Editing Hormonal Therapy (section)

== Intermittent versus Continuous Androgen Deprivation Therapy ==

* In animal models, exposure to androgen deprivation on an intermittent—rather than continuous—basis lengthened the time to the emergence of androgen-refractory cancer growth
* In theory, the quality-of-life side effects of ADT on intermittent treatment should be improved compared to when ADT is used continuously.
* '''PR7'''
** '''Population: Patients with a rising PSA after primary or salvage radiotherapy received an 8-month induction of ADT and were then'''
** '''Randomized to intermittent vs. continuous ADT'''
*** Intermittent treatment was provided in 8-month cycles, with nontreatment periods based on PSA levels.
** '''Primary outcome: OS'''
** '''Results:'''
*** Median follow-up: 6.9 years
*** '''OS non-inferior with intermittent ADT''' (8.8 years intermittent ADT vs. 9.1 years continuous ADT)
*** '''Attrition from intermittent ADT progressively increased over time as patients either developed CRPC or died of another cause.''' '''Attrition occurred in 5% of men in the 1st interval, whereas 68% had stopped intermittent therapy by the 3rd interval.'''
*** '''Duration of intermittent ADT progressively shortened over time'''
**** Median nontreatment interval between cycles was 20.1 months for the 1st treatment cycle, 13.2 months for the 2nd cycle, 9.1 months for the 3rd, and 4 to 5 months thereafter.
*** A secondary end point, improved quality of life in the intermittent therapy arm, was associated with significantly better scores for hot flashes, desire for sexual activity, and urinary symptoms. For the functional domains of physical, role, and global health the intermittent therapy arm was slightly better, but the differences were not significant. Overall, the authors concluded that “the difference in quality of life is not as profound as one might expect”
*** Crook, Juanita M., et al. "Intermittent androgen suppression for rising PSA level after radiotherapy." ''New England Journal of Medicine'' 367.10 (2012): 895-903.
** Noninferiority trials require fewer subjects than an equivalence trial, making them easier to accrue and complete. It is important to recognize that noninferiority is not the same as equivalence; trial design is based on a definition of noninferiority if a prespecified upper margin of a hazard ratio is not exceeded. In this trial, the upper limit was 1.25, meaning up to 25% more men on the intermittent arm could die of any cause and intermittent treatment would still be considered noninferior. In this trial, the upper limit of the 95% CI was 1.22 (p=0.009), which is below 1.25 and therefore met the prespecified definition.
* '''SWOG 9346'''
** '''Population: patients with newly diagnosed metastatic prostate cancer whose PSA level had declined to ≤ 4 ng/mL after a 7-month induction of ADT (indicating androgen sensitivity)'''
** '''Randomized to intermittent vs. continuous ADT'''
** '''Co-primary outcomes: OS and QOL at 3 months after randomization'''
** '''Results'''
*** '''Median follow-up: 9.8 years'''
*** '''Median OS was significantly lower with intermittent ADT (5.8 years continuous vs. 5.1 years intermittent (HR for death with intermittent therapy, 1.10; 90% CI 0.99-1.23)).'''
** '''Unfortunately, these findings are statistically inconclusive: the CI for survival exceeded the upper boundary for noninferiority (1.20), therefore cannot conclude that intermittent therapy was noninferior to continuous therapy. Furthermore, because the lower limit of the CI (0.99) did not exclude 1.00, cannot conclude that intermittent therapy was significantly inferior to continuous therapy.''' A reasonable clinical interpretation of this statistically inconclusive study is that intermittent therapy is not superior to continuous therapy in men presenting with metastatic prostate cancer, and may be worse. In the words of the authors “given that nearly the entire confidence interval tends to favor continuous therapy, the results suggest that intermittent therapy may compromise survival”
** Hussain, Maha, et al."Intermittent versus continuous androgen deprivation in prostate cancer." ''New England Journal of Medicine'' 368.14 (2013): 1314-1325.
* '''Comparing the intermittent ADT trials'''
** '''Similarities'''
**# '''Used an induction period of ADT (8 months and 7 months, respectively)'''
**# '''Stopped ADT if PSA < 4 ng/mL'''
**# '''CRPC was managed with continuous ADT'''
** '''Differences'''
**# '''Patient population (post-radiation vs. newly diagnosed metastatic)'''
**# '''PSA threshold to restart PSA (10 after radiation therapy or 20 ng/mL for metastatic disease)'''
**#* The treatment schedules provide some guidance but there is no consensus on the ideal schedule in managing patients on intermittent ADT