Intermittent androgen deprivation in prostate cancer cases with biochemical progression after radical prostatectomy: Are we ready to treat?

Critical Reviews in Oncology/Hematology 99 (2016) 351–361

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Critical Reviews in Oncology/Hematology journal homepage: www.elsevier.com/locate/critrevonc

Intermittent androgen deprivation in prostate cancer cases with biochemical progression after radical prostatectomy: Are we ready to treat? Susanna Cattarino, Stefano Salciccia, Alessandro Gentilucci, Michele Innocenzi, Vincenzo Gentile, Alessandro Sciarra ∗ Department of Urology, University Sapienza Rome, Italy

Contents 1.

2. 3. 4.

5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 1.1. Clinical trials on IAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 1.2. International guidelines and IAD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 Aim and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 2.1. Evidence acquisition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 IAD for biochemical progression after radical prostatectomy: the rationale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352 IAD for biochemical progression after radical prostatectomy: clinical trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 4.1. Clinical trials: population and treatment planning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 4.1.1. Phase 2 trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 4.1.2. Phase 3 trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 4.1.3. Critical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 4.2. Clinical trials: oncological results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 4.2.1. Phase 2 trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 4.2.2. Phase 3 trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 355 4.2.3. Critical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 4.3. Clinical trials: quality of life and safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 4.3.1. Phase 2 and 3 trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 4.3.2. Critical analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 Critical conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 360 Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361

a r t i c l e

i n f o

Article history: Received 12 April 2015 Received in revised form 7 January 2016 Accepted 12 January 2016 Keywords: Prostate cancer Intermittent androgen deprivation therapy Biochemical failure Radical prostatectomy Radiotherapy

a b s t r a c t Purpose: To evaluate clinical data from published trials on the use of intermittent androgen deprivation (IAD) therapy in patients with biochemical relapse after radical prostatectomy (RP). Methods: We searched the Medline and Cochrane Library databases for literature published on IAD and biochemical progression after radical prostatectomy. Results: To date, we have oncological and functional data from phase 3 studies focused on metastatic and locally advanced stages that confirmed IAD as a valid option treatment. For the aim of this review, only Tunn study, was specifically focused on patients who relapsed after surgery but clear and mature results are still missed. Conclusions: The use of IAD in cases who relapse after RP is common in the clinical practice. Although specific recommendation on the use of IAD in this setting of patients are not available, we concluded that the real benefit of IAD in terms of long survival and quality of life is mainly for patients treated with surgery. © 2016 Published by Elsevier Ireland Ltd.

∗ Corresponding author at: Prostate Unit, Department of Urological Sciences, University Sapienza, Policlinico Umberto I, Rome, Italy. E-mail address: [email protected] (A. Sciarra). http://dx.doi.org/10.1016/j.critrevonc.2016.01.008 1040-8428/© 2016 Published by Elsevier Ireland Ltd.

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1. Introduction Intermittent Androgen Deprivation (IAD) consists of an alternate androgen blockade (on-phase therapy) with treatment cessation (off-phase therapy), which allows for a restoration of testosterone between treatment periods (Chengalvala et al., 2003; Chen and Petrylak, 2004; Higano, 2006). IAD has been found to have two purposes: to delay the time to tumor progression due to castration-induced resistance and to reduce the side effects related to androgen deprivation therapy (ADT) (Heidenreich et al., 2013; Bruchovsky et al., 1990). The rate of diagnosis of prostate cancer (PCa) is increasing in younger men (40–60 years of age) (Siegel et al., 2014) and hormonal therapy is now mainly used as continuous regime in advanced and metastatic cases; thus a great interest has been shown for the hypothesis of IAD. One of the first pieces of evidence of the effects of androgen suppression was derived from a preclinical study by Bruchovsky et al. (1990) who observed a change in stem cell phenotype from an androgen-dependent state to an androgen independent state after androgen suppression. The cessation of androgen deprivation prior to this change seems to be the rationale for IAD. In another preclinical study that used a murine model, Akakura et al. (1993) showed that the time to progression in an androgen-sensitive tumor model was increased 3-fold with IAD compared with continuous androgen deprivation therapy (ADT). The way in which to design a correct schema of IAD is now more clear: the first cycle of ADT (the “induction” phase), which represents a crucial point in IAD therapy, is continued (mainly 6–9 months in clinical trials) until the prostate specific antigen (PSA) level reaches a nadir (a value that depends on PCa cases); then, this therapy is discontinued (off-phase), which allows the testosterone level to return to normal. The on-phase therapy is resumed when the PSA rises to a predetermined level (a value that depends on PCa characteristics) or when signs of clinical progression are evident. In Table 1, we reviewed the key points on the use of IAD in different populations of patients according to the European Association of Urology guidelines (EAU). 1.1. Clinical trials on IAD IAD has been recently investigated as a valid alternative to continuous ADT in several phase 2 and 3 studies in different populations of patients: those with locally advanced, metastatic and recurrent prostate cancer after primary treatment (radiotherapy or radical prostatectomy). It is evident that the correct use of IAD and the follow-up depend on the tumor characteristics and the treatment used. Recent results from randomized phase 3 clinical trials have established that IAD is a valid approach that should be considered as a standard of care in most patients with locally advanced and metastatic disease (Heidenreich et al., 2013). For the subset of metastatic patients, contrasting data are available from randomized studies: Hussain et al. (2013) observed a large cohort of 1535 patients with metastatic disease. This study was inconclusive from a statistical point of view (HR 1.10; 95% CI, 0.97–1.25, p = 0.25) and therefore it did not demonstrate the inferiority or non inferiority of IAD to continuous ADT. However, the overall survival results were better in the continuous therapy group (5.8 years in the continuous-therapy group as compared with 5.1 years in the intermittent-therapy group). Salonen et al. (2012) showed no statistically significant differences between IAD and continuous ADT in terms of time to progression (IAD: 34.5 months vs continuous ADT: 30.2 months, HR: 1.08) and overall survival (IAD: 45.2 months vs continuous ADT: 45.7, HR: 1.15) in a cohort of 554 men with locally advanced or metastatic PCa. In the SEUG 9401 trial (Calais da Silva et al., 2009). the analysis of a mixed population of 766

patients with non metastatic and metastatic PCa demonstrated that the time to progression was slightly longer in the continuous arm (HR: 0.81 in favor of continuous ADT, p = 0.11) than in the IAD arm with no significant difference in the overall survival (IAD: 54.1% dead vs continuous ADT: 54.2% dead, HR: 0.99, p = 0.84). In these studies, patients who were treated with IAD had often a better overall quality of life (QoL) and a reduced frequency of side effects. For the subset of patients with biochemical relapse (BR) after primary treatment (radiotherapy or radical prostatectomy (RP)), the data are still lacking. Only Crook et al. (2012) enrolled a homogeneous group of 1386 patients with BR after radiotherapy and concluded that IAD was not inferior to continuous therapy with regards to the time to progression and overall survival (HR for death 1.02; 95% CI: 0.86–1.21). Phase 3 trials that have exclusively investigated biochemical recurrence after RP are currently lacking. In Table 2, we briefly present data from all phase 3 trials on the use of IAD in different populations: those with locally advanced, metastatic and recurrent prostate cancer after primary treatment. 1.2. International guidelines and IAD Table 3 presents a summary of what the international guidelines currently recommend in regard to the use of IAD. Only EAU guidelines are updated to 2015 for IAD. They consider IAD as a treatment that should be offered to patients with PCa on the basis of phase 3 clinical trials results. Currently, no standardized indications exist about the use of IAD in different populations of patients (i.e., those with metastatic, locally advanced and clinical progression after primary treatment). 2. Aim and methods In contrast to other available reviews, our review analyzes the oncological and functional results from phase 2 and 3 studies specifically in patients with biochemical recurrence (BR) after radical prostatectomy (RP). This setting most likely has less experimental and clinical trials evidence, but it has a higher use in clinical practice. 2.1. Evidence acquisition We searched the Medline and Cochrane Library databases (inclusion criteria: primary fields were prostate neoplasm and intermittent androgen deprivation therapy; secondary fields were biochemical recurrence, randomized and nonrandomized trials, and overall survival) for literature published without time limits. We included and reviewed original articles, clinical trials and reviews. In addition, abstracts from trials when the trials were not available online were used to ensure that the information was complete and current. There were no restrictions on the basis of years and language, but we included only clinical trials conducted in humans. 3. IAD for biochemical progression after radical prostatectomy: the rationale The selection of patients for IAD is considered the crucial point for the utilization of this treatment option. Two systematic reviews (Abrahamsson, 2010; Klotz, 2013) analyzed data regarding the rationale of the use of IAD in patients with different tumor stages. The real benefits that IAD offers to patients involve quality of life (through a reduction in the side-effects and co morbidities related of testosterone reduction during the off-phase treatment periods) and costs (a reduction in the duration of treatment). Based on these considerations, we can hypothesis that the patients who can really

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353

Table 1 Key points for the correct use of IAD according to the EAU guidelines (Heidenreich et al., 2013). Drug

Induction period

On-phase stopped PSA NADIR

On-phase resumed PSA TRIGGER

Follow-up

LH-RH analogue + antiandrogen (for flare up or with complete androgen deprivation (CAD))

3–9 months

0.5 ng/ml in localized PCa

4–10 ng/ml in nonmetastatic PCa

Patients must be monitored closely for PSA and testosterone levels (at least) every 3–6 months during off-phase treatment

4.0 ng/ml in advanced PCa

10–20 ng/ml in metastatic PCa *The new on-phase therapy is continued for at least 3–6 months depending on the time needed to achieve a PSA nadir

have the chance for a long survival and a higher consideration for QoL are those who are treated with a primary treatment, RT or RP, that present only biochemical recurrence. This group of patients not only represent the most frequent category of patients in clinical practice but they have the longest natural history of PC. Actually a debate exists regarding when and how to treat these cases. Time period between biochemical and clinical progression could be of several years. 4. IAD for biochemical progression after radical prostatectomy: clinical trials In our search, we found nine non-randomized phase 2 (Kurek et al., 1999; Goldenberg et al., 1999; Grossfeld et al., 1998; De La Taille et al., 2003; Lane et al., 2004; Sciarra et al., 2013; Prapotnich et al., 2003; Yu et al., 2010; Peyromaure et al., 2005) and four randomized phase 3 clinical trials (De Leval et al., 2002; Tunn et al., 2012; Salonen et al., 2012; Crook et al., 2012) who considered the use of IAD in PCa cases with BR after RP. For each study, we presented the data on the population and treatment planning in a systematic way; we also analyzed the oncological results and functional aspects in terms of early and long-term side-effects as well as the quality of life. 4.1. Clinical trials: population and treatment planning The population and treatment planning in phase 2 and 3 studies are reported in Tables 4 and 5. 4.1.1. Phase 2 trials We analyzed 9 phase II trials that were conducted between 1998 and 2011. All of these trials are retrospective and were also singleinstitution series with relatively small numbers of patients. Two trials (Kurek et al., 1999; Goldenberg et al., 1999) are available only in abstract form and thus we do not have access to many details with regards to the design of the studies. Most of the trials that were analyzed included patients with a mix of disease stages from biochemical recurrence after primary treatment to metastatic disease. Kurek et al. (1999), Sciarra et al. (2013) and Peyromaure et al. (2005) analyzed only patients with BR after Goldenberg et al. (1999), Grossfeld et al. (1998), De La Taille et al. (2003), Lane et al. (2004), Prapotnich et al. (2003), Yu et al. (2010) included patients with locally advanced or metastatic disease or recurrence after RT or RP. In trials where a mixed population is analyzed, we reported, when available in the original article, data regarding the population and treatment characteristics of the patients with BR after RP. The induction period ranged from 3 to 9 months. The value of PSA at entry ranged from 7 ng/ml (Grossfeld et al., 1998) to 14.7 ng/ml (Prapotnich et al., 2003). The PSA levels used to stop and start offphase therapy ranged from 0.5 ng/ml to 4 ng/ml while the level required to re-start the treatment varied from 4 ng/ml to 10 ng/ml,

according to cancer stage. The therapy regimen was the same for all trials that were analyzed: an LHRH analogue plus antiandrogen. The follow-up was also variable: from 24 months in the Grossfeld study (Grossfeld et al., 1998) to 134 months in the Lane series (Lane et al., 2004). The number of cycles of IAD therapy ranged from 1 to 12, with an average of 2–3 per patient. The median duration of the first cycle ranged from 12 to 33 months, and the median time of the off-phase therapy was determined to be a significant prognostic factor for response. Some of these studies (De La Taille et al., 2003; Sciarra et al., 2013; Yu et al., 2010) identified some prognostic factors including pre-treatment parameters and first cycle characteristics that may influence the endpoints of the IAD regimen such as the time to progression to castration resistance. In particular, age, baseline PSA, and Gleason score at surgery are pre-treatment parameters and the off-phase therapy duration of the 1st cycle is a IAD treatment parameter who significantly predict IAD response. 4.1.2. Phase 3 trials A limited number of phase 3 trials that compared IAD with continuous ADT including cases of recurrence after RP are now available in the literature. We analyzed four randomized clinical trials, but the full details of each trial are often missed. Three trials included a mixed population (De Leval et al., 2002; Salonen et al., 2012; Crook et al., 2012); Tunn et al. (2012) considered only patients with BR after RP. Detailed population characteristics are not available for most of these trials. The induction period was similar in all the trials, and the median length was 7 months. The treatment regimen consisted of an LHRH agonist plus antiandrogen. The value of PSA at entry was not reported in the Tunn trial (Tunn et al., 2012), a level >3 ng/ml was reported in the NCIC CTG PR7 (Crook et al., 2012), and any value was considered in De Leval et al. (2002) and FinnProstate VII trials (Salonen et al., 2012). The level of PSA for ADT discontinuation ranged from <0.5 (Tunn et al., 2012) to <4.0 ng/ml (Salonen et al., 2012), and the level to restart the treatment varied from 3 (Tunn et al., 2012) to 20 ng/ml (Salonen et al., 2012), according to cancer stage. All of the patients were monitored every 2–3 months, but the follow-up time was quite variable (28 months in the Tunn series (Tunn et al., 2012) and 7 years in the NCIC CTG PR7 (Crook et al., 2012)). Only two trials give us details as to the cycle length and the number of cycles completed (De Leval et al., 2002; Salonen et al., 2012). In the EC507 trial by Tunn et al. (2012), 82 patients completed the first cycle. 4.1.3. Critical analysis The first limitation of phase 2 studies to be underlined is that the cohort sizes were modest and included mixed populations. There is no universal value of PSA at the inclusion time because the majority of the trials analyzed mixed patients with different tumor stages. The follow-up was not always specified in terms of the timing of the visits, and a close monitoring every 3–6 months

354

Table 2 Results from phase 3 trials on IAD. De Leval et al. (2002)

SEUG 9401 (Calais da Silva et al., 2009)

FinnProstateVII (Salonen et al., 2012)

NCIC CTG PR7 (Crook et al., 2012)

EC507 (Tunn et al., 2012)

SWOG 9346 (Hussain et al., 2013)

Miller 2007 (Miller et al., 2007)

Irani 2008 (Irani et al., 2008)

SEUG 9901 (Silva et al., 2014)

TULP (Langenhuijsen et al., 2013)

TAP22 (Mottet et al., 2012)

# of cases Tumor stage

68 Locally advanced/ biochemical recurrence Flutamide + goserelin

766 Locally advanced/M+

554 Locally advanced/M+/ recurrence

1386 Recurrence after RT

244 Recurrence after RP

1535 M+

335 Locally advanced/M+

129 Locally advanced/M+

918 Locally advanced/M+

193 M+

173 M+

Goserelin + CPA(in the first 12 days) 6

LHRH + nonsteroidal antiandrogen 8

Leuprorelin 11.25 + CPA 200 mg/daily 6

LHRH + bicalutam-ide

Goserelin + bicalutamide

Goserelin + flutamide

Triptoreline + CPA

7

6

6

3

Buserelin depot + nilutamide 6

CAD

6

LHRH/monthly + CPA 200 mg/daily 3

6

<4

<4

<10

<4

<0.5

<4

<4

–

<4

<4

<4

>10

>10 for symptomatic

>20

>10

>3

>20

–

After 6 months

>20

>10 or >20

>10

5.4

7

2.4

9.2

–

5

5.5

31

44

IAD:34.5 vs continuous ADT:30.2 (HR:1.08)

–

Continuous ADT:986 days vs IAD:976 days (p = 0.8)

–

IAD:16.6 vs continuous ADT:11.5 (HR:0.69)

HR:1.1 in favor of IAD

HR:1.1 in favor of IAD

IAD: 18.0 vs continuous ADT:24.1

IAD:20.7 vs continuous ADT:15.1 (p = 0.74)

IAD:45.2 vs continuous ADT:45.7 (HR:1.15) p = 0.17

IAD:38.8% dead;8.8 years vs continuous ADT: 36% dead;9.1 years (HR:1.02) (95% CI:0.87–1.23; p = 0.009)

–

IAD:38.8% dead vs continuous ADT:36.8% dead (HR:1.02)

IAD:51.4 mo vs continuous ADT:53.8 mo (HR:1.04)

HR:0.6 in favor of IAD

HR:0.90 in favor of IAD

–

–

In favor of IAD In favor of IAD in activity limitation, physical capacity

In favor of IAD In favor of IAD

– –

– In favor of IAD at 3 months

– In favor of IAD

– In favor of IAD

– In favor of IAD

Therapy regimen Induction period (months) PSA (ng/ml) level to stop PSA (ng/ml) level to restart

>20 for asymptomatic Follow-up (year) median Time to progression (months) (median)

Overall survival (months) (median)

Sexual function Quality of Life

2.7

4.7

IAD:28.0 HR:0.8 in favor of continuous (median, 25.7 months; range ADT (95% CI: 5.4–56.0 0.63–1.05; months) vs p = 0.11) continuos ADT:21.0(median, 14.4 months;range 6.3–39.0 months) (HR:0.57) IAD 54.1% dead – vs continuous ADT 54.2% dead. HR:0.99 in favor of continuous ADT (95% CI: 0.80-1.23; p = 0.84) – In favor of IAD – No clinically relevant differences

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Parameter

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Table 3 Comparison of international guidelines on indications for intermittent androgen deprivation. EAU 2015 (Heidenreich et al., 2013)

AUA 2007 (Prostate cancer, 2007)

NCCN 2012 (Mohler et al., 2012)

ASCO 2007 (Loblaw et al., 2007)

IAD should be widely offered to patients with PCa in various clinical settings after a standardized induction period. IAD should be the standard of care for those who relapse after radiotherapy (if some form of ADT is required). It might be an option in metastatic situations, even if the benefits are fewer compared with those with less advanced PCa (LE: 1b)

Not included

If ADT is going to be administered at all, intermittent therapy is a reasonable option based on its non-inferiority.

Data are insufficient to support the use of IAD outside of clinical trials.

for PSA and testosterone was mandatory. An induction period of 8–9 months seems reasonable, but some of the authors (Grossfeld et al., 1998; Peyromaure et al., 2005) decided to implement shorter periods. A comment should be made about the PSA value for ADT discontinuation and the criteria for the resumption of treatment: they were not uniform and they depended on the stage. Most of the phase 2 trials used the combination of an LHRH agonist and an antiandrogen (CAB). The role of CAB in intermittent therapy is still unproven. Some models (Klotz, 2013) have suggested that more aggressive hormonal blockade during the treatment periods may provide a benefit, but this benefit is not demonstrated in clinical practice. Finally, these studies (Kurek et al., 1999; Goldenberg et al., 1999) are also relatively older. Regarding phase 3 trials, most of these tended to focus on advanced or metastatic disease rather than biochemical failure, except for the NCIC CTG PR7 (Crook et al., 2012) that included a large homogeneous cohort of patients who relapsed after primary RT or salvage radiotherapy after RP. At now, there are some risks in the application of the NCIC CTG PR7 results to the patients who relapse after a surgical approach and who present different characteristics and different follow-up. The trials by De Leval et al. (2002) and Salonen et al. (2012) included patients with recurrence after RP, but the percentage of these patients out of the total number of cases was not clearly indicated. The FinnProstate VII study (Salonen et al., 2012) was originally designed to enroll patients with metastatic PCa, but in order to increase the recruitment during the study they decided to include also patients with locally advanced or recurrent PCa. Only the EC507 trial by Tunn et al. (2012) included all patients with BR after RP (184 cases). An accurate analysis of the Tunn trial (Tunn et al., 2012) results should be performed. The author emphasized that the normalization of testosterone levels was a prerequisite for the utilization of the IAD regimen; in his study, the normalization of testosterone levels was achieved in 79.3% and 64.9% of patients in the first cycle and second cycles, respectively. Also Crook et al. (2012) analyzed the testosterone level recovery: 35% of patients during IAD treatment returned to pretreatment levels within 2 years after completing the first cycle and 79% of them had a level of at least 5 nmol/l. 4.2. Clinical trials: oncological results The oncological results of the phase 2 and 3 studies are reported in Tables 6 and 7. 4.2.1. Phase 2 trials We analyzed the primary end-points of the 9 phase 2 trials that were selected: the time to castration-resistance is the end point that is most widely considered. In most of these trials, the castration-resistance is defined as biochemical progression when the serum PSA was increased despite complete androgen suppression and a castrate testosterone level. Grossfeld et al. (1998) gave a definition of castration-resistance as follows: (1) the failure of the serum PSA to decrease; (2) the failure of the serum PSA to reach a

nadir value; (3) any evidence of disease progression, while testosterone is fully suppressed. Additionally, Lane et al. (2004) reported a median time to castration-resistance, defined as two progressive PSA increments despite androgen ablation, of 92 months (11–93) in the 14% of patients. Sciarra et al. (2013) reported two primary endpoints in his trial: the time to clinical progression, which is defined as evidence of recurrence or metastatic spread according to a bone scan, CT and MRI and the time to castrate-resistant disease, which is defined as >2 serial increases in PSA levels with a castrate level of testosterone. This trial gave the following results: 29.7% of patients who were treated with IAD developed castrateresistance, and 14.2% of cases showed a clinical progression with a mean time of 88.4 months and 106 months respectively with a mean follow-up of 88.6 months. Other end-points of survival, such as overall survival and cancer-specific mortality, were often missed in these studies. The overall survival was considered only by Lane et al. (2004): the median survival time from the first cycle of androgen suppression was 95 months (range: 12–115 months) for patients with local disease. The cancer-specific mortality was reported by Kurek et al. (1999) and Peyromaure et al. (2005). In the first trial it was not reported in a specific way (only the abstract is available), but in the Peyromaure series, a total of 9/57 patients died of metastatic PCa with a cancer-specific mortality of 12.3%; moreover, the interval between starting IAD and cancer-related death was 86 months. The level of testosterone recovery was discussed in approximately 30% of the studies (Kurek et al., 1999; Goldenberg et al., 1999). When this was reported, the proportion of men with testosterone normalization was high during the first cycle but tended to decrease during subsequent cycles. 4.2.2. Phase 3 trials The four phase 3 trials that were analyzed included the time to progression, the overall survival and the cancer-specific survival as end points. De Leval et al. (2002) concluded that IAD treatment may maintain the androgen-dependent state at least as long as continuous ADT treatment. The mean time to castrateresistant progression showed no significant differences between the treatment groups, which was 32.86 months ± 10.0 days and 32.53 months ± 14.0 days in the continuous ADT and IAD arms, respectively. In the Finn Prostate VII trial (Salonen et al., 2012) that included a mixed population, 186 patients (68%) in the IAD arm and 206 (74%) in the continuous ADT arm died (p = 0.12). No statistically significant differences were observed between the treatment arms in terms of progression and survival parameters, and the risk analysis (progression-free survival, overall survival and PCa-specific survival) showed an HR of 1.08–1.17 respectively for the continuous ADT arm. In the NCIC CTG PR 7 (Crook et al., 2012), no significant differences were found in terms of overall survival between the IAD and continuous ADT arm (HR:1.02; p = 0.009), which supports the hypothesis that IAD is not inferior to continuous ADT. With regards to testosterone recovery, which is considered a fundamental prerequisite of IAD treatment, only Tunn et al. (2012) gave details about the time to testosterone normalization during

356

Table 4 Summary of the details of phase 2 studies (population and treatment planning). Kurek et al. (1999)

Goldenberg et al. (1999)

Grossfeld et al. (1998)

De La Taille et al. (2003)

Lane et al. (2004)

Sciarra et al. (2013)

Prapotnich et al. (2003)

Yu et al. (2010)

Peyromaure et al. (2005)

# of cases Tumor stage (when available # of cases of BR after RP)

44 All patients with BR after RP

87 BR after RT or RP

146 Locally advanced/ M+/ recurrence BR after RP or RT (74/146 cases)

75 Locally advanced/ M+/recurrence BR after RP (13/75)

84 All patients with BR after RP

233 Locally advanced/ M+/recurrence BR after RP (55/233)

72 Recurrence after RT or RP BR after RP (55/72)

57 Recurrence after RP

Initial PSA (ng/ml) at entry median Age (years) Median Gleason score (number of cases)

–

–

47 BR after local therapy after RT or cryotherapy or RP (20/47 cases) 7.3

10.6

–

>0.4

14.7

9.5

–

–

–

69.0

67.6

–

64.0

72.7

61.5

–

–

–

2–4: (0)

Mean: 6.75 (3–9)

–

≤7 (3 + 4):(43)

2–4: (5)

<6: (14)

<6: (10)

≥7 (4 + 3): (41)

5–6: (16) 7:(23) 8–10: (11)

7: (36) >8: (19)

7: (27) >8: (20)

5–6: (8) 7: (9) 8–10: (3) Induction period (months) PSA (ng/ml) level to stop PSA (ng/ml) level to re-start

–

6

<0.5

<4.0

>3.0

>10.0

Therapy regimen

Leuprorelin + CPA

GnRH agonist + Antiandrogen

Follow-up (months) median # of cycles First cycle length (months) Off-phase therapy time

48.0

65.5

1–4 –

# of patients who completed 1st cycle

1 or 2 months after PSA was undetectable <0.1

6

9

6

–

9

3

<1.0

<4.0

<1.0

<4.0

<0.1

<1.0

>10.0 or PSA level >than 50% PSA pre-treatment or patient request GnRH agonist + Antiandrogen or GnRH alone (flare-up)

>4.0

–

>1.0

–

1.0–4.0

>4.0

GnRH agonist + Antiandrogen nonsteroid or GnRH alone

Tryptorelin + CPA

GnRH agonist + Antiandrogen

Leuprolide + Flutamide (250 mg × 3 times/daily)

LHRH analogue + Antiandrogen (BAT)

24.0

GnRH agonist + Antiandrogen nonsteroidal or GnRH alone (flare-up) 45.6

134.0

88.6

35.0

40 weeks

92.0

1–4 22

1–3 16

– 14

1–3 33.0

6.4 12.5

5 19.6

1–8 9.0

4 14.0

44-58%: 26.6 months

54%: 15 months

47%: –

–

–

415 days

40.9 weeks

–

–

–

29/47

62/74

17.8 months for localized and 8.5 months for M+ 13/13

84/84

40/55

55/55

57/57

S. Cattarino et al. / Critical Reviews in Oncology/Hematology 99 (2016) 351–361

Parameter

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357

Table 5 Summary of the details of phase 3 studies (population and treatment planning). Parameter

De Leval et al. (2002)

EC507 (Tunn et al., 2012)

FinnProstate VII (Salonen et al., 2012)

NCIC CTG PR7 (Crook et al., 2012)

# of cases Tumor stage(when available # of cases of BR after RP)

68 Mixed (locally advanced, Metastatic, relapsed) 8/68 BR after RP >4 70.8

184 BR after RP

554 Mixed (Not specified number of cases of BR after RP) Any value <70 years: 36.8% >70 years: 63.2%

1386 Recurrence after RT or RP 158/1386 BR after RP

Gleason score (number of cases)

4–6: (43) 7: (7) 8–10: (18)

–

3 + 4:(13.2%) 4 + 3: (22.8%) 8–10: (58.2%)

–

Induction period (months) PSA (ng/ml) level to stop

7 <4.0

6 <0.5

8 <4.0

PSA (ng/ml) level to re-start Therapy regimen

>10.0 Goserelin + Flutamide

Follow-up median # of cycles First cycle length (months) Off-phase therapy time (median)

31 months 1–3 9 3.3–8.3 range months 28/68 (80.0%)

>3.0 Leuprorelin acetate + CPA 28.4 months 1-3 – –

6 Not defined only for BR after RP >20.0 Goserelin + CPA 65 months 3 14 10.9–33.5 range weeks 273/554 (99.6%)

7 years

Initial PSA (ng/ml) (at entry) median Age (years) median

# of pts who completed 1st cycle

the off-phase therapy time. In all, 91% of patients achieved a normal testosterone level after the first cycle; however, these findings were less favorable during the subsequent cycles. Also Crook et al. (2012) analyzed the testosterone level recovery: 35% of patients during IAD treatment returned to pretreatment levels within 2 years after completing the first cycle and 79% of them had a level of at least 5 nmol/l. 4.2.3. Critical analysis The first limitation of the phase 2 studies that were analyzed is that survival data were not included. The following considered endpoints largely varied: time to castrate-resistance, cancer-specific mortality, testosterone recovery and often the identification of the predicting factors of a successful therapy with IAD. De La Taille et al. (2003) identified the following as the best predictors of castrateresistant PCa: Gleason score >8, off-phase therapy time <1 year, positive lymph nodes, metastases and age <70 year. Sciarra et al. (2013) also identified some prognostic factors that influence the time to clinical progression and time to castration-resistance: Gleason score, PSA nadir and off-phase therapy time. For both of these studies, the crucial point was to identify the best candidates for IAD, but the authors concluded that only randomized prospective trials of IAD VS continuous ADT can truly address the potential benefits of IAD in terms of survival and the time to delay castration-resistance. The four phase 3 trials analyzed the time to progression and the overall or cancer-specific survival as the primary endpoints. The conclusions of these trials support the hypothesis that IAD can produce similar results (“not inferior”) to those of continuous ADT. The most important limitation is that all of them included mixed populations, with the exception of Tunn et al. (2012) where the data of patients with recurrence after RP were actually missed. In addition, the study by Crook et al. (2012) analyzed a homogeneous cohort of patients who were treated with radiotherapy. There is some risk in the application of the results that were obtained from this series to the patients who were treated with RP. A recent sub-

– 67.4

82/184

3–15 ng/ml 74.2

>10.0 LHRH + Antiandrogen

20–59.6 range months

analysis of NCIC CTG PR7 serie (biochemical failure after primary radiotherapy or salvage therapy after surgery) reported interesting results regarding the correlation between testosterone levels and cancer specific survival and time to castrate-resistant progression (Klotz et al., 2015): patients with first-year nadir testosterone consistently >0.7 nmol/l had significantly higher risks of dying as a result of disease (0.7–1.7 nmol/l: hazard ratio [HR], 2.08; 95% CI, 1.28–3.38; >1.7 nmol/l: HR, 2.93; 95% CI, 0.70–12.30) and developing castration-resistance (0.7–1.7 nmol/l: HR, 1.62; 95% CI, 1.20–2.18; ≥1.7 nmol/l: HR, 1.90; 95% CI, 0.77–4.70). Maximum testosterone ≥1.7 nmol/l predicted for a higher risk of dying as a result of disease (p = 0.02). 4.3. Clinical trials: quality of life and safety Quality of life a safety results in phase 2 and phase 3 trial are reported in Tables 8 and 9. 4.3.1. Phase 2 and 3 trials Finally, we analyzed the phase 2 and 3 trials in terms of the functional results of IAD: early and long-term side-effects that are related to testosterone deprivation and the quality of life analysis. The early side-effects considered in the trials are sexual dysfunction, hot flushes, fatigue, anemia, while the long-term side effects are decreased bone density (with the risk of increased number of fractures), altered lipid profile, cognitive dysfunction, metabolic changes, and cardiovascular disease. The majority of phase 2 studies that were analyzed showed promising results with regards to the tolerability profile and the improvement in quality of life during the off-phase therapy periods of IAD as a result of testosterone recovery. Moreover also phase 3 studies that were analyzed suggested a better tolerability profile and quality of life, when measured, with IAD than continuous ADT. Crook et al. (2012) reported significantly better scores for hot flashes (p < 0.001), desire for sexual activity (p < 0.001), and urinary symptoms (p = 0.006), with a trend toward

358

Table 6 Summary of the details of phase 2 studies (oncological results). Kurek et al. (1999)

Goldenberg et al. (1999)

Grossfeld et al. (1998)

De La Taille et al. (2003)

Lane et al. (2004)

Sciarra et al. (2013)

Prapotnich et al. (2003)

Yu et al. (2010)

Peyromaure et al. (2005)

End points considered

Cancer-specific mortality; testosterone recovery

Time to androgenresistance

Time to androgen resistance

Time to androgenresistance; overall survival

Time to clinical progression; time to androgenresistance; identification of predicting factors

Time to androgenresistance

Time to androgenresistance; time to death; Testosterone recovery

Metastatic progression; cancer- specific mortality

Time to clinical progression

–

–

–

Time to progression; Overall 5-year biochemical progressionfree survival; identification of predicting factors of hormoneresistance –

–

–

–

Progression to Metastases: 15.8%

23/87 patients at a median of 32 months of treatment

–

24/146 patients in progression

92 months

24.4 months

×2.9 times for patients with off-phase therapy <40 weeks

–

–

–

68%

95 months

106.5 ± 20.6 months (median 118.0 months, range 60.0–120.0 months) 88.4 ± 14.3 months (median 90.0 months, range 42.0–110.0 months) (29.7% of cases) –

–

–

0 cases

–

–

5.2% at 5 year

–

–

4%

–

Time to androgen-resistance (or number,% of cases)

Overall survival (% cases of median months) Cancer-specific mortality (number case,% or median time)

12.3%

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Parameter

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359

Table 7 Summary of the details of phase 3 studies (oncological results). Parameter

De Leval et al. (2002)

EC507 (Tunn et al., 2012)

FinnProstate VII (Salonen et al., 2012)

NCIC CTG PR7 (Crook et al., 2012)

End points considered

Time to progression

Time to PSA progression during on- phase

Continuous ADT: 20.6 months ± 4.0 months (median, 14.4 months; range 6.3–39.0 months) vs IAD: 28.0 months ± 14.8 months (median, 25.7 months; range 5.4–56.0 months) IAD: 2 cases (5.7% deaths) vs continuous ADT: 4 cases (12.1% deaths)

Time to progression; testosterone recovery IAD: 37 patients risk of progression vs continuous ADT: 16 patients risk of progression (HR:0.97) p = 0.853

Time to progression; survival IAD: 34.5 months vs continuous ADT: 30.2 months (HR:1.08) p = 0.43

Time to progression; survival IAD:9.8 years vs continuous ADT: 10 years HR:0.80 (0.67–0.98) p = 0.024

–

IAD:43% dead; 45.2 months vs continuous ADT:47% dead; 44.3 months (HR:1.17) p = 0.29 IAD: 45.2 months vs continuous ADT 45.7 months (HR:1.15) p = 0.17 –

IAD 17.4% dead vs continuous ADT 13.5% dead (HR:1.23) p = 0.13

PCa-specific survival

Overall survival

–

–

Testosterone recovery

–

79.3% of patients with normalization of testosterone in the first cycle; 64.9% in the second cycle

IAD 38.8% dead; 8.8 years vs continuous ADT 26.8% dead; 9.1 years (HR:1.02) 35% of patients in IAD recovered their baseline level of testosterone in first cycle but 79% recovered to the age appropriate testosterone range

Table 8 Quality of life and safety in phase 2 studies. Parameter

Kurek et al. (1999)

Goldenberg et al. (1999)

Grossfeld et al. (1998)

De La Taille et al. (2003)

Lane et al. (2004)

Sciarra et al. (2013)

Prapotnich et al. (2003)

Yu et al. (2010)

Peyromaure et al. (2005)

Early side-effects (SE)

–

–

–

–

–

Reduction of hot flushes during the off-phase treatment

–

–

Long-term complications Quality of life

–

–

Reduction of SE after each patient entered the off-phase treatment –

–

–

–

–

–

–

Better in IAD

Better in IAD

–

–

–

–

–

–

Better in IAD

Table 9 Quality of life and safety in phase 3 trials. Parameter

De Leval et al. (2002)

EC507 (Tunn et al., 2012)

FinnProstate VII (Salonen et al., 2012)

NCIC CTG PR7 (Crook et al., 2012)

Early side-effects

–

Less in IAD

IAD: 47.1% vs continuous ADT: 50.4% (hot flushes) IAD:15.7% vs continuous ADT:7.9% (sexual dysfunction)

–

Long-term complications

–

–

–

Quality of life

–

–

IAD:12.8% vs continuous AD: 15.4% (cardiovascular deaths) In favor of IAD in terms of activity limitation, physical capacity and sexual function domains.

improvement in the level of fatigue (p = 0.07) in favor of IAD. All of the trials reported that as the follow-up time increased, more patients who were treated with IAD were in on-therapy phases and that all of the positive effects that were related to testosterone recovery decreased.

In favor of IAD in terms of hot flashes (p < 0.001), sexual activity (p < 0.001), urinary symptoms (p = 0.006) and level of fatigue (p = 0.07).

4.3.2. Critical analysis Very few data on the functional outcome are available in the analyzed phase 2 studies. Grossfeld et al. (1998) and Prapotnich et al. (2003) observed a reduction in early and long-term side effects in patients who were treated with IAD when they entered

360

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the off-phase treatment period or immediately after (3 mo in the Prapotnich serie (Prapotnich et al., 2003)) the discontinuation therapy. Only the Finn Prostate VII phase 3 trial (Salonen et al., 2012) and the NCIC CTG PR7 (Crook et al., 2012) published formally measured results. They found that the frequency of early side effects such as hot flushes, sexual dysfunction and fatigue was significantly decreased in the IAD group compared with the continuous ADT group. Precise information about the quality of life was still missed, and it is possible that questionnaires regarding the quality of life have to be used in a standardized way for all patients in the on- and off-phase therapy periods. 5. Critical conclusions At now the most updated international guidelines EAU guidelines (Heidenreich et al., 2013) underlines that IAD should be widely offered to patients with PCa in various clinical settings, in particular those patients who relapse after RT. The use of IAD in cases who biochemical relapse after RP is common in the clinical practice nonetheless it is most specifically cited from guidelines. There could be some risk in the application of the results that were obtained from Crook series (Crook et al., 2012) (relapse after RT) to the patients who are treated with RP. Patients treated with RT differ a lot from patients treated with surgery and also the answer to therapy is different: for example the modification of PSA, crucial point of a correct use of IAD, is easier to evaluate in RP patients than RT patients. Moreover it has been demonstrated that pathological gleason score and a PSA nadir after first cycle of IAD are important predictive factors of response to IAD in patients treated with RP. Recently a subset analysis from Crook et al. (NEJM supplement) reported an advantage of 14 months in survival in patients with gleason score 8–10 treated with continuous therapy but no differences in patients with gleason score 6–7 [11-Supplement]. For this reason patients treated with surgery should be more likely to be treated with IAD. This indication is not strongly supported by phase 3 trials. At now all phase 3 trials analyzed included mixed populations with a minority of cases relapsing after RP. Only Tunn et al. (2012) study was specifically focused on this setting but clinical results are actually missed in extended publications. In phase 2 trials oncological endpoints largely varied. An advantage of IAD in terms of tolerability and side effects is reported in particular in the first cycles where patients spend more time off-therapy. Otherwise, with the exception of the FinnProstate VII trial (Salonen et al., 2012), precise information about quality of life is still missed and specific questionnaires have to be used in a standardized way. Conflict of interest None of the authors has any financial or personal relationships with organizations that could inappropriately influence the work. Funding None of the authors has a funding source for the work. References Abrahamsson, P.A., 2010. Potential benefits of intermittent androgen suppression therapy in the treatment of prostate cancer: a systematic review of the literature. Eur. Urol. 57, 49–59. Akakura, K., Bruchovsky, N., Goldenberg, S.I., Rennie, P.S., Bukley, A.R., Sullivan, L.D., 1993. Effects of intermittent androgen suppression on androgen-dependent tumors: apoptosis and serum prostate specific antigen. Cancer 71, 2782–2790. Bruchovsky, N., Rennie, P.S., Coldman, A.J., Goldenberg, S.L., To, M., Lawson, D., 1990. Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res. 50, 2275–2282. Calais da Silva, F., Bono, A., Whelan, P., et al., 2009. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a

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Biography Alessandro Sciarra is Asociated professor in the University Sapienza of Rome, Italy, Department of Urological sciences. Chairman of the Prostate cancer Unit from the same Univeristy. Member of the Italian and European a ssociation of Urology. On PUBMED 144 publication with an Hirsch index = 22 (Scopus 2015) and citation index = 1822 (Scopus 2015). Main interest oncologi c urology and prostate diseases.