805.  Back to cited text no. 13    
14.Evan GI, Wyllie AH, Gilbert CS. Induction of apoptosis in fibroblast by c-myc protein cell. 1992; 63: 119-125.  Back to cited text no. 14    
15.Keuppens FP, Whelan JL, Carcinoma de Moura, Denis L et al. Orchiectomy versus Goserline plus Flutamide in patients with metastatic prostatic cancer (ORTC 30853). Cancer (Suppl.) 1993; 72: 3863.  Back to cited text no. 15    
16.Keuppens F, Denis L, Smith PH et al. Zoladex R and Flutamide versus bilateral orchiectomy: a randomized phase III Vial EORTC 30853 study. Cancer 1990; 66: 1045-1057.  Back to cited text no. 16    
17.Crawford ED, Eisenberger M, McLeod DG et al. A controlled trial of leuprolide with and without flutamide in prostate carcinoma. N Engl J Med 1989; 321: 419-424.  Back to cited text no. 17    
18.Janknegt RA. Total androgen blockade with the use of orchiectomy and nilutamide (Andron) or placebo as treatment of metastatic prostate cancer. Cancer (Suppl.) 1993; 72: 3874.  Back to cited text no. 18    
19.Robinson MRG. A further analysis of European Organisation for research and treatment of cancer protocol 30805. Cancer (Suppl.) 1993; 72:3855.  Back to cited text no. 19    
20.Klijn JGM, De Voogt HJ, Studer UE, De Pauw M. Short-term versus long-term addition of cyproterone acetate to buserline therapy in comparison with orchiectomy in the treatment of metastatic prostate cancer. Cancer (Suppl.) 1993; 72: 3858.  Back to cited text no. 20    
21.Tyrrell CJ, Atwein JE, Klippel F, Sotarauta M et al. Multicenter randomized trial comparing zoladex with treatment of advanced prostate cancer. Cancer (Suppl.) 1993; 72: 3878.  Back to cited text no. 21    
22.Maximum androgen blockade in advanced prostate cancer: An overview of 22 randomized trials with 3283 deaths in 5710 patients. Prostate Cancer Trialist's collaborative group. Lancet 1995; 346: 265.  Back to cited text no. 22    
23.Laufer M, Denmeade Sr, Eisenberger MA et al. Complete androgen blockade for prostate cancer: What went wrong? J Urol 2000; 164: 3-9.  Back to cited text no. 23    


    Figures

  [Figure - 1]
 
 
    Tables

  [Table - 1], [Table - 2], [Table - 3]



 

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    Introduction
    Materials and Me...
    Objective
    Results
    Discussion
    Conclusion
    References
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