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Year : 2003  |  Volume : 19  |  Issue : 2  |  Page : 135-139

Early report of randomized double blind clinical trial of hormonal therapy of carcinoma of prostate (CAP) stage D2

Department of Uro-Oncology, Tata Memorial Hospital, Mumbai, India

Correspondence Address:
Jagdeesh N Kulkarni
Department of Uro-Oncology, Tata Memorial Hospital, Parel, Mumbai - 400 012
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Source of Support: None, Conflict of Interest: None

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Objectives: We herein report our experience of double blind randomized clinical trial comparing combined an­drogen blockade vs monotherapy in stage D2 CaP.
Patients and Methods: Through June 1999 and May 2001, 100 patients of stage D2 CaP were randomized into placebo (44) and flutamide (42) group after orchiectomy in double blind fashion using the strictest criteria. All men and histological proof of CaP with bone metastasis dem­onstrated on imaging: bone scan and skeletal survey. These patients were further substratified according to number o f bony metastases into high volume disease (HVD>5 sites) and low volume disease (LVD<5 sites). The follow-up was at 3 month intervals. Criteria for decoding were clinical or serological progression and serious adverse effects.
Results: Of the 100 patients recruited in the trial, 48 had HVD and 52 LVD. Treatmentwise they were almost equally distributed in flutamide group and placebo group. In the follow-up ranging front 6 to 24 months, 30 out of 100 patients (30%) required decoding, reasons for decod­ing were progression of disease in 25 and serious adverse effects in remaining 5. These 25 patients were further analyzed according to treatment group, volume of metas­tasis pre -orchiectomy PSA and Gleason score. We observed that number of bony metastases had impact over the dura­tion of response to hormonal therapy.
Discussion: We initiated this simple trial to address the issue of benefit of total androgen blockade over monotherapy in Indian population. In the initial analysis, we observed that treatment group did not make any impact over the response. While subset of prostate cancer with large number of bony metastases has higher propensity to convert into hormone refractory cancer
Conclusions: Addition of flutamide did not provide ben­efit. We observed that large number of bony metastases had poor response to hormonal therapy, hence it requires large trial to substantiate this initial observation.

Keywords: Advanced carcinoma of prostate, bony metastasis, com-bined androgen blockade.

How to cite this article:
Kulkarni JN, Gupta R. Early report of randomized double blind clinical trial of hormonal therapy of carcinoma of prostate (CAP) stage D2. Indian J Urol 2003;19:135-9

How to cite this URL:
Kulkarni JN, Gupta R. Early report of randomized double blind clinical trial of hormonal therapy of carcinoma of prostate (CAP) stage D2. Indian J Urol [serial online] 2003 [cited 2022 May 18];19:135-9. Available from:

   Introduction Top

We initiated a multicentric randomized double blind clinical trial of carcinoma of prostate stage D2 and it was aimed at the results of total androgen blockade or mono­therapy in Indian population. At the end of 2 years fol­lowing the strict inclusion criteria, 100 patients were recruited. We herein report our early observations in them.

   Patients and Methods Top

Between July 1999 and June 2001, 100 patients of car­cinoma of prostate stage D2 were recruited after satisfy­ing the strict inclusion criteria which included previously untreated histologically proven adenocarcinoma of pros­tate with metastasis to bones with or without metastasis to lymph nodes or other sites. Exclusion criteria were: pa­tients already on the treatment, progressive fatal illness/ terminal stage of disease or patient with Karnofsky's in­dex <40. A baseline evaluation included a detailed medi­cal history and physical examination including DRE, Karnofsky's index, complete blood count and biochemis­try, PSA, urine analysis, USG abdomen and pelvis, chest x-ray, bone scan/skeletal survey, prostatic biopsy and signed informed consent. All patients were followed at 3 monthly intervals. In the follow-up, symptomatology, clini­cal evaluation of the primary as well as metastatic sites. serum PSA and biochemical study were performed. Ap­propriate follow-up forms were completed at each visit and sent to the central office. Sample size in this trial was calculated accordingly to find 10% improvement in sur­vival at 36 months with a 80% power of confidence level and a 5% level of significance. All patients had bilateral orchiectomy, were later assigned randomly to the flutamide and placebo arms. They were further substratified into ei­ther high volume of metastatic disease (HVD) if bone scan showed 5 or more metastatic sites and low volume disease (LVD) if bone scan had less than 5 bony metastases. Flutamide was given 250 mg thrice a day. Patients were decoded from the trial when there was evidence of clinical progression or serological progression, i.e., 2 consecutive rises in PSA levels at 3 months interval or serious adverse events to drugs.

   Results Top

Of the 100 patients recruited in the trial, 48 had HVD (22 in flutamide and 26 in placebo) and 52 LVD (28 in flutamide and 24 in placebo). At the follow-up ranging from 6 to 24 months, 30 out of 100 (30%) required decod­ing : 25 because of progression of disease and remaining 5 had severe adverse reaction to drugs. These 25 patients who were decoded due to either clinical or serological pro­gression, were further analyzed according to treatment group, volume of metastasis, pre-orchietomy PSA and Gleason score. Of these 25 patients, 13 received flutamide therapy and 12 had placebo [Figure - 1]. Gleason score in them was <7 in 15 and >5 in 10 [Figure - 2]. According to volume of metastasis, 17 had HVD and 8 had LVD [Fig­ure 3]. Pre-orchiectomy PSA were 20-100 in 11, 101-1000 in 8 and >1000 ng/ml in 6 [Figure - 4]. Time of decoding was <12 months in 23 and 2 after 12 months. In follow­up, 10 of the 25 patients died at 9-24 months due to pro­gression.

   Discussion Top

Standard therapy for carcinoma of prostate D2 is hor­monal manipulation based on its inherent hormone sensi­tivity. [1],[2] Interestingly enough in the same tumor, there are hormone refractory cells which did not respond to hor­mone therapy and are the cause of failure of progression. [3],[4] Recently there has been lot of debate on total androgen blockade vs monotherapy [5],[6] and hence we initiated this sim­ple trial to address the issue of benefit of total androgen blockade over monotherapy.

Our initial observations in first 100 patients showed that 30 patients had to be decoded for various reasons like clini­cal or serological progression and adverse drug reaction. All 100 patients after randomization showed reduction in PSA and symptoms. However in spite of excellent initial response, 25 had progression indicating conversion to hor­mone refractory nature of the disease or inadequacy of the treatment. Further analysis shows that of the various fac­tors like mode of therapy, pre-orchiectomy PSA and Gleason score do not have impact over the progression but it was observed that volume of metastatic disease has the impact. [7] It is worth noting that the maximum relapses occurred in first 12 months which further confirms ag­gressive biology and the view of large number of HRPC cells in the time which go unharmed.

   Conclusions Top

In our study, total androgen blockade does not make any impact on the progress of disease. Furthermore there is subset of tumor, which has higher propensity of devel­oping into the hormone refractory state. We observed that diseases with higher number (>5) of bony metastases con­stitute a poor risk factor. A large trial is required to sub­stantiate these initial observations.

   References Top

1.Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941; 1: 43-209.  Back to cited text no. 1    
2.Nesbit RM, Larson-Keller JJ, Bergstrahl EJ, et al. Endocrine con­trol of prostatic carcinoma. JAMA 1950: 143: 1317-1320.  Back to cited text no. 2    
3.Isaacs IT. Lundmo PI, Berges R. et al. Androgen regulation of pro­grammed cell death of normal and malignant prostatic cells. J Androl 1992: 13: 457-464.  Back to cited text no. 3    
4.Berges RJ, Epstein J, et al. Implications of cell kinetic changes dur­ing the progression of human prostatic cancer. Clin Cancer Res 1995; 1: 473-480.  Back to cited text no. 4    
5.Labrie F. Belanger A, et al. Rationale for maximal androgen with­drawal in the therapy of prostate cancer. Bailiere's Clin Oncology 1988: 2: 597-619.  Back to cited text no. 5    
6.Robinson MRG, Smith PH, Richards B, et al. The final analysis of the EORTC Genito-Urinary Group Phase III clinical trial (Protocol 30805) comparing orchidectomy. orchidectomy plus cyproterone acetate and low dose stilboesterol in the management of metastatic carcinoma of the prostate. Eur Urol 1995: 28: 273-283.  Back to cited text no. 6    
7.Yamashita K, Dennok, et al. Prognostic significance of bone me­tastasis in patients with metastatic prostatic cancer. Cancer 1993; 71(4): 1297-302.  Back to cited text no. 7    


  [Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4]

  [Table - 1]


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