Intermittent Hormone Therapy: What Is Its Place in Clinical Practice?☆

3.1.1. Phase 2 trials 

Over the years, >20 phase 2 trials including >2000 patients have evaluated the feasibility, efficacy, and safety of IHT [15], [17]. These studies, however, generally included small numbers of patients with different disease stages (ie, patients with localised disease, locally advanced disease, metastatic disease, prostate-specific antigen [PSA] relapse after local therapy) [15], [17], [18]. Additionally, they differed in their study design and methodology. A meta-analysis combined 10 phase 2 trials including a total of 1446 patients [18]. In all trials combined, patients spent a mean of 39% of the time off treatment. Fig. 1 displays the overall results regarding the percentage of patients off treatment at 2 yr, overall survival, and the percentage of patients progressing to CRPC for patients with localised disease, patients with a PSA relapse after radical prostatectomy (RP) or radiotherapy (RT), and patients with node-positive or metastatic PCa. Multivariate analysis showed that the initial PSA level and PSA nadir were important predictors of clinical outcome for PCa patients treated with IHT.

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Fig. 1. Results of a meta-analysis of 10 phase 2 studies on intermittent hormone therapy (IHT) showing the percentage of patients off treatment at 2 yr, overall survival, and the percentage of patients progressing to castration-resistant prostate cancer (CRPC) separately for patients with localised prostate cancer (PCa), patients with a prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or radiotherapy (RT), and patients with node-positive (N+) or metastatic (M+) PCa [18].

The phase 2 trials have limitations, but they do demonstrate that IHT has good acceptance and feasibility. Patients experienced improved QoL, and treatment-related morbidity was reduced during off-treatment periods. Additionally, IHT did not appear to have a negative effect on time to progression or survival. Because these phase 2 studies were of different quality regarding design and the use of small and heterogeneous study populations, these results need to be confirmed in well-designed phase 3 trials. These phase 3 trials also are needed to answer some outstanding questions related to the effect of IHT on time to CRPC and on overall and PCa-specific survival and which patients will benefit most from IHT [3].

3.1.2. Phase 3 trials 

Randomised controlled phase 3 trials evaluating IHT are being conducted in Europe, the United States, Canada, and Japan, but unfortunately, most of these trials are not mature yet [3]. Recently, the results of the South European Uroncological Group (SEUG) trial were published, including a total of 626 patients with T3–4 M0–1 PCa receiving no previous treatment [19]. After a 3-mo HT induction period (consisting of maximum androgen blockade [MAB] with cyproterone acetate and a luteinising hormone-releasing hormone [LHRH] agonist), patients whose PSA level decreased to <4 ng/ml or by at least 80% of the initial level were randomised to continuous HT (n=312) or IHT (n=314). For patients in the IHT group whose PSA levels had decreased <4 ng/ml, therapy was restarted when PSA levels increased to ≥10 ng/ml for symptomatic patients and to ≥20 ng/ml for asymptomatic patients. For patients whose PSA level had decreased to at least 80% of the initial value, therapy was restarted when PSA levels rose to ≥20% above the nadir. At a median follow-up of 51 mo, 54% of the included patients had died. Median time of treatment for patients in the IHT arm was 13 mo, with 50% of patients being off therapy for ≥13 mo and 29% of patients being off therapy for ≥36 mo. There was no difference in overall survival between both groups (170 deaths in the IHT arm vs 169 deaths in the continuous HT arm; Table 1). Time to objective progression and/or subjective progression was slightly longer for patients treated with continuous HT compared to IHT (Table 1). The slightly greater number of cancer deaths in the IHT arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous HT arm (52 vs 41). Side-effects were more pronounced in the continuous HT arm compared to the IHT arm (Fig. 2). Both PSA level and metastatic status at randomisation were independently associated with survival. It was concluded that although further randomised studies are needed, IHT should be considered for use in routine practice because it seems to be associated with no reduction in survival, with better QoL, and with a considerable economic benefit to the individual and community.

Table 1. Intermittent hormone therapy versus continuous hormone therapy: results from the South European Uroncological Group (SEUG) trial [19]

	Overall survival	HR: 0.99 (95% CI, 0.80–1.23; p=0.84)
	Subjective/objective progression	HR: 0.81 (95% CI, 0.63–1.05; p=0.11)

HR=hazard ratio; CI=confidence interval.

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Fig. 2. Percentage of patients reporting side effects at least once in the South European Uroncological Group (SEUG) trial [19]. HT=hormone therapy; IHT=intermittent hormone therapy.

Another phase 3 randomised trial evaluating IHT versus continuous HT is the Southwest Oncology Group (SWOG) 9346 trial. This trial included 1395 patients with newly diagnosed metastatic stage IV PCa and a baseline PSA level of at least 5 ng/ml [20]. 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 HT or IHT. The patients in the IHT group remained untreated (off-treatment period) in the absence of rising PSA levels or clinical symptoms of progressive disease. The SWOG 9346 trial has not closed yet, and final results are awaited. In a preliminary analysis, Hussain et al have evaluated whether the PSA level after the 7-mo induction period is a prognostic factor for survival for patients with metastatic stage IV PCa treated with HT [20]. At the end of the induction period, 965 patients (71%) had a PSA level of ≤4 ng/ml and 604 patients (45%) had a PSA level of ≤0.2 ng/ml. Median survival was 13 mo for patients with a PSA level >4 ng/ml, 44 mo for patients with a PSA level 0.2–4.0 ng/ml, and 75 mo for patients with a PSA level <0.2 ng/ml. A PSA level ≤4 ng/ml after 7 mo of HT was a significant predictor of risk of death (hazard ratio [HR]: 0.26; 95% confidence interval [CI], 0.22–0.31; p < 0.0001), indicating that these patients had one-fourth the risk of dying relative to those who did not have a PSA level of ≤4 ng/ml. A PSA level of ≤0.2 ng/ml was also a significant predictor of longer survival (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.

Contrary to the previous trials that evaluated IHT in patients with advanced or metastatic PCa, the randomised, multicentre, European phase 3 trial EC507 evaluated IHT in PCa patients in whom a relapse in PSA level after radical prostatectomy had occurred [3], [17], [21]. Patients received 6 mo induction therapy with MAB; if the PSA level decreased <0.5 ng/ml, the patient was randomised to either IHT (n=109) or continuous HT (n=92). In the off-treatment period, treatment was reinstituted when the PSA level increased >3 ng/ml or when there was clinical progression. The 2-yr results were presented at the 2007 annual meeting of the American Urological Association (AUA) [22]. Patients spent a median of 57% of the total time in the first cycle off treatment and 53% of the total time in the second cycle off treatment [3]. Kaplan-Meier analysis showed no statistically significant difference in progression-free survival between the IHT and the continuous HT arms (p=0.883). Patients in the IHT group experienced fewer days with side-effects such as hot flushes than patients in the continuous HT group. Additionally, there was less bone degradation in patients treated with IHT versus continuous HT [15]. Early results from a European phase 3 trial comparing IHT monotherapy (n=460) with continuous HT consisting of MAB (n=454) in patients with advanced PCa also showed that IHT monotherapy was associated with fewer side-effects and better sexual activity than continuous combined HT [23].

3.2.1. How should intermittent hormone therapy be applied? 

IHT is a cyclic therapy consisting of on-treatment periods followed by off-treatment periods. A complete IHT cycle comprises both the on- and off-treatment periods and is thus the period between initiating HT and reinstituting treatment after an off-treatment period [3]. In most clinical trials, an induction therapy of 6–9 mo is applied; however, there is no clinical evidence supporting one duration over another. Treatment can consist of MAB or LHRH agonist monotherapy and should ideally be continued until castration-induced apoptosis is maximal and tumour regression is induced, but it should be stopped before the androgen-independent phenotype is developed [15], [16]. Generally, a fixed, on-treatment period is used, lasting for 6–9 mo. In some protocols, however, this period lasts until a PSA nadir of <4 ng/ml is reached [15]. The off-treatment period is variable and depends on local progression and/or progression of PSA. Trigger points for restarting therapy should be individualised and should depend on the pretreatment PSA level, clinical stage, PSA velocity, presence of symptoms, and tolerance of HT [16]. Gleave et al suggest that in patients with metastatic disease and high pretreatment PSA levels, therapy should be restarted when the PSA level increases to 20 ng/ml [16]. In patients with locally recurrent disease and moderately elevated pretreatment PSA levels, therapy should be restarted when the PSA level reaches 6–15 ng/ml [24], and HT should be started earlier than this for patients with relapses after RP. It should be noted, however, that these PSA-threshold levels for reinstituting therapy are currently chosen empirically and are based on the ongoing phase 3 trials [3].

During the IHT cycles, patients should be monitored with testosterone and PSA measurements at the start of therapy and every 2–3 mo during the off-treatment interval [24]. A clinical evaluation should take place every 6 mo.

3.2.2. Who can be treated with intermittent hormone therapy? 

IHT can be considered in patients who respond to HT with a decline in PSA levels to normal values (<4 ng/ml). 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, the level should be <0.5 ng/ml [15].

Caution is warranted in patients with high pretreatment PSA levels or low PSA doubling times, patients with a high clinical stage or high-grade disease, or patients with a high metastatic burden [16], [17]. In a Finnish multicentre study comparing IHT with continuous HT, it was shown that patients with advanced PCa with a high baseline PSA level, high alkaline phosphatase level, high proportion of T4 tumours, poorly differentiated tumours, metastatic disease, and those with more than five skeletal hot spots did not show an adequate PSA response to HT [25]. According to the authors, these patients should not be candidates for IHT. IHT, however, does seem to be a feasible treatment option for patients with locally advanced hormone-sensitive PCa.