Παρασκευή, 20 Ιανουαρίου 2017

INTERMITTENT ADT FOR PROSTATE CANCER

Androgen deprivation therapy (ADT) is a cornerstone of locally advanced and metastatic prostate cancer treatment but is associated with an array of adverse events.
Intermittent ADT (wherein the treatment is stopped for periods of time) has been investigated as a way of reducing side effects without compromising overall survival (OS), but results have differed depending on the specific patient population.
For example, among men with localized disease, OS appears similar for continuous and intermittent ADT, with some quality-of-life (QOL) factors favoring intermittent administration.
However, for metastatic disease, there has been concern that intermittent therapy could compromise survival.
The issue of whether intermittent ADT has a place in prostate cancer care is debated in a pair of papers in JAMA Oncology, arguing both for and against the practice.
Yes, Intermittent ADT Has a Role 
Taking the "pro" viewpoint, Laurence Klotz, MD, from Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada, and Celestia S, Higano, MD, from the Fred Hutchinson Cancer Research Center, Seattle, Washington, argue that intermittent ADT "is a viable treatment option for men who experience the adverse effects of ADT."
"Clinicians who are experienced in administration of [intermittent ADT], sometimes for decades, can attest to the QOL benefits for the individual patient (and his partner) over time," the authors write.
In their article, Dr Klotz and Dr Higano review some of the published data that attest to the viability of this option for some patients with prostate cancer.
Intermittent ADT is not an entirely new concept, having first been explored in the mid-1980s among a small group of men with symptomatic, metastatic disease (Cancer1986;58:2546-2550).
In that early study, sexual function returned in 9 of 10 patients who had normal erectile function at baseline; thus, the researchers concluded that this modality could adequately palliate symptoms while improving QOL.
These results prompted additional research, including nine phase 3 trials that compared OS and QOL between continuous ADT and intermittent therapy. While these trials consistently showed no survival differences and QOL benefits, seven were limited by populations and/or heterogeneous patient cohorts, Dr Klotz and Dr Higano note.
The two largest phase 3 trials published to date found that intermittent therapy was at least noninferior to continuous ADT, the authors say.
In the PR7 trial (N Engl J Med2012;367:895-903) designed by the National Cancer Institute of Canada and conducted in men with nonmetastatic hormone-sensitive disease, median OS outcomes were similar: 8.8 years with intermittent ADT vs 9.1 years with continuous ADT (hazard ratio [HR], 1.02).
Intermittent ADT met the criteria for noninferiority, and side effects, including hot flashes, sexual activity, and urinary symptoms, were significantly better for patients receiving intermittent therapy.
However, a post hoc analysis showed that the median OS for men with Gleason scores of 8 to 10 was about 14 months longer in the continuous therapy group (HR, 1.23; P = .31). Even though the trial was not powered to detect a small or moderate difference in survival, and Gleason score was not a planned stratification, the researchers did caution that intermittent therapy was probably not a good option for this subgroup. 
The other large phase 3 trial was the S9346, initiated by the Southwest Oncology Group (SWOG), in men with hormone-sensitive metastatic disease. (N Engl J Med2013;368:1314-1325).
The authors note that results were largely inconclusive; they did not show inferiority, noninferiority, or superiority of either treatment, although there was a nonsignificant trend for improved OS in the continuous therapy group: 5.8 years vs 5.1 years (HR, 1.10).
An unspecified subanalysis stratified by minimal disease also demonstrated a survival benefit for continuous ADT (6.9 vs 5.4 years), but there was no difference among patients with extensive disease.
Long-term QOL, the authors note, was confounded because by 15 months, 78% of men in the intermittent group had restarted ADT. But at 3 months after stopping of ADT in the intermittent group or at 11 months of continuous treatment, the intermittent group had less erectile dysfunction (P < .001) and better mental health (P = .003), with significant libido (P < .04), compared with the continuous therapy group.
Dr Klotz and Dr Higano note that median survival was longer than predicted for both studies and that both had "statistical issues discussed at length elsewhere."
While both trials could not fully capture the QOL changes in the intermittent therapy arms because of the "choice of fixed time points for collecting data," there was a "signal" in both trials that various domains of QOL were better for men receiving intermittent therapy.
Finally, a recent meta-analysis (JAMA Oncol2015;1:1261-1269) comparing both modalities found that intermittent therapy was not inferior to continuous ADT for survival outcomes and that some QOL criteria were improved.
"Taken together, the results of the 2 large phase 3 trials and the most recent meta-analysis call for taking the individual patient into account when deciding about the option of [intermittent ADT]," Dr Klotz and Dr Higano write.
Patients treated with intermittent therapy see a "light at the end of the tunnel," the authors add, "when their testosterone levels rise, and they feel 'more normal,' and, according to their partners, 'act more like the person I knew.'"
"Intermittent ADT should be offered in the context of good clinical judgment and should include both the patient and his partner in the deliberations," the authors conclude.
No Role for Intermittent ADT 
However, in the opposing viewpoint article, Maha Hussain, MD, University of Michigan, Ann Arbor, and Mario Eisenberger, MD, from the Johns Hopkins Sidney Kimmel Cancer Center, Oncology, Baltimore, Maryland, are less convinced about the merits of intermittent ADT.
They note that in 26 years after its introduction, the concept remains "unsupported by clinical trials data despite thousands of patients and millions of dollars. Attempts to derive reliable conclusions based on meta-analyses of aggregate studies data are limited by patients' and outcomes' heterogeneity."
They note that last year, a review (J Clin Oncol2016;34:280-285) and an editorial (J Clin Oncol2016;34:211-214) both discussed the seven randomized phase 3 clinical trials to date that have compared intermittent and continuous ADT.
All the reviewed studies "underestimated outcomes assumptions," with the sole exception of the SWOG S9346 trial, they note. In addition, all the studies were underpowered for OS and/or had a follow-up period that wasn't long enough to capture the number of events needed to allow for adequate testing of the null hypothesis.
There were many other limitations as well, they write. These include broad inclusion criteria (stage M0, M1 disease), a variety of ADT strategies, and failure of several studies to select for responsive disease.
In addition, some studies included agents of unproven efficacy, such as cyproterone acetate, which has not been approved for prostate cancer but was used in two studies.
"Most studies used broadly defined and/or unvalidated criteria for time to progression to castration resistance (TTP); of note, TTP artificially favors [intermittent ADT]," the authors point out. "None of the trials demonstrated significant and/or sustainable impact on QOL with [intermittent ADT]."
One of the studies, the TAP22 (BJU Int2012;110:1262-1269) was a superiority study. Despite the small sample size, the results showed that intermittent ADT was associated with poorer median survival (3.5 vs 4.3 years).
Dr Hussain and Dr Eisenberger also focus on the two largest studies, the PR7 and the S9346 trials, which are also discussed in the "pro" viewpoint article.
These two trials were designed as noninferiority (NI) studies, but to adequately interpret these studies, "it is critical to understand the basis for the actual design assumptions of NI studies," they comment.
More specifically, the noninferiority margin (NIM) must be considered clinically acceptable in order to allow for "reliable and clinically meaningful conclusions," they say. Thus, the NIM can be translated into a variety of "absolute survival differences" depending on the patient population and expected survival.
The PR7 trial was designed with an NIM of 1.25, which implies that the investigators "determined a priori that a 1.8-year reduction in OS with intermittent ADT is clinically acceptable and noninferior."
Median OS was 9.1 years vs 8.8 years in favor of continuous therapy, and the conclusion was that intermittent ADT was noninferior. But the authors point out that based on the observed OS and HR confidence interval, "a 1.6-year reduction in OS with [intermittent ADT] cannot be ruled out with 95% confidence."
The follow-up for the PR7 trial was only 6.9 years, but despite this short follow-up, more deaths due to prostate cancer occurred the intermittent group.
Results for the S9346 trial showed worse median survival with intermittent ADT (5.1 vs 5.8 years), and the HR upper limit of 1.23 with median survival of 5.8 years in the continuous therapy group translated "into an absolute survival difference of 1-year in favor of [continuous ADT]."
The authors also point out that while QOL data showed that patients receiving intermittent therapy had better erectile function and mental health at 3 months, these did not persist.
Treatment-related grade 3 and 4 adverse events did not differ between groups, and when long-term, late adverse events were analyzed separately among older patients, there were no apparent reductions in bone, endocrine, or cognitive adverse events among those receiving intermittent therapy. In fact, write the authors, the intermittent ADT group actually had an increased incidence of ischemic and thrombotic events.
"Compared with the 1980s and 1990s when the concept of [intermittent androgen therapy] was introduced, we have come a long way at multiple levels," Dr Hussain and Dr Eisenberger conclude.

"The evolving clinical/biological data and the unprecedented OS improvements with docetaxel plus ADT strongly argue that it is time to move on and focus our efforts on translating compelling discoveries into therapies that are most likely to result in true value and meaningful impact for men with prostate cancer," they add.

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