- Email: [email protected]
Hormone Therapy in Prostate Cancer: Moving into the 21st Century
European Urology Supplements
European Urology Supplements 4 (2005) 53–56
HormoneTherapy in Prostate Cancer: Moving into the 21st Century Peter Whelan Department of Urology, St James’ University Hospital, Beckett Street, Leeds, West Yorkshire, 9 7TF, UK
1. Introduction Since the introduction of PSA testing in the early 1990s there has, throughout most of the world, been a significant stage shift in prostate cancer at presentation [1]. Fifteen years ago 50% of the patients would have had metastases and only small numbers would have been eligible for attempted definitive therapy. Now in many parts of the United States of America less than 10% of patients present with metastases and even in Europe these figures are rarely more than 12% to 15% at maximum. Whilst there is no argument that this minority of patients with metastases at presentation require immediate hormone treatment the place of hormones in patients with locally advanced or localised disease remains controversial, principally because the lack of randomised prospective clinical trials to answer questions on their utility and effectiveness.
2. Metastatic disease Whilst there remains some vestiges of the controversy generated by the advocates of maximum androgen blockade (the use of LHRH agonist and antiandrogens in combination) it seems that the minimal possible increase in survival would seem not to justify the expense this regime, in patients with metastatic disease generates. There appears in the meta-analyses carried out that a small group of younger men with small burdens of metastatic disease that may benefit with MAB over conventional castration (either medical or surgical) but there is certainly no clear cut gain or unassailable benefit in general to patients with metastatic disease, as was suggested originally by Labrie in the early 1980s. E-mail address: [email protected]. 1569-9056/$ – see front matter # 2004 Published by Elsevier B.V. doi:10.1016/j.eursup.2005.01.002
Patients, however, have improved both their length of survival and the quality of survival in the last 20 years. In 1989/90 the average duration of response to castration was between 18 and 24 months and when patients progressed after this their further survival was rarely longer than 6 months. In contemporary studies these patients appear to survive twice as long on average now and this is probably because of the closer monitoring, and the active attention to controlling symptomatic changes together with the utilisation of more than one hormone in a secondary or even tertiary setting before non-hormonal therapy is introduced. In men in their late 70s or early 80s (still the majority of prostate cancer patients) who present with metastases, the average 4-year survival may well equate to their expected natural survival [2]. What has been helpful is recognising that the 4 hormonal therapies, surgical castration, anti-androgens, LHRH agonists, or oestrogen therapy may be used sequentially and that second hormone responses in significant numbers of patients as judged by the fall in PSA values is a frequent concomitant of this hormone therapy and often similar benefits can be achieved using oestrogens as a third line therapy if anti-androgens had been used initially followed by LHRH treatment. The duration of PSA responses to second and third line treatment may each be of the order of 12 months or more and certainly at present is both less toxic and immensely more beneficial than current chemotherapeutic agents whose survival benefit appears to be no better than 2 months [3,4]. Because of the significant side effects associated with hormonal treatment, studies in the utility of intermittent hormone therapy have been carried out since the original description by Klotz in 1988. A feasibility study carried out by the EORTC showed that in men with metastatic disease a 3–4 month course of hormones was sufficient in over 80% to reduce the PSA to a nadir value, and that utilising an arbitrary
54
P. Whelan / European Urology Supplements 4 (2005) 53–56
value of 20 ng/ml as a threshold to recommence treatment patients even with a heavy burden of metastatic disease were entirely safe. Both it and the early reports of randomised prospective trials in intermittent therapy have frequently showed prolonged responses after initial therapy such that patients may be off treatment for up to 12 months with significant benefit as far as side effects from therapies concerned accruing to the patient. But it is noteworthy that most intermittent therapy regimes demonstrate, as more cycles are past through that the duration off the hormonal medication begins to get shorter and in many patients eventually the duration is of the order of a month or so being so short as to suggest that continual hormonal therapy is now the preferential option. To date in the small number of studies published, there is no evidence that intermittent therapy is less effective in patients with metastatic disease that continual therapy, but survival has not been compromised but that the total of side effects has been reduced [5,6].
3. Locally advanced prostate cancer Although it is arbitrary, patients presenting with PSAs over 20, Gleason scores of 7 and greater, or evidence on imaging of stage T3 disease, even in the absence of lymphadenopathy or proven bone metastases are rarely considered as good subjects for treatment with curative intent, although many of them with no evidence of metastases will receive external beam radiotherapy and some, indeed, may well undergo radical surgery although the rationale for this, let alone the evidence base as formulated by clinical trials is vanishingly small. Many of these patients may receive a course of neo adjuvant and/or adjuvant hormone treatment which may last as long as 3 years. This was demonstrated to be better than radiotherapy alone in a landmark paper by Bolla et al. 1997 [7] and confirmed in RTOG studies [8]. It remains a moot point as to whether or not there is a greater benefit from the combination than with hormones alone and a prospective trial to address this problem is currently nearing completion under the aegis of the MRC in the UK and NCI Canada. Many of these patients with locally advanced disease may choose to go on to hormone therapy and frequently an anti-androgen would seem a logical first choice as compared with LHRH; especially in the younger men there is a slow loss of potency which may be important. Many of these patients will, after a variable period of time, show progressive rise in PSA
even in the absence of objective evidence of metastases whether in the bones or in the lymph glands [9]. There remains controversy as to what is the correct treatment for these patients. There is no evidence currently available that non-hormonal treatment makes any change in the course of the natural history of this disease although some recent positive responses to chemotherapy in hormone resistant disease is likely to need clinicians to consider moving chemotherapy into this earlier phase. This should and must be done as a prospective randomised trial. Especially as all information in the past suggests that chemotherapy has a limited role in this disease whereas hormonal treatment remains demonstrably effective when used even as second and a third line treatment after an initial hormone therapy. It is arguable but extremely doubtful that a patient can be truly said to be hormonal refractory unless they have been exposed to all forms of hormonal treatment (allowing that surgical and medical castration are equivalent). It would seem increasingly important therefore that studies of intermittent therapy with proven effective agents (the hormones) be continued to be undertaken at the same time as chemotherapeutic agents and other novel therapies are looked at. It would seem wrong to deny a patient effective treatment just because something is fashionable (and almost invariably very expensive) [9]. The continuing difficulty of knowing whether early or late hormonal therapy in patients with locally advanced disease has an effect on the outcome may well be answered by an EORTC study commenced in 1989 and now analysed for the first time and submitted as an abstract to the AUA and the EAU. This compared immediate versus deferred therapy in locally advanced disease and suggests, as did the previous MRC study, that there is some benefit in immediate hormone treatment in terms of crude survival but expresses caution and urges a balance to be struck as to whether the side effects stretched over many years of continual hormone treatment is a price worth paying for a small survival benefit. Intermittent therapy again if tested in this setting may well help to bridge the gap between keeping the disease under control and possibly gaining some survival advantage and minimising the inevitable effects of long term hormone treatment.
4. Biochemical failure following definitive treatment for early stage prostate cancer At least a third and possibly as many as half or more of patients undergoing attempted curative therapy with
P. Whelan / European Urology Supplements 4 (2005) 53–56
either radical surgery, radical external beam radiotherapy, brachytherapy or novel treatments such as HIFU will have sooner or later evidence of biochemical failure [10]. The treatment of these patients is difficult especially psychologically as they will have all felt they were having treatment which would have cured their cancer. The presence of a PSA value is certain evidence that this has not been so and may well be more psychologically upsetting in patients choosing radical surgery whilst there will be evidence of some local recurrence at times very often a rise in the PSA indicated that the disease is metastatic. The amount of support these patients need is poorly documented and understood. The role of hormone therapy remains even more controversial in this category above all others especially now as in the modern era it is become increasingly the largest group which is encountered. For reasons that remain controversial and puts urologist in a less than favourable light the logical trial of immediate versus deferred hormonal treatment in patients with a rising PSA following definitive therapy whilst it has been attempted by several international research organisations has never been completed principally because patients have demanded early treatment and so called ‘‘experts’’ seem to have changed their opinions as to whether immediate or deferred treatment is preferable as often as their socks. The end result sadly has meant that there has been no consensus on enabling patients to enter trials. There remains the observational study of a cohort group from Johns Hopkins published by Pound et al. 1999 [11] demonstrating that there was at least 8 years from initial rise of PSA following a radical prostatectomy to objective evidence of metastases and that a further 5 years on average ensued before these patients died of their cancer. This group had therefore recommended that patients should not commence treatment straight away but this should be reserved until objective metastases were evident. There is no indication as the amount of psychological support the patients were offered during the period of 8 years whilst the PSA was persistently rising. What has become obvious is the course of the disease even if it is not effectively cured will be long and that the prospect of being on continual hormone therapy for more than 10 years especially if LHRH agonists are used, will induce significant side effects the principle one being osteopeania which will go on to develop osteoporosis almost certainly at an accelerated rate compared with age related controls. Allied to this there is evidence of increasing muscle wasting, lack of strength, increasing lethargy and anecdotal evidence, usually produced by wives and partners of many men that those on long term hormone treatment undergo
55
profound personality changes which may well be attributable to the hormone treatment [12]. Because of these problems it seems very difficult, just as it was 10 years ago to initiate a trial of immediate versus deferred hormonal treatment. A way through this again may be possible by utilising intermittent therapy using not only hormones which we know work but are palliative and work in the majority of cases for a limited period or time but incorporating in on an intermittent model chemotherapeutic and other novel agents to try and control PSA rise and hopefully progression of the disease. In this fashion shorter term studies or side effects and quality of life and be publishable and valid without needing to wait 10 or 15 years for a definitive study which will look at survival alone.
5. Conclusions Prostate cancer remains a hormone sensitive tumour. In studies dating from the original ones of Huggins and Hodges (1941) [13] approximately 10% of patients appear to be cured by hormone treatment but the vast majority of the other 90% get symptomatic and palliative relief which now having the ability to offer at least 2 options if not 3 options of hormone treatment appears to have doubled the survival in all stages of advanced prostate cancer. We must be active in setting up clinical trials to look how patients who have failed definitive therapy or present when definitive therapy will not effect a cure, but who nevertheless have a life expectancy that will be measured in many years rather than in a handful of years, receive the maximum benefit that current treatments have and that hormonal therapy must remain the bedrock of disease control until prospective clinical trials conclusively prove that either newer chemotherapeutic agents or novel therapies have supplanted the hormonal benefits. Hormones themselves now that we recognise at least 3 categories of hormones each of which may be used in sequence may further be explored by the intelligent use of trials looking at intermittent therapy monitoring the control of the PSA and giving to patients the maximum benefit with respect to side effects of being off therapy. Because prostate cancer has such a long history surrogate end points such as quality of life and disease control may legitimately be looked at but quality of life should be the prominent factor that drives treatment options and newer and inevitable more expensive treatments have to be vigorously and rigorously tested and not allowed to become part of the armamentarium of the management of prostate cancer patients merely by fashion.
56
P. Whelan / European Urology Supplements 4 (2005) 53–56
References [1] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer. J Clin 1999;49:8–31. [2] Dennis LK, Resnick MI. Analysis of recent trends in prostate cancer incidents and mortality. Prostate 2000;42:247. [3] Smith DC, Redmond BG, Flaherty R. A phase II trial of oral diethyloesterol as a second line hormonal agent in advanced prostate cancer. Urology 1988;52:257. [4] Iverson P. Orchidectomy and oestrogen therapy revisited. Eur Urol 1998;34(Suppl):7. [5] Goldenberg SC, Bruchovsky N, Gleave ME. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. J Urol 1997;157(Suppl):390. [6] Albrecht W, Collette L, Fava C, Kariakine OB, Whelan P, Struder UE, et al. Intermittent maximal androgen blockade in patients with metastatic prostate cancer. An EORTC feasibility study. Eur Urol 2003;44:505–11. [7] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295.
[8] Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy Oncology Group (RTOG) trial 86-10 of androgen depravation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243. [9] Iverson P, Tyrrell CL, Kaisery AV, et al. Bicalutamide monotherapy compared with castration in patients with locally advanced prostate cancer. 6.3 years of follow up. J Urol 2000;164:159. [10] Blute ML, Bergstralch EJ, Iocca A, et al. Use of Gleason score, prostate specific antigen seminal vessels and margin status to predict biochemical failure after radical prostatectomy. J Urol 2001;165:119. [11] Pound CR, Partin AW, Eisenberger MA, et al. National history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591. [12] Litwin MS, Saigal CS, Lubeck DP, et al. Health-related quality of life in men with metastatic prostate cancer: the misleading effect of lead time bias. BJU Int 2003;91:9. [13] Huggins C, Hodges CV. Studies in prostate Cancer: effect of castration, oestrogen’s and or androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941;1:293.
European Urology Supplements 4 (2005) 53–56
HormoneTherapy in Prostate Cancer: Moving into the 21st Century Peter Whelan Department of Urology, St James’ University Hospital, Beckett Street, Leeds, West Yorkshire, 9 7TF, UK
1. Introduction Since the introduction of PSA testing in the early 1990s there has, throughout most of the world, been a significant stage shift in prostate cancer at presentation [1]. Fifteen years ago 50% of the patients would have had metastases and only small numbers would have been eligible for attempted definitive therapy. Now in many parts of the United States of America less than 10% of patients present with metastases and even in Europe these figures are rarely more than 12% to 15% at maximum. Whilst there is no argument that this minority of patients with metastases at presentation require immediate hormone treatment the place of hormones in patients with locally advanced or localised disease remains controversial, principally because the lack of randomised prospective clinical trials to answer questions on their utility and effectiveness.
2. Metastatic disease Whilst there remains some vestiges of the controversy generated by the advocates of maximum androgen blockade (the use of LHRH agonist and antiandrogens in combination) it seems that the minimal possible increase in survival would seem not to justify the expense this regime, in patients with metastatic disease generates. There appears in the meta-analyses carried out that a small group of younger men with small burdens of metastatic disease that may benefit with MAB over conventional castration (either medical or surgical) but there is certainly no clear cut gain or unassailable benefit in general to patients with metastatic disease, as was suggested originally by Labrie in the early 1980s. E-mail address: [email protected]. 1569-9056/$ – see front matter # 2004 Published by Elsevier B.V. doi:10.1016/j.eursup.2005.01.002
Patients, however, have improved both their length of survival and the quality of survival in the last 20 years. In 1989/90 the average duration of response to castration was between 18 and 24 months and when patients progressed after this their further survival was rarely longer than 6 months. In contemporary studies these patients appear to survive twice as long on average now and this is probably because of the closer monitoring, and the active attention to controlling symptomatic changes together with the utilisation of more than one hormone in a secondary or even tertiary setting before non-hormonal therapy is introduced. In men in their late 70s or early 80s (still the majority of prostate cancer patients) who present with metastases, the average 4-year survival may well equate to their expected natural survival [2]. What has been helpful is recognising that the 4 hormonal therapies, surgical castration, anti-androgens, LHRH agonists, or oestrogen therapy may be used sequentially and that second hormone responses in significant numbers of patients as judged by the fall in PSA values is a frequent concomitant of this hormone therapy and often similar benefits can be achieved using oestrogens as a third line therapy if anti-androgens had been used initially followed by LHRH treatment. The duration of PSA responses to second and third line treatment may each be of the order of 12 months or more and certainly at present is both less toxic and immensely more beneficial than current chemotherapeutic agents whose survival benefit appears to be no better than 2 months [3,4]. Because of the significant side effects associated with hormonal treatment, studies in the utility of intermittent hormone therapy have been carried out since the original description by Klotz in 1988. A feasibility study carried out by the EORTC showed that in men with metastatic disease a 3–4 month course of hormones was sufficient in over 80% to reduce the PSA to a nadir value, and that utilising an arbitrary
54
P. Whelan / European Urology Supplements 4 (2005) 53–56
value of 20 ng/ml as a threshold to recommence treatment patients even with a heavy burden of metastatic disease were entirely safe. Both it and the early reports of randomised prospective trials in intermittent therapy have frequently showed prolonged responses after initial therapy such that patients may be off treatment for up to 12 months with significant benefit as far as side effects from therapies concerned accruing to the patient. But it is noteworthy that most intermittent therapy regimes demonstrate, as more cycles are past through that the duration off the hormonal medication begins to get shorter and in many patients eventually the duration is of the order of a month or so being so short as to suggest that continual hormonal therapy is now the preferential option. To date in the small number of studies published, there is no evidence that intermittent therapy is less effective in patients with metastatic disease that continual therapy, but survival has not been compromised but that the total of side effects has been reduced [5,6].
3. Locally advanced prostate cancer Although it is arbitrary, patients presenting with PSAs over 20, Gleason scores of 7 and greater, or evidence on imaging of stage T3 disease, even in the absence of lymphadenopathy or proven bone metastases are rarely considered as good subjects for treatment with curative intent, although many of them with no evidence of metastases will receive external beam radiotherapy and some, indeed, may well undergo radical surgery although the rationale for this, let alone the evidence base as formulated by clinical trials is vanishingly small. Many of these patients may receive a course of neo adjuvant and/or adjuvant hormone treatment which may last as long as 3 years. This was demonstrated to be better than radiotherapy alone in a landmark paper by Bolla et al. 1997 [7] and confirmed in RTOG studies [8]. It remains a moot point as to whether or not there is a greater benefit from the combination than with hormones alone and a prospective trial to address this problem is currently nearing completion under the aegis of the MRC in the UK and NCI Canada. Many of these patients with locally advanced disease may choose to go on to hormone therapy and frequently an anti-androgen would seem a logical first choice as compared with LHRH; especially in the younger men there is a slow loss of potency which may be important. Many of these patients will, after a variable period of time, show progressive rise in PSA
even in the absence of objective evidence of metastases whether in the bones or in the lymph glands [9]. There remains controversy as to what is the correct treatment for these patients. There is no evidence currently available that non-hormonal treatment makes any change in the course of the natural history of this disease although some recent positive responses to chemotherapy in hormone resistant disease is likely to need clinicians to consider moving chemotherapy into this earlier phase. This should and must be done as a prospective randomised trial. Especially as all information in the past suggests that chemotherapy has a limited role in this disease whereas hormonal treatment remains demonstrably effective when used even as second and a third line treatment after an initial hormone therapy. It is arguable but extremely doubtful that a patient can be truly said to be hormonal refractory unless they have been exposed to all forms of hormonal treatment (allowing that surgical and medical castration are equivalent). It would seem increasingly important therefore that studies of intermittent therapy with proven effective agents (the hormones) be continued to be undertaken at the same time as chemotherapeutic agents and other novel therapies are looked at. It would seem wrong to deny a patient effective treatment just because something is fashionable (and almost invariably very expensive) [9]. The continuing difficulty of knowing whether early or late hormonal therapy in patients with locally advanced disease has an effect on the outcome may well be answered by an EORTC study commenced in 1989 and now analysed for the first time and submitted as an abstract to the AUA and the EAU. This compared immediate versus deferred therapy in locally advanced disease and suggests, as did the previous MRC study, that there is some benefit in immediate hormone treatment in terms of crude survival but expresses caution and urges a balance to be struck as to whether the side effects stretched over many years of continual hormone treatment is a price worth paying for a small survival benefit. Intermittent therapy again if tested in this setting may well help to bridge the gap between keeping the disease under control and possibly gaining some survival advantage and minimising the inevitable effects of long term hormone treatment.
4. Biochemical failure following definitive treatment for early stage prostate cancer At least a third and possibly as many as half or more of patients undergoing attempted curative therapy with
P. Whelan / European Urology Supplements 4 (2005) 53–56
either radical surgery, radical external beam radiotherapy, brachytherapy or novel treatments such as HIFU will have sooner or later evidence of biochemical failure [10]. The treatment of these patients is difficult especially psychologically as they will have all felt they were having treatment which would have cured their cancer. The presence of a PSA value is certain evidence that this has not been so and may well be more psychologically upsetting in patients choosing radical surgery whilst there will be evidence of some local recurrence at times very often a rise in the PSA indicated that the disease is metastatic. The amount of support these patients need is poorly documented and understood. The role of hormone therapy remains even more controversial in this category above all others especially now as in the modern era it is become increasingly the largest group which is encountered. For reasons that remain controversial and puts urologist in a less than favourable light the logical trial of immediate versus deferred hormonal treatment in patients with a rising PSA following definitive therapy whilst it has been attempted by several international research organisations has never been completed principally because patients have demanded early treatment and so called ‘‘experts’’ seem to have changed their opinions as to whether immediate or deferred treatment is preferable as often as their socks. The end result sadly has meant that there has been no consensus on enabling patients to enter trials. There remains the observational study of a cohort group from Johns Hopkins published by Pound et al. 1999 [11] demonstrating that there was at least 8 years from initial rise of PSA following a radical prostatectomy to objective evidence of metastases and that a further 5 years on average ensued before these patients died of their cancer. This group had therefore recommended that patients should not commence treatment straight away but this should be reserved until objective metastases were evident. There is no indication as the amount of psychological support the patients were offered during the period of 8 years whilst the PSA was persistently rising. What has become obvious is the course of the disease even if it is not effectively cured will be long and that the prospect of being on continual hormone therapy for more than 10 years especially if LHRH agonists are used, will induce significant side effects the principle one being osteopeania which will go on to develop osteoporosis almost certainly at an accelerated rate compared with age related controls. Allied to this there is evidence of increasing muscle wasting, lack of strength, increasing lethargy and anecdotal evidence, usually produced by wives and partners of many men that those on long term hormone treatment undergo
55
profound personality changes which may well be attributable to the hormone treatment [12]. Because of these problems it seems very difficult, just as it was 10 years ago to initiate a trial of immediate versus deferred hormonal treatment. A way through this again may be possible by utilising intermittent therapy using not only hormones which we know work but are palliative and work in the majority of cases for a limited period or time but incorporating in on an intermittent model chemotherapeutic and other novel agents to try and control PSA rise and hopefully progression of the disease. In this fashion shorter term studies or side effects and quality of life and be publishable and valid without needing to wait 10 or 15 years for a definitive study which will look at survival alone.
5. Conclusions Prostate cancer remains a hormone sensitive tumour. In studies dating from the original ones of Huggins and Hodges (1941) [13] approximately 10% of patients appear to be cured by hormone treatment but the vast majority of the other 90% get symptomatic and palliative relief which now having the ability to offer at least 2 options if not 3 options of hormone treatment appears to have doubled the survival in all stages of advanced prostate cancer. We must be active in setting up clinical trials to look how patients who have failed definitive therapy or present when definitive therapy will not effect a cure, but who nevertheless have a life expectancy that will be measured in many years rather than in a handful of years, receive the maximum benefit that current treatments have and that hormonal therapy must remain the bedrock of disease control until prospective clinical trials conclusively prove that either newer chemotherapeutic agents or novel therapies have supplanted the hormonal benefits. Hormones themselves now that we recognise at least 3 categories of hormones each of which may be used in sequence may further be explored by the intelligent use of trials looking at intermittent therapy monitoring the control of the PSA and giving to patients the maximum benefit with respect to side effects of being off therapy. Because prostate cancer has such a long history surrogate end points such as quality of life and disease control may legitimately be looked at but quality of life should be the prominent factor that drives treatment options and newer and inevitable more expensive treatments have to be vigorously and rigorously tested and not allowed to become part of the armamentarium of the management of prostate cancer patients merely by fashion.
56
P. Whelan / European Urology Supplements 4 (2005) 53–56
References [1] Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1999. CA Cancer. J Clin 1999;49:8–31. [2] Dennis LK, Resnick MI. Analysis of recent trends in prostate cancer incidents and mortality. Prostate 2000;42:247. [3] Smith DC, Redmond BG, Flaherty R. A phase II trial of oral diethyloesterol as a second line hormonal agent in advanced prostate cancer. Urology 1988;52:257. [4] Iverson P. Orchidectomy and oestrogen therapy revisited. Eur Urol 1998;34(Suppl):7. [5] Goldenberg SC, Bruchovsky N, Gleave ME. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. J Urol 1997;157(Suppl):390. [6] Albrecht W, Collette L, Fava C, Kariakine OB, Whelan P, Struder UE, et al. Intermittent maximal androgen blockade in patients with metastatic prostate cancer. An EORTC feasibility study. Eur Urol 2003;44:505–11. [7] Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997;337:295.
[8] Pilepich MV, Winter K, John MJ, et al. Phase III radiation therapy Oncology Group (RTOG) trial 86-10 of androgen depravation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243. [9] Iverson P, Tyrrell CL, Kaisery AV, et al. Bicalutamide monotherapy compared with castration in patients with locally advanced prostate cancer. 6.3 years of follow up. J Urol 2000;164:159. [10] Blute ML, Bergstralch EJ, Iocca A, et al. Use of Gleason score, prostate specific antigen seminal vessels and margin status to predict biochemical failure after radical prostatectomy. J Urol 2001;165:119. [11] Pound CR, Partin AW, Eisenberger MA, et al. National history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591. [12] Litwin MS, Saigal CS, Lubeck DP, et al. Health-related quality of life in men with metastatic prostate cancer: the misleading effect of lead time bias. BJU Int 2003;91:9. [13] Huggins C, Hodges CV. Studies in prostate Cancer: effect of castration, oestrogen’s and or androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941;1:293.