The objective of androgen deprivation therapy (ADT) in men with prostate cancer is to maintain very low levels of testosterone so that the hormone does not promote tumor growth. But a new analysis found that drugs commonly used to achieve this are administered later than the recommended 28-day regimen, and this late dosing was associated with ineffective suppression of testosterone.
"Evidence suggests achieving and sustaining T levels <20 mg/dL with ADT is desirable and correlates with improved disease-specific survival in patients with advanced prostate cancer," lead author David Crawford, MD, professor of urology, University of California, San Diego, and colleagues point out.
They looked at administration schedules for luteinizing hormone-releasing hormone (LHRH) agonists and found that they were frequently (84%) administered later than the recommended schedule of every 28 days. Nearly half of the late testosterone values for the extended month were greater than 20 ng/dl, and mean testosterone was almost double the castration level, they report.
"Considering the presumed clinical benefits of maintaining effective T suppression throughout the course of ADT, clinicians should administer treatments within approved dosing instructions, monitor T levels, and consider prescribing treatments with proven efficacy through the dosing interval to maintain T below castration levels," they emphasize.
The analysis was published in the Journal of Urology and was presented during the virtual American Urological Association 2020 annual meeting.
The study was done before the current pandemic, which canceled the in-person gathering of AUA 2020. Now, in the COVID-19 era, the interval between when men are scheduled for their next injection and when they actually get it may well be growing longer. Crawford says he recently saw one patient who waited 3 months before getting his next "monthly" injection.
28-day Injection Cycle
For the review, Crawford and colleagues examined electronic health records (EHRs) and associated insurance claims for a total of 85,030 injections to evaluate the frequency of late dosing.
When the pivotal registration trials for LHRH agonist were done, a 1-month injection of an LHRH formulation was defined as every 28 days, and not 30 or 31 days as per calendar months.
The current analyses were done using 2 definitions of a month: a 28-day month with late dosing defined as injections given after day 28, and an "extended" month with late dosing defined as injections given after day 32, for products that are dosed once-monthly. The analyses also looked at products that are dosed once every 3-months, once every 4 months, and once every 6 months.
The team also evaluated how often testosterone exceeded the castration level of 20 ng/dL, as well as mean T levels and frequency of T tests and prostate specific antigen (PSA) tests taken by physicians prior to administering the injection.
Results showed that 84% of the 28-day dosing interval and 27% of the extended-month dosing administrations were late.
Furthermore, "when LHRH agonist dosing was late, both the proportion of T tests with T >20 ng/dL and mean T were higher compared to when the dosing was early or on-time," Crawford and colleagues point out.
For example, 43% of T values exceeded 20 ng/dL when injections were late compared to only 21% of T values when injections were given early or on time.
Furthermore, mean T values were 21 ng/dL when injections were given early or on time, but they rose to a mean of 79 ng/dL when injections were late.
Physicians were also far less likely to measure T levels at the time of administering the injections when compared to measuring PSA levels, the team found. T levels were assessed only 13% of the time, whereas PSA levels were assessed 83% of the time while administering LHRH injections.
"All of the package inserts say clinicians should measure T periodically when men are on these drugs, yet urologists don't do it most of the time. They are more interested in PSA because that is what the patient wants to know," Crawford commented in an interview with Medscape Medical News.
The thinking is that "so as long as the PSA is fine, everything else is fine too," he added.
That, however, is not necessarily the case.
As Crawford and his colleagues explain, rising PSA levels can reflect disease progression to castrate-resistant prostate cancer but they may also simply reflect late ADT dosing or other technical issues such as inappropriate dosing for a patient's body weight.
With a number of new therapies now available for castrate-resistant prostate cancer, it's important that physicians ensure that T levels remain below castration levels in order to not wrongly diagnose a man with castrate resistance disease as subsequent changes in management could be entirely inappropriate.
More of an issue, Crawford suggests, is that every time a patient receives an injection of an LHRH agonist, not only do his T levels flare, but so does his PSA.
Crawford suspects that levels of follicle-stimulating hormone (FSH) are also going up in response to LHRH agonist injections.
"We know that hormone therapy is associated with a lot of side effects but the big one for us right now is cardiovascular, so you may be doing the patient a significant disservice by allowing these 'mini-flares' to occur with late injections," Crawford said.
As to why men are receiving their injections beyond recommended intervals, Crawford feels that many urologists are not taking the timing of dosing as seriously as they should.
"There may also be scheduling issues and patient compliance issues as well," he acknowledged.
Disturbingly, however, if a man does show up in a timely way for his next injection, "insurance companies may refuse to reimburse him unless he comes back on days 30 or 31," Crawford observed.
For men who are concerned about COVID-19 and reluctant to attend the clinic for the next injection, there are ways to deliver healthcare that can facilitate timely dosing.
For example, some big urology clinics are having men drive up to their parking lots and receive their next injection in the car, by appointment only of course. Some centers are trying out at home administration.
The other solution to the late dosing problem is to prescribe longer-acting depot formulations so men need less frequent infections.
"It is simply not acceptable to be giving drugs out of their indication and time frame for which they were approved, so people need to take this more seriously," Crawford said.
"We need to administer these drugs on time," he emphasized.
"We need to monitor T levels because some patients will still experience escapes even if they are getting the drug on time," Crawford explained, "and we now have evidence that when patients do have these T failures, this is reflected in rising PSA levels and that may be an indication of disease progression, which we clearly don't want to happen."
The study was funded by Tolmar. Crawford reports receiving fees from Tolmar and Ferring. The other study authors have disclosed no relevant financial relationships.
The American Urologist Association (AUA) 2020 Annual Meeting: Abstract MP37-18.
J Urol. Published online April 1, 2020. Abstract
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Cite this: ADT for Prostate Cancer: Concern That Injections Often Given Late - Medscape - Jul 30, 2020.