Intermittent Androgen-deprivation Therapy in Prostate Cancer: A Critical Review Focused on Phase 3 Trials

Sciarra, Alessandro; Abrahamsson, Peter; Brausi, Maurizio; Galsky, Matthew D.; Mottet, Nicolas; Sartor, Oliver; Tammela, Teuvo L.J.; Silva, Fernando Calais da

doi:10.1016/j.eururo.2013.04.020

Cited by 52 publications

(42 citation statements)

References 33 publications

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“…In fact, survival in two of the M1 trials (S9346 and TAP22) was worse for the IAD arm compared with the CAD arm. 7,10 Interestingly, many of the recent reviews concluded that IAD is as effective as CAD in PC [2][3][4][5][6]17 ; however, these reviews often overlooked important issues, such as NIM selection including clinically meaningful differences in survival, follow-up time too short to observe disease-specific end points, suboptimal design of mixed patient populations, and small underpowered trials.…”

Section: Discussionmentioning

confidence: 99%

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

Hussain¹,

Tangen²,

Higano³

et al. 2016

JCO

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Purpose Intermittent androgen deprivation (IAD) has been widely tested in prostate cancer. However, phase III trials testing continuous androgen deprivation (CAD) versus IAD have reached inconclusive and seemingly contradictory results. Different design and conduct issues must be critically evaluated to better interpret the results. Patients and Methods Seven published phase III trials were examined for prespecified design and outcomes. Treatment specifications; primary end point; superiority versus noninferiority design assumptions, including magnitude of assumed versus observed noninferiority margin (NIM); duration of follow-up; and quality-of-life (QOL) outcomes were considered in terms of the results and conclusions reported. Results Five trials had a superiority and three had a noninferiority primary hypothesis. Only three trials had a uniform population and overall survival (OS) end point. All trials observed better outcomes in terms of OS and progression-free survival (PFS) than assumed at time of study design, translating into prespecified NIMs or hazard ratios that reflected larger absolute differences in OS or PFS between arms. Lower-than-expected event rates also reduced statistical power for the trials. Other factors, including length of follow-up, cause of death, QOL, and primary end point, and their impact on trial interpretation are discussed. Conclusion No trial to date has demonstrated survival superiority of IAD compared with CAD. Trials concluding IAD is noninferior to CAD were based on wide NIMs that included clinically important survival differences, not likely to be considered comparable by physicians or patients. Interim analyses relying on short follow-up and including a majority of non–prostate cancer deaths will favor a noninferiority conclusion and should be interpreted cautiously. Adequate follow-up is required to ensure capture of prostate cancer deaths in both superiority and noninferiority trials.

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Section: Discussionmentioning

confidence: 99%

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

Hussain¹,

Tangen²,

Higano³

et al. 2016

JCO

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“…The relevant clinical trials are summarized in the excellent review of Zisis Kratiras (1), as well as recently by Sciarra et al (2).…”

Section: To the Editormentioning

confidence: 99%

Re: A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a ?perpetual dispute?

Mearini

2014

Int. braz j urol.

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After mature randomized clinical trial, some criticisms on what we expect from intermittent androgen deprivation and how we have to administer IAD are still open. An extensive discussion on testosterone as ruler for retreatment should be opened.I read the review by Zisis Kratiras et al.(1) with great interest and expectancy because intermittent androgen-deprivation (IAD) therapy, which is commonly used, is still in the 'empirical' stage. After many randomized clinical trials, who is the best candidates to IAD, what we expect from IAD and how we should administer IAD remain unknown.Androgen-deprivation therapy (ADT) for the treatment of prostate cancer is old and it is based on the reduction of androgen hormones to a castration level. To effectively evaluate the response to surgical or chemical castration, we have to measure testosterone levels, which is the key point of the definition of castration-resistant prostate cancer.The definition and strategy of IAD is to alternate androgen blockade (on-phases) with treatment cessation (off-phases), which allows for androgen recovery between treatment periods. The relevant clinical trials are summarized in the excellent review of Zisis Kratiras (1), as well as recently by Sciarra et al. (2).The hypothetical value of IAD comes from the original experiment of Akakura et al. (3), which hypothesized and demonstrated in vivo that the replacement of androgens at the end of a period of castration-induced, apoptotic regression might result in the regeneration of differentiated tumor cells with further apoptotic potential.Consequently, we expect that testosterone levels are the primary consideration of all clinical trials, but this is not always the case.Laurence Klotz (4) and Gustavo Franco Carvalhal in his editorial comment to current paper correctly poses some questions. The review paper (1) shows that the induction periods and the criteria for resuming treatment are extremely variable and that both are PSA-driven. The selection criteria for IAD was a variable reduction with respect to the baseline PSA levels, but it is not clear whether the inadequate drop in PSA levels was linked to the primary extent of disease or

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“…13 Recent reviews comparing efficacy, side effects, time to castration resistance, overall and cancer-specific survival between intermittent and continuous ADT have been summarised; however, the evidence regarding the tradeoffs between the benefits and risks of intermittent ADT remains inconclusive. [17][18][19][20][21][22][23] Generally the consensus is that overall survival is equivalent between intermittent and continuous ADT in most settings. However, concerns remain with high-risk disease, as one of the larger trials did not meet criteria for non-inferiority of an intermittent regimen in men with metastatic cancer.…”

Section: How Might This Impact On Clinical Practice?mentioning

confidence: 99%

International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.

Liede

Hallett

Hope

et al. 2015

JCO

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Background: Continuous androgen deprivation therapy (CADT) is commonly used for patients with non-metastatic prostate cancer as primary therapy for high-risk disease, adjuvant therapy together with radiation or for recurrence after initial local therapy. Intermittent ADT (IADT), a recently developed alternative strategy for providing ADT, is thought to potentially reduce adverse effects, but little is known about practice patterns relating to it. We aimed to describe factors related to physicians' ADT use and modality for patients with non-metastatic prostate cancer.Methods: A 45 min online survey was completed by urologists and oncologists responsible for treatment decisions for non-metastatic prostate cancer from 19 countries with high or increasing prevalence of nonmetastatic prostate cancer.Results: There were 441 treating physicians who completed the survey which represented 99 177 patients with prostate cancer under their care, of which 76 386 (77%) had non-metastatic prostate cancer. Of patients with non-metastatic prostate cancer, 38% received ADT (37% gonadotropin-releasing hormone (GnRH), 2% orchiectomy); among patients on GnRH, 54% received CADT (≥6 without >3 months interruption), 23% IADT and 23% <6 months. Highest rates of ADT were reported among oncologists (62%) and in Eastern Europe (Czech Republic, Hungary and Poland). Prostate-specific antigen (PSA) levels (65%), Gleason score (52%) and treatment guidelines (48%) were the most common reasons for CADT whereas PSA levels (54%), patient request (48%), desire to maintain sexual function (40%), patient age and comorbidities (38%) were cited most frequently as reasons for IADT.

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Intermittent Androgen-deprivation Therapy in Prostate Cancer: A Critical Review Focused on Phase 3 Trials

Cited by 52 publications

References 33 publications

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

Evaluating Intermittent Androgen-Deprivation Therapy Phase III Clinical Trials: The Devil Is in the Details

Re: A review of continuous vs intermittent androgen deprivation therapy: Redefining the gold standard in the treatment of advanced prostate cancer. Myths, facts and new data on a ?perpetual dispute?

International survey of androgen deprivation therapy (ADT) for non-metastatic prostate cancer in 19 countries.

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