Clinical phase II studies of IAS

2.2.1. Comparison of therapeutic efficacies of IAS and CAS

Following apparently successful pilot studies, a number of phase II IAS trials were conducted (Table 1) [16]. Since the end points of most phase II studies were safety and feasibility of IAS, survival data were not reported in general. Out of the 19 studies reviewed by Abra-hamsson only five involved more than 100 patients (102, 103, 146, 250 and 566 patients, respectively) and the other smaller studies employed a mean number of 52 patients [16]. Although patients with advanced, metastatic prostate cancer were included in several studies, most patients treated in phase II IAS trials had localized disease or biochemical progression following prostatectomy/radiation therapy. The number of IAS cycles given ranged from 1 to 12, with an average of 2-3 per patient, and the length of time off therapy generally decreased or remained stable with each succeeding cycle. Most of the studies reported off-treatment periods of approximately 50% of the duration of the IAS cycles, dependent on the tumor stage of the respective prostate cancer patients [16]. A metaanalysis by Shaw et al. involving ten phase II trials reported a median number of two cycles per patient and a median time off-therapy of 15.4 months [21]. Time on treatment also varied but was usually in the region of 6-9 months [16]. The proportion of men in whom serum testosterone normalized was generally high following the first cycle (70-90%) but tended to decrease during subsequent cycles [16]. Factors influencing time to delay in testosterone normalization may include advanced age, low baseline testosterone levels, and duration of AS. Testosterone recovery to baseline values was achieved in 79% during the first and in 65% during the sec ond IAS cycle, respectively [22]. No significant difference was observed up to 1000 days between IAS and CAS with regard to time to androgen-independent tumor progression.

Endpoint(s)

Calais da Silva et al. [13] 626 Time to subjective or objective progression

Verhagen et al. [35] Klotzet al. [34] Salonen et al. [41,42] Hussain et al. [17]

68 Time to androgen-independence

335 Time to clinical or biochemical progression

173 Overall survival

290 Time to clinical progression or PSA escape

184 Clinical or PSA progression

366 QoL

1386 Survival

554 Progression/ Survival

1345 Survival

Tumor stage

Locally advanced or metastatic

Locally advanced, metastatic or recurrent locally advanced or D1/D2

Metastatic PCa (D2) Advanced or locally advanced

PSA relapse after radical prostatectomy

Metastatic

PSA recurrence after radical Radiotherapy

Advanced or locally advanced

Advanced (D2)

Androgen suppression

GnRH agonist + cyproterone acetate

Goserelin + flutamide

Goserelin + bicalutamide

Leuprorelin + flutamide Buserelin depot + nilutamide

Leuprorelin + cyproterone acetate

Cyproterone acetate All types of AS

Goserelin + cyproterone acetate Goserelin + bicalutamide

Table 1. Overview of the published phase II IAS trials

In a study by Bruchovsky et al. men who quickly recovered serum testosterone levels experienced a more rapid rise in PSA levels and a shorter time off therapy [23]. Generally, low levels (2-16%) of progression to hormone-refractory prostate cancer have been reported [16,22]. In a review by Zhu et al. there were 16 trials that compared IAS with CAS with a total of 3264 patients (1624 with IAS and 1640 with CAS) [24]. Pooled effects indicated no significant difference between IAS and CAS groups in terms of death and progression rate (hazard ratio HR=0.99, 95% CI 0.80-1.23, and HR=1.03, 95% CI 0.84-1.26 respectively). Calculated results indicated that quality of live (QoL) on sexual activity was significantly higher in the IAS group (HR=0.24, 95% Cl 0.17-0.33, p<0.00001). Moreover, IAS could effectively reduce side effects associated with AS. Thus, the therapeutic efficacy was not significantly different between the IAS and CAS groups. However, IAS could effectively preserve the QoL (in particular sexual life) and reduce the side effects.

2.2.2. Comparison of the side effects/QoL of IAS and CAS

Because it became increasingly clear that the time to androgen-independence seems not to be prolonged by IAS, trials focussed on the impact of the intermittent therapy on side effects of AS and QoL. Malone et al estimated that approximately 50% of patients recovered from anaemia during off-therapy periods and that the weight gain normally associated with CAS was prevented [25]. Bouchot et al reported hot flushes in most cases during the on-therapy period, which showed significant improvement during treatment cessation periods and pain significantly improved during on-therapy periods with no new pain occurring once therapy was withdrawn [26]. Goldenberg et al. observed that all patients tolerated therapy well and responded in a positive physical and psychological manner to the cycling approach [27]. The attenuation of spine and hip bone mineral density (BMD) decline after 3-year IAS compared with those reported for CAS appears to be due to testosterone-driven BMD recovery in the cessation period [28]. Failure of testosterone recovery was associated with worse final BMD. Patients experienced the greatest average change in BMD during early treatment periods of IAS with a smaller average change thereafter and fractures were rare [29]. During the first off-treatment period (median duration 37.4 weeks), BMD recovery at the spine was significant; however, subsequent periods had heterogeneous changes of BMD without significant average changes. By reducing the potential risk for adverse bone complications, intermittent therapy may become an important consideration when the therapeutic ratio is narrow [30]. We examined the effect of IAS on bone metabolism by determinations of CrossLaps levels, a biochemical marker of collagen degradation, in blood samples of prostate cancer patients. Measurements of the CrossLaps concentration in patients under IAS revealed that treatment cessation phases rapidly reversed increased bone degradation, which was associated with the AS phases, in good agreement with the clinical observations of reduced loss of BMD in IAS [31]. Since pretreatment concentrations of CrossLaps were restored within several months of treatment cessation and mean duration of the off-treatment periods ranged from 8-16 months in our patients, this protective effect of IAS is expected to be effective for several treatment cycles. Additionally, procollagen I N-terminal peptide (PINP), a parameter of bone synthesis was increased during off-treatment phases in IAS [32].

Improvement of sexual activity was highlighted in several studies and concerned approximately half of the patients [16]. Sato et al reported significant worsening of potency and physical well-being during AS and significant improvements in potency, lack of energy, social/family well-being, and ability to enjoy life during off-therapy periods [33]. In a study by Spry et al. QoL scores also deteriorated during androgen suppression, but had generally achieved baseline levels by the end of the off-treatment period [28]. In summary, IAS showed benefits in the treatment of prostate cancer with respect to QoL in the majority of trials.

2.2.3. IAS phase II studies - conclusion

In phase II studies there has been considerable variation in the particular approaches in regard to medication, duration of AS phases, target PSA nadir and selection of the PSA value for restarting therapy. At that time preliminary results of the the ongoing randomized controlled trials have generated evidence that the use of IAS in patients with advanced or locally advanced disease was at least as safe as CAS [16,24]. In conclusion, phase II studies of IAS demonstrated that several cycles of IAS were feasible, the duration of response was not worse than historical controls of CAS and well-being was better during treatment cessation periods. Patients with localized disease fared superior under IAS compared to patient with extended disease. The need for randomized phase III trials was stressed in order to get firm data on progression-free and overall survival (OS) as well as time to androgen insensitivity for IAS and CAS, respectively.

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