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RESEARCH ARTICLE
Year : 2003  |  Volume : 19  |  Issue : 2  |  Page : 129-134
 

Estramustine phosphate in the treatment of hormone escape prostatic carcinoma - a 3 year follow-up


1 Department of Urology, Western General Hospital, Lothian University Hospitals NHS Trust, Edinburgh, United Kingdom
2 Southern General Hospital, Glasgow, United Kingdom

Correspondence Address:
Altaf H Syed
Department of Urology, Western General Hospital, Lothian University Hospitals NHS Trust, Edinburgh, EH4 2XU
United Kingdom
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Source of Support: None, Conflict of Interest: None


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   Abstract 

Objective: A recent literature review has shown rekin­dled interest in the use of estramustine phosphate (EMP) inpatients with advanced prostatic cancer. This led us to assess prostate specific antigen (PSA ) response and drug tolerability following EMP therapy inpatients with hor­mone refractory prostate cancer
Patients and Methods: Twenty-five patients with a mean age of 73.5 years (range 49 to 85 years) received EMP for hormone insensitive prostate cancer from January 1996 onwards. They were received at 6 weeks initially followed by 3 monthly intervals to monitor further progression of disease. At each visit clinical examination and blood chem­istry (PSA, etc) was done and further investigations, i.e., bone scan, CT scan, etc. were requested if thought neces­sary.
Results: According to the WHO score of pain 71 %found immediate symptomatic relief following EMP treatment but only 29% were pain free after one year PSA level showed a persistent decline of >50% of pre-treatment value in 16 patients (64%) at 6 weeks. However, at 1 year 22% had either a still declining PSA or had reached a stable nadir PSA level while the rest showed rising PSA suggesting in­sensitivity to EMP. Three out of 5 patients (excluding I patient with intolerance at 2 months) with >80% decrease in PSA at 6 weeks had longer period of progression free interval (1 year in 2 and 2 years in 1 patient). The treat­ment was generally well tolerated (72%) as only 7 patients had to discontinue EMP because of severe side ef­fects.
Conclusions: EMP treatment in patients with hormone escaped prostatic cancer does produce immediate PSA response which is reflected simultaneously in pain improve­ment in the majority of cases but overall the benefit is shortlived. Patients who have >80% reduction in pre-treat­ment PSA value at 6 weeks may have longer period of pro­gressionfree intervals. However EMP was generally well tolerated.


Keywords: Estramustine phosphate. prostate specific antigen. advanced prostate cancer, bone pain, side effects/toxicity.


How to cite this article:
Syed AH, Akhtar MN, Shearing C, Bollina P R, Tulloch D N. Estramustine phosphate in the treatment of hormone escape prostatic carcinoma - a 3 year follow-up. Indian J Urol 2003;19:129-34

How to cite this URL:
Syed AH, Akhtar MN, Shearing C, Bollina P R, Tulloch D N. Estramustine phosphate in the treatment of hormone escape prostatic carcinoma - a 3 year follow-up. Indian J Urol [serial online] 2003 [cited 2019 Nov 15];19:129-34. Available from: http://www.indianjurol.com/text.asp?2003/19/2/129/37144



   Introduction Top


Each year there are approximately 85,000 newly diag­nosed cases of prostate cancer in the 12 member states of European Community making this the 2nd most common form of cancer (after lung cancer) in men. [1] Even though its clinical incidence is high, there are many more prostate cancers that occur without being clinically apparent dur­ing the patient's lifetime, although at present it is gener­ally accepted that, in Western industrialised societies, prostate cancer will be diagnosed in 10% of men during their lifetime, and 3-4% will eventually die from the dis­ease. It is the 2nd commonest leading cause of cancer death in men throughout the world as indicated by both trun­cated and overall age-adjusted mortality rates. The major­ity of deaths result from continued proliferation of tumor cells despite androgen-ablation therapies, and once hor­mone insensitive disease is established, median survivals are measured in months. [2] At the present time no standard therapy for hormone-refractory prostate cancer exists, al­though a variety of secondary endocrine and cytotoxic regi­mens have been tried. However none has consistently produced objective tumour responses. Interest has been revived in the use of estramustine phosphate (EMP) which was previously used either alone or in combination with other cytotoxic agents on a wider scale. It had shown a response rate of up to 30% in hormone-refractory patients [3],[4] but more recently due to introduction of newer agents, i.e., LHRH analogues, antiandrogens, combined androgen blockade, etc., EMP has not been used so frequently.

In 1971 Swedish investigators [5] developed and used es­tramustine phosphate with favourable results in patients with advanced carcinoma of prostate. Essentially EMP is a combination of estradiol and a non nitrogen mustard [Figure - 1] and its main metabolites - estramustine and estromustine, act as antimitotic agents by binding to microtubule organi­sation, thereby leading to disruption of protein assembly. [6],[7] Due to poor condition of patients generally found in ad­vanced prostatic cancer and the toxicity of various con­comitant therapies treatment has often been terminated prematurely. Therefore, it has been rather difficult to iden­tify response criteria which would be universally accept­able. [8] However since the aim of treatment in this patient group is to improve quality of life, symptomatic relief com­bined with failure of progression of prostate cancer could be considered generally as an acceptable outcome.

Prostate specific antigen, a glycoprotein, acts as a tu­mour marker in patients with prostatic cancer [9] and its plasma levels generally correlate well with the extent of disease, [10],[11],[12] although absolute values do not determine the stage. Changes in PSA have shown to correlate with clini­cal outcome in patients treated by radical surgery, radia­tion therapy or androgen ablation. [13],[14],[15] Because more than 70% of patients with metastatic hormone-escape prostate cancer do not have bidimensionally measurable disease, PSA serves as a useful surrogate end point tumour marker following therapy in patients with hormone-refractory prostate cancer. [16],[17],[18] Even some investigators believe that post-therapy declines in PSA of 80% or more within I month after treatment was associated with long progression-free intervals. [19] However the immediate limiting factor in con­tinuing medical treatment is intolerance/inefficacy which has been noted with EMP as well.

The advantage of EMP therapy over other cytotoxic drugs is its ease of administration (oral) and relatively good tolerability at the effective dose. In addition it can be given for extended periods without any cumulative toxicity.


   Patients and Methods Top


Twenty-five patients with an age range of 49-85 years (mean age of 73.5 years) were treated with EMP and re­viewed prospectively from January1996 onwards. All of these patients had either hormone refractory disease or had recurred following previous local radical radiotherapy plus hormones. The patient details are given in [Table - 1].

According to Gleason grading system 2 patients had well differentiated cancer, 6 patients had moderately differen­tiated tumour while 16 patients had poorly differentiated prostatic cancer and the remaining 1 patient had endometroid carcinoma of prostate. Prior to treatment all patients had elevated PSA (more than 2 readings despite treatment) although the range of rise was variable. Patients on anti-androgen were given a `hormone holiday' before starting EMP therapy.

EMP was given in a dose of 280 mg twice daily in all except in a few patients with extensive metastases where dosage was increased to 420 mg twice daily. Patients were instructed to take medications at least 2 hours before or , after meals and to avoid any dairy products/antacids along with the tablets. Patients were followed up at 6 weeks ini­tially followed by 3 monthly intervals to monitor sympto­matic improvement, local control of the disease on digital rectal examination and biochemical analysis of prostate specific antigen (PSA), renal/liver function tests and hae­matocrit. Bone and CT scans were requested if progres­sion of disease was suspected. Treatment was discontinued in patients with intolerable side-effects/toxicity or if dis­ease was progressing. Patients with medical history indi­cating high risks of cardiovascular complications or significant hepatic/renal impairment were excluded. Any concomitant therapy like analgesics, palliative radio­therapy, etc., was allowed if it improved the quality of life.


   Results Top


From January 1996 onwards 25 patients were given EMP and followed up prospectively until their disease became resistant to this treatment modality. 24 patients had prior hormone insensitive disease and the remaining 1 had re­curred following previous radical radiotherapy plus hor­mones.

Follow-up:

All patients were reviewed initially at 6 weeks followed by 3 monthly intervals except I who refused to attend fur­ther but was regularly seen and apparently asymptomatic as reported by family doctor. The range of clinical review was 1 to 36 months with a mean of 11.5 months. However only 12 patients reached 1 year follow-up while the rest had either died from other ailments [2] or EMP was stopped due to side effects [7] or lack of efficacy (4: out of which 3 died). Two patients had a shorter follow-up of 1 month only because of intolerance to estramustine.

Symptom relief:

The only noticeable symptom was bone pain in the ma­jority of patients. [23] Excluding patients in whom EMP was stopped in less than 1 month due to intolerance, [2] 71% of patients found symptomatic relief following EMP therapy at initial review. i.e., 6 weeks. According to WHO pain scoring system 10 patients out of 14 with mild pain had subjective relief, 4 patients with evident pain and the only patient with heavy pain were downgraded to mild category with EMP treatment. Simultaneously performance status also improved in those patients who had complete or par­tial pain relief. One patient had mild but persistent back­ache probably secondary to a small abdominal aortic aneurysm (bone scan showed no secondary deposits in this area), while remaining patients had disseminated skeletal metastases plus local progression of prostate cancer that needed further treatment, i.e., medical adrenalectomy, so­dium clodronate along with palliative radiotherapy, etc. The relief/improvement in pain lasted for 3 months in 50% of cases but only 29% were pain free (from mild category) at 1 year's follow-up.

Biochemical parameters:

The first indication for the use of PSA (and the only use for which most assays have been approved in the USA) was in the monitoring of patients after therapy. Indeed. PSA is extraordinarily sensitive in this respect - a rise in PSA without any other identifiable cause is almost invari­ably a harbinger of the eventual failure of treatment. Fol­lowing EMP therapy a PSA decline of >50% pre-treatment value was noted in 16 patients at 6-weeks' initial followup - this includes 2 patients with intolerance within 6 weeks who had >50% falling PSA at 1st visit and thus were included with responders initially. Those patients who did not show any change in PSA from the start had either recurred following radiotherapy [1] or had extensive local as well as systemic metastatic disease. [4] Subsequently sus­tained fall in PSA continued further in 4 patients (out of 12) at 1 year, 2 patients (out of 5) at 2 years but none thereafter.

These results suggest temporary biochemical tumour con­trol of short duration (6 weeks to 3 months) with EMP in the majority of cases (60-64%), although only 22% of pa­tients had falling PSA at 1 year. Pre-treatment PSA value had no impact with the final outcome but post-treatment decline of 80% or more had positive correlation. We had 3 patients out of 5 (67%) with >80% reduction in PSA after EMP therapy who had prolonged periods (1 year in 2 pa­tients and 2 years in 1 patient) of biochemical and sympto­matic control. Gleason scoring seems to have no apparent bearing on the response to EMP treatment in our patients - may be this is due to the fact that most of our patients had moderate to poorly differentiated metastatic prostate cancer according to Gleason grading. [Table - 2] shows patients' re­sponse characteristics to EMP treatment. Haematocrit re­mained stable in all cases except 2 with widespread skeletal metastasis but without any gastro-intestinal upset to account for low haemoglobin. Blood transfusion was given to these patients to correct low haemoglobin. Liver function tests remained normal in all but 1 in whom treatment had to be discontinued within 2 months.

Side effects/toxicity:

Twelve patients tolerated treatment well without any no­ticeable side effects. Six patients complained of mild nau­sea and/or fatigue (4), diarrhoea (1) and weight gain with mild breast tenderness (1) which was not too bothersome as to discontinue treatment. In 7 patients treatment was stopped - in 5 due to intractable nausea/anorexia within 6 weeks; worsening of left ventricular failure in I patient at 2 months, and pulmonary embolism in the other at 8 months.


   Discussion Top


Patients with prostate cancer show a wide variability in biologic behaviour and metastasis potential which has been a source of major confusion and controversy regarding what is appropriate care for various stages of prostate can­cer. Prostate carcinomas are heterogenous tumours com­posed of hormone-sensitive and hormone-insensitive cells (primary hormone therapy is ineffective in 20% of all cases). Because of this and previous treatment failures only 22% of patients had persistent decline in PSA at 1 year which is almost similar to the findings observed by Yagoda et al (1991) (21 %). In our series we had only 1 young patient (49 years) with moderately differentiated metastatic hormone-refractory prostate cancer who had good symp­tomatic and biochemical response with EMP for more than 2 years and still continues to be asymptomatic despite es­calating PSA. Further studies may be needed to evaluate the role of EMP in younger patients as has been suggested by Janknegt RA et al (1997). However PSA declines of 80% or more within 6 weeks noted in 5 patients (excluding 1 with intolerance at 2 months) showed positive cor­relation with prolonged periods of progression-free inter­val in 3 patients (67%) as has been observed by Arai Y et al [19] also. The improvement in PSA was reflected clini­cally as pain was less or nil in 29% of cases at 1 year which is slightly higher than that found by Mittleman et al (1976) (17%). However duration of prostate cancer had no impact on outcome, and in addition, nature of prior treatments with orchiectomy, anti-androgens, or combined androgen blockade did not show any superiority in response to EMP. Most of our patients have tolerated the treatment well (72%) as only 7 patients had to discontinue EMP due to side effects.

We accept that there are some drawbacks in our study - the most important being the small number of cases. This is partly due to patient consent or compliance/time factor and partly due to other trial drugs/treatments being run simultaneously. Secondly our study was uncontrolled and non-randomised because of lack of volunteers.

However it has been shown in experimental situation in animals that primary hormono/chemotherapy is more ef­fective than hormonal therapy alone [22] and moreover estramustine phosphate has got certain advantages over all other chemotherapeutic agents that has revived its use at the present time. These are : 1. Ease of administration: oral. 2. Relatively good tolerability without any risk of cumulative effect. 3. It is a steroidal N-mustard derivative but without any alkylating effects [23] and therefore bone suppression is rare. Hence it can be given to previously irradiated patients or to those with a limited bone marrow reserve because of widespread skeletal metastases. 4. EMP has a certain degree of preferential distribution to prostate as concentrations in the tumor have been noted to be higher than in the plasma. [24] In view of these benefits use of EMP is being instigated again on a wider scale either as a pri­mary treatment or following failure of initial therapy. [25] If more hospitals cooperate on a similar protocol then it may be interesting to see the results in a larger series. Estramustine resistance occurs primarily due to modifica­tions in tubulin expression [26] and therefore, combination with other microtubule inhibitors especially with synergistic effects may enhance its efficacy. If this is con­firmed in ongoing Phase III trials then EMP could be used on a wider scale again as so far Phase II studies have shown an improved response rate of up to 45% with a median duration of 7 months. [27] EMP as a primary therapy espe­cially in younger patients who cannot be cured by radical surgery may need further evaluation although some recent studies have shown prolongation of survival and improve­ment in quality of life by prolonging time to tumour pro­gression. [25] Considering earlier experience and the present results, the role of EMP should be considered as a 2nd line treatment especially in bone marrow suppressed patients.


   Conclusions Top


The treatment of hormone escaped prostate cancer con­tinues to be a dilemma. At the present time the mainstay of treatment remains palliative. From our study it appears that those patients with >80% reduction in PSA immedi­ately after EMP treatment may have longer periods of bio­chemical and symptomatic control. Other studies have shown that the role of EMP as a primary treatment in younger patients with advanced prostate cancer may have better progression-free intervals, and combination with other micro-tubule inhibitors with synergistic effects cer­tainly does increase its efficacy. Further studies are already underway and it would be interesting to know their re­sults.[34]

 
   References Top

1.Jensen OM. Esteve J, Moller H, Renard H. Cancer in European Community and its member states. Fur J Cancer 1990; 26: 1126­-256.  Back to cited text no. 1    
2.Berry Benson RC Jr, Gill GM. Estramustine phosphate compared with diethylstilbestrol: A randomised. double blind, crossover trial for stage D prostate cancer. Am J Clin Oncol CCT 1986; 9: 341-­351.  Back to cited text no. 2    
3.Jonsson G. Hogberg B, Nilsson T. Treatment of advanced prostatic carcinoma with estramustine phosphate (Estracyt). Scand J Urol Nephrol 1977; 11: 231-8.  Back to cited text no. 3    
4.Nilsson T. Estracyt - clinical experiences. Scand Urol Nephrol suppl 1980: 55: 135-8.  Back to cited text no. 4    
5.Jonsson G, Hogberg K. Treatment of advanced prostatic carcinoma with estracyt. A preliminary report. Scand J Urol Nephrol 1971: 5: 103-7.  Back to cited text no. 5    
6.Eklov S. Nilsson S, Larsson A, Bjork P, Hartely-Asp B. Evidence for a non-estrogenic cytostatic effect of estramustine on prostatic carcinoma cells in vivo. The Prostate 1992; 20: 43-50.  Back to cited text no. 6    
7.Stearns ME, Wang M, Tew K, Binder Lt. Estramustine binds a MAP­1 like protein to inhibit microtubule assembly in vitro and disrupt microtubule organisation in DU 145 cells. J Cell Biol 1988; 107: 2647-56.  Back to cited text no. 7    
8.Iversen P. Rasmussen F, Asmuseen C et al. Estramustine phosphate versus placebo as second line treatment after orchiectomy in pa­tients with metastatic prostate cancer : DAPROCA study 9002. J Urol 1997: 157: 929-934.  Back to cited text no. 8    
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12.Pontes JE, Chu TM, Slack N, Karr J, Murphy GP. Serum prostatic antigen measurement in localised prostatic cancer : correlation with clinical course. J Urol 1982; 128: 1216-1268.  Back to cited text no. 12  [PUBMED]  
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24.Norlen BJ, Anderson S-B, Bjork P, Gunnarsson PC, Fritjofsson A. Uptake of estramustine phosphate (Estracyt) metabolites in pros­tate cancer. J Urol 1988: 140: 1058-1062.  Back to cited text no. 24    
25.Janknegt RA, Boon TA, Beek C van de, Grob P. Combined hormono/ chemotherapy as primary treatment for metastatic prostate cancer: A randomised, multicenter study of orchiectomy alone versus orchiec­tomy plus estramustine phosphate. Urol 1997; 49(3): 411-420.  Back to cited text no. 25    
26.Sangrajrang S. Denoulet P, Laing NM et al. Association of estra­mustine resistance in human prostatic carcinoma with modified patterns of tubulin expression. Biochem Pharmacology 1998: 55: 325-331.  Back to cited text no. 26    
27.Hedges G, Greenberg R, Krigel R. Phase II study of estramustine and vinblastine, two microtubule inhibitors, in hormone-refractory prostate cancer. J Clin Oncol 1992: 10: 1754-1761.  Back to cited text no. 27    
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31.Majeed FA, Burgess NA. Trends in death rates and registration rates for prostate cancer in England and Wales. Br J Urol 1994; 73: 377­-81.  Back to cited text no. 31  [PUBMED]  
32.Newling DWW, Fossa SD, Tunn UW, Kurth KH, Pauw MDE, Sylvester R. Mitomycin C versus estramustine in the treatment of hormone resistant metastatic prostate cancer : the final analysis of the European Organisation for Research and Treatment of Cancer. Genitourinary Group prospective randomised phase III study (30865). J Urol 1993: 150: 1840-44.  Back to cited text no. 32    
33.Tveter KJ, Hagen S, Holme I et al. A randomised study on hor­mone-resistant prostatic cancer : estramustine phosphate versus low dose epirubicin with or without medroxyprogesterone acetate. A Norwegian Multicenter Study. Scand J Urol Nephrol 1990: 24: 243­-47.  Back to cited text no. 33    
34.Van Poppel H, Werbrouck PW, Baert L. Effect of estramustine phos­phate on free androgens. A comparative study of the effects of or­chiectomy and estramustine phosphate on free androgens in patients with prostatic cancer. Acta Urol Belg 1990; 58: 89-95.  Back to cited text no. 34    


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