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Can Intermittent Hormone Therapy Fulfil its Promise? Ulf Tunn * Klinikum Offenbach, Academic Hospital of JW Goethe University Frankfurt/Main, Urological Department, Starkenburgring 66, Offenbach am Main, Offenbach 63069, Germany
Keywords: Intermittent hormone therapy Prostate cancer Review article Side effects Quality of life
Context: Hormone therapy (HT) is the mainstay treatment for patients with metastatic prostate cancer (PCa) and is increasingly being used in patients with advanced PCa and those with relapse in a prostate-specific antigen (PSA) level after local therapy. Intermittent HT (IHT) is being investigated as an alternative to continuous HT with a potential for reduced morbidity and a delay of the progression to hormone refractory PCa (HRPC). Objective: This paper aims to give an overview of the current status of IHT in PCa. Evidence acquisition: This paper was based on a presentation given at a satellite symposium on PCa that was held at the 2008 annual meeting of the European Association of Urology in Milan, Italy. Data were retrieved from recent review articles, original articles, and abstracts on IHT. Evidence synthesis: Several phase 2 trials have demonstrated the feasibility of IHT, its beneficial effects on quality of life (QoL), and its potential for reduced morbidity. In these studies IHT did not appear to have a negative effect on time-to-progression or on survival. Phase 3 trials are currently ongoing, and preliminary results suggest that indeed IHT has no negative impact on overall or progression-free survival compared with continuous therapy. In these studies patients treated with IHT also had a better overall QoL and a reduced frequency of side-effects. However, the phase 3 studies are not yet mature, and final data regarding survival and time-to-progression to HRPC are awaited. Conclusions: Although final data from phase 3 trials are awaited, IHT appears to have no negative impact on overall and progression-free survival, and it may improve QoL. # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Tel. +49 (69) 8405 3840; Fax: +49 (69) 8405 4080. E-mail address: [email protected]
, [email protected]
Hormone therapy (HT) is being used for treatment of several stages of prostate cancer (PCa). It has proven efficacy and has been the mainstay treatment for
metastatic PCa for many years . The goal of HT in patients with metastatic PCa is to avoid, delay, or palliate symptoms and to prevent or reduce the risk of complications of advanced disease, but not to improve overall survival . HT is also increasingly
1569-9056/$ – see front matter # 2008 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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being used in earlier stages of PCa such as in cases of a relapse in prostate-specific antigen (PSA) levels after previous local therapy and in cases of advanced PCa . Whether immediate HT is beneficial in these clinical settings, however, is still a matter of debate . The use of HT is typically continuous and maintained until the disease progresses or the patient dies. Many patients will thus receive HT for a (very) long time, which makes them increasingly vulnerable to the side-effects of this therapy. In the short term, HT may be associated with hot flushes, impotence, loss of libido, and fatigue [3–5]. Longer use of HT may lead to bone demineralisation, anaemia, decreased muscle mass, lipid disorders, obesity, mood changes, and neurocognitive decline. The risk of cardiovascular morbidity and mortality may also be increased [6–8]. With long-term therapy, sideeffects can be a continuous bother rather than a transient nuisance and can have a negative impact on quality of life (QoL). However, although HT has side-effects, most of them may be reversible upon withdrawal of treatment [5,9]. Another aspect of continuous HT is the development of hormoneresistant PCa (HRPC). It has been shown that the majority of patients with metastatic PCa treated with continuous HT will progress to HRPC within 2–3 yr [9,10]. In addition, preclinical studies have shown that androgen replacement restored the apoptotic potential of the androgen-dependent tumour cells that had survived HT and had delayed the development of androgen independence [11–13]. In intermittent HT (IHT) tumour models, such as androgendependent Shionogi carcinomas in mice and human prostate cancer (LNCaP) xenografts, androgen independence was prolonged up to three times. The authors concluded that IHT can induce multiple apoptotic regressions in these tumours [11,14–16]. The advantages and disadvantages of continuous HT need to be carefully balanced. IHT is increasingly being investigated as an alternative to continuous HT with the aim of minimising side-effects, maintaining or improving QoL, and delaying the progression to HRPC. IHT may additionally imply a reduction in treatment costs . This paper reviews the current evidence on the use of IHT for PCa.
This paper was based on a presentation given at a satellite symposium on PCa that was held during the 23rd annual meeting of the European Association of Urology (EAU) on March 26, 2008 in Milan, Italy. Data were retrieved from recent review articles, original articles, and abstracts on IHT.
3.1. What is intermittent hormone therapy and who can be treated with it?
IHT is a cyclic therapy consisting of on-treatment periods followed by off-treatment periods . A complete cycle comprises both the on- and offtreatment periods and is thus the period between initiating HT and reinstituting treatment after an off-treatment period. The on-treatment period of the cycle is generally fixed. It should last up to the point that HT-induced apoptosis is maximal but should be stopped before the cancer progresses to the hormone refractory status. In general, patients are treated for 6–9 mo or in some protocols until a PSA nadir (<4 ng/ml) is reached. It has also been suggested that patients be treated for 2–3 mo after the PSA nadir has been reached. The off-treatment period is variable, and its duration is determined by the patient’s PSA level. If a rise in PSA level is observed during the offtreatment period, a new treatment cycle is initiated. The PSA-level thresholds for reinstituting therapy are currently chosen empirically and are based on ongoing phase 3 trials. In hormone-naı¨ve patients without metastatic disease, the threshold PSA level is 6–15 ng/ml, whereas in those with metastatic disease the threshold level is 10–20 ng/ml. In patients with a relapse in PSA level after radical prostatectomy (RP) or radiotherapy (RT) the threshold PSA levels are >3 ng/ml and >6–10 ng/ml, respectively . IHT can be considered in patients who respond to HT with a decline in PSA levels to normal values . In previously untreated patients a normal value is considered to be <4 ng/ml; for patients who have had a relapse in PSA level after RP or RT this is <0.5 ng/ml [3,9]. 3.2. What is the evidence on intermittent hormone therapy? 3.2.1.
Phase 2 trials
Over the years, >20 phase 2 trials which have included >2000 patients have evaluated the feasibility, efficacy, and safety of IHT [3,9]. These studies have generally included small, heterogeneous study populations, (ie, patients with localised disease, locally advanced disease, metastatic disease, or a relapse in PSA level after local therapy) and have had various designs [3,9,17]. Most studies evaluating IHT used maximum androgen blockade (MAB; a combination of a luteinising hormone-releasing hormone (LHRH) agonist and an antiandrogen); some studies used monotherapy with a LHRH
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agonist or an antiandrogen. Recently, a metaanalysis of 10 phase 2 trials was published, including data on 1446 patients . In all trials combined, patients spent a mean of 39% of the treatment cycle off-treatment. Multivariate analysis showed that the initial PSA level and the PSA nadir were important predictors for clinical outcome for PCa patients treated with IHT. Overall, the phase 2 trials demonstrated that IHT has a good feasibility. Patients experienced improved QoL during off-treatment periods and treatmentrelated morbidity was reduced. In addition, in the phase 2 studies IHT did not appear to have a negative effect on time-to-progression or on survival. However, because these phase 2 studies were of different quality in terms of study design and use of small and heterogeneous study populations, these results need to be confirmed in well-designed phase 3 trials. In addition, results from these phase 3 trials are needed in order to answer some outstanding questions about the effect of IHT on time-to-HRPC and on overall survival, and about which patients benefit most from IHT . 3.2.2.
Phase 3 trials
Several randomised, controlled phase 3 trials evaluating IHT are currently ongoing in the United States, Canada, Japan, and Europe (Table 1). These trials are being performed in patients with advanced or metastatic PCa or patients with a relapse in PSA level after RP or RT. 126.96.36.199. Phase 3 trials in patients with advanced or metastatic prostate cancer. Three trials that have all closed,
evaluated IHT in patients with advanced or metastatic PCa: Southwest Oncology Group (SWOG) 9346 trial, AP 17/95 trial, and South European Urological Group (SEUG) trial.
Table 1 – Phase 3 trials evaluating intermittent hormone therapy Trial NCIC/PR7 EC 507 ICELAND SEUG Japan AP 17/95 SWOG 9346 EC 210
Study population PSA relapse after RT PSA relapse after RP PSA relapse/locally advanced Advanced PCa Locally advanced PCa Advanced PCa and M+ PCa M+ PCa (PSA > 5 ng/ml) M+ PCa (PSA > 20 ng/ml)
No. of patients 1340 201 700 766 300 325 1500 387
PSA = prostate specific antigen; RT = radiotherapy; RP = radical prostatectomy; PCa = prostate cancer; M+ = metastatic; NCIC = National Cancer Institute of Canada; SEUG = South European Urological Group; SWOG 9346 = Southwest Oncology Group 9346 trial.
The SWOG 9346 trial included 1395 patients with metastatic, stage IV PCa . These patients received MAB (LHRH agonist plus bicalutamide) for 7 mo as an induction therapy; those with a PSA level <4 ng/ml were then randomised to either continuous MAB or IHT. In the absence of rising PSA levels or clinical symptoms of progressive disease, patients remained untreated (off-treatment period) . When PSA levels rose (>20 ng/ml) or clinical symptoms of progressive disease appeared, patients resumed MAB. Patients whose PSA levels normalised after 8 mo stopped MAB (off-treatment period). Patients whose PSA levels did not normalise after 8 mo continued MAB therapy. Using data from the SWOG 9346 trial, Hussain et al have evaluated whether the PSA level after the 7-mo induction therapy can be prognostic for patients with metastatic stage IV PCa . During the induction therapy, in 965 of the included patients (69%) a PSA level of 4 ng/ml was achieved and maintained, and in 604 patients (43%) a PSA level of 0.2 ng/ml was achieved and maintained. Median survival was 13 mo for patients with a PSA >4 ng/ml, 44 mo for patients with a PSA level 0.2–4 ng/ml and 75 mo for patients with a PSA level of <0.2 ng/ml. A PSA level 4 ng/ml was a predictor of risk of death after 7 mo HT (hazard ratio (HR): 0.26; 95% CI, 0.22–0.31; p < 0.0001) as was a PSA level of 0.2 ng/ml (HR: 0.34;95% CI 0.29–0.40; p < 0.0001). It was concluded that a PSA level of 4 ng/ml after 7 mo of MAB induction therapy is a strong predictor of survival. Patients with a PSA level of 0.2 ng/ml have the greatest survival advantage. The AP 17/95 trial was a multicentre, randomised, phase 3 study evaluating intermittent MAB versus continuous MAB in patients with advanced/ metastatic PCa (T1–4, N1–3, M0 or T1–4, N0–3, M1 (D1 or D2) . After an induction therapy for a period of 6 mo, 335 patients whose PSA level decreased <4 ng/ml or who had a 90% decrease from baseline were randomised to IHT or continuous HT. In the IHT group, on-treatment periods consisted of 6 mo of MAB, and off-treatment periods were variable and restarted when PSA levels increased >10 ng/ml. About two-thirds of the patients in both the IHT and continuous HT groups experienced clinical and/or biochemical progression. There were no statistically significant differences between the groups in median time to disease progression and median time to death (Table 2). A total of 88% of all patients treated with IHT spent >50% of their treatment cycle off treatment. Overall health and sexual activity was perceived to be better by patients in the IHT group compared with those treated continuously.
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Table 2 – Intermittent hormone therapy versus continuous hormone therapy: results from the AP 17/95 trial .
Median time to disease progression, mo Median time to death, mo
Intermittent hormone therapy
Continuous hormone therapy
Table 3 – Intermittent hormone therapy versus continuous hormone therapy: results from the South European Urological Group (SEUG) trial . Overall survival Subjective/objective progression
HR: 1.03 (95% CI, 0.83–1.28; p = 0.79) HR: 1.09 (95% CI, 0.84–1.42; p = 0.52)
HR = hazard ratio; CI = confidence interval.
It was concluded that IHT appears to be safe and feasible in patients with advanced PCa. The SEUG trial is another randomised, phase 3 trial that is comparing intermittent with continuous MAB in patients with T3–4, M0–1 PCa with no previous treatment . After an induction therapy of 3 mo, 626 patients whose PSA decreased <4 ng/ml or to a level 80% below their initial value were randomised to IHT and continuous HT [9,20]. Of the 314 patients on IHT, 50% were off-treatment for 52 wk, and 29% were off-treatment for 36 mo. Statistically, there were no significant differences between the groups in overall survival or subjective/ objective progression (Table 3). It should be emphasised that, at the time of this analysis, 54.4% of all randomised patients had already died. The estimated survival rate at 5 yr was 53.8% in the IHT group and 51.0% in the continuous HT group. IHT was associated with fewer side-effects and a better sexual activity compared with continuous HT . A preliminary analysis suggests that patients with advanced/metastatic disease may have a better survival rate when treated with IHT compared with continuous HT; however, final results of this study are awaited. Very recently, results from the Finn Prostate Study VII were presented that evaluated which patients might benefit from IHT . This study demonstrated that patients with high pretreatment PSA levels, a higher clinical stage, and a higher metastatic burden do not show an adequate biochemical PSA-level response to HT and may therefore not be suitable candidates for IHT.
188.8.131.52. Phase 3 trials in patients with a relapse in prostatespecific antigen level after local therapy. The National
Cancer Institute of Canada (NCIC)-PR7 and EC 507 are two phase 3 trials that are currently being undertaken in patients with a relapse in PSA level after RT or RP. The NCIC-PR7 is a randomised, multicentre trial that includes approximately 1500 patients with a relapse in PSA level after RT and with no evidence of distant metastases . This study opened in January 1999 and closed in November 2005. Patients were randomised to IHT or to continuous HT with MAB. The IHT arm consisted of an 8-mo ontreatment period which was reinstituted in offtreatment periods if PSA levels increased to >10 ng/ml. The final results of this trial are expected at the beginning of 2009. The randomised, multicentre, European, phase 3 trial EC507 is evaluating IHT in PCa patients in whom a relapse in PSA level occurred after RP [3,9,22]. Patients received induction therapy with MAB for 6 mo and, if PSA levels decreased <0.5 ng/ml, were randomised to either IHT (n = 84) or continuous HT (n = 83). The on-treatment period consisted of 6 mo MAB and therapy was discontinued if PSA levels decreased <0.5 ng/ml and if there were no signs of clinical progression. The therapy was reinstituted in the off-treatment period when the PSA level increased >3 ng/ml. The 2-yr data were presented at the 2007 annual meeting of the American Urological Association (AUA) . The median duration percentages in patients with completed first and second IHT cycles were 57% and 53% of the total cycle lengths. There was no statistically significant difference in time-to-progression to HRPC between the two groups ( p = 0.883). Patients in the IHT group experienced less days with sideeffects (eg, hot flushes) than patients in the continuous HT group. The study concluded that IHT is an attractive treatment option in men with a relapse in PSA level.
LHRH agonists have proven efficacy in the treatment of PCa . Although HT has side-effects, most of them may be reversible upon withdrawal of treatment [5,9]. Over the years IHT has been evaluated in several phase 2 trials. These trials have shown the feasibility of IHT and its beneficial effects in terms of improvement in QoL and reduction of side-effects. Well-designed phase 3 trials are currently ongoing. Preliminary results suggest that IHT has no negative impact on overall survival or progression-free
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survival compared with continuous HT. These studies confirmed the benefits of IHT with respect to QoL and treatment-related morbidity. However, they could not demonstrate that IHT prolongs the time to HRPC. Because the phase 3 studies are not yet mature, final data regarding survival, time to HRPC, and QoL benefits are awaited. In addition, there is a clear need for guidance on the use of IHT in clinical practice because the various studies that have been conducted use a range of PSA values for stopping and starting treatment as well as different treatment regimens. The predefined proposed thresholds to stop and resume treatment are based only on the currently ongoing phase 3 trials. Specific clinical trials should therefore be conducted to evaluate these thresholds. The 2008 EAU guidelines conclude that it is possible to offer IHT to selected patients, but results from clinical trials are still lacking. A minimum therapy induction period of 7 mo and a PSA-level response to a level of <4 ng/ml in previously untreated patients is recommended for use in clinical practice .
Conflict of interest Ulf Tunn is a consultant for Abbott and Aeterna Centaris. He is a lecturer for Astellas, Orion, and Takeda Germany. Additionally, he is a consultant and lecturer for Novartis Germany and Takeda Europe. Funding support
The publication of this review was supported by Astellas Pharma Europe. 
Acknowledgements The authors are grateful to Ismar Healthcare NV for their assistance with writing the manuscript.
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