摘要
In a pivotal phase 3 randomized con trolled trial, Hussain et al. tested thehypothesis that, with respect to survival, intermittent androgen deprivation therapy （ADT） is noninferior to continuous in men with newly diagnosed metastatic prostate cancer. While the trial findings were statis tically inconclusive, the study suggests, but does not prove, that intermittent may do more harm than good, although findings are not definitive. While outcomes of ongoing trials are awaited, the trial by Hussain et al., in conjunction with an ear lier trial in men with nonmetastatic pro state cancer by Crook et al., does provide important new guidance regarding the choice of ADT in men with androgensensitive prostate cancer. ADT is one of the most effective palliat ive therapies for patients with metastatic prostate cancer, but not without drawbacks. While not as toxic as chemotherapy, ADT carries a significant risk of morbidity, including sexual dysfunction, fatigue, ane mia, accelerated bone loss and fractures, sarcopenia, increased risk of diabetes, and possibly, of cardiovascular events.1＇2 In addition, despite an initial response rate of more than 90%, most patients develop res istance to ADT, resulting in a median sur vival of 2.53 years. Predinical data suggest that continuous use of ADT may accelerate the emergence of resistance to this therapy, and that reexposure of prostate cancer stem cells to androgens can reinduce dif ferentiation and increase their apoptotic potential.3 These ADTassociated shortcom ings, in addition to treatment expense, havespurred the development of strategies to min imize the exposure to ADT, including the use of intermittent ADT. While several smaller randomized controlled clinical trials have compared the use of intermittent with con tinuous ADT, no definitive information is available for patients with metastatic prostate cancer. To fill this evidence gap, a large mul tinational randomized controlled trial led by Hussain et al.4 was designed in 1993, and out comes have been published recently in the New England Journal of Medicine. In a coprimary end point, the authors tested the hypotheses that （i） intermittent ADT is not inferior to continuous ADT with respect to survival in men with metastatic, hormone sensitive prostate cancer; and （ii） compared to continuous therapy, intermittent ADT improves quality of life. The primary finding from the study was inconclusive, that is, intermittent ADT was not proven to be as good as continuous ADT, and there was instead a trend to inferiority. While intermit tent ADT was associated with better erectile function and mental health, this benefit did not persist beyond 3 months. Due to the inconclusive finding of this noninferiority trial its findings may be difficult to interpret and apply to clinical practice. Therefore, we explore this trial in more detail. The study by Hussain et al.4 enrolled 3040 men from the Unite States, Canada and UK who had newly diagnosed prostate cancer with lymph node, visceral or bone metastases and a prostatespecific antigen （PSA） 〉 5 ng ml 1. Men received a 7month induction course with a luteinizing hormone releasing hormone agonist and antiandrogen （goser elin and bicalutamide, or equivalent） to select androgendependent disease, defined by a PSA G〈 4 ng ml 1 at induction end. One thou sand five hundred and thirtyfive men fulfilled this criterion and were then rando mized but not blinded to intermittent orcontinuous ADT, stratified by performance status, prior hormone therapy and extent of disease. Men assigned to continuous therapy continued, whereas men assigned to intermit tent therapy discontinued ADT at completion of the 7-month induction course. The
In a pivotal phase 3 randomized con trolled trial, Hussain et al. tested thehypothesis that, with respect to survival, intermittent androgen deprivation therapy （ADT） is noninferior to continuous in men with newly diagnosed metastatic prostate cancer. While the trial findings were statis tically inconclusive, the study suggests, but does not prove, that intermittent may do more harm than good, although findings are not definitive. While outcomes of ongoing trials are awaited, the trial by Hussain et al., in conjunction with an ear lier trial in men with nonmetastatic pro state cancer by Crook et al., does provide important new guidance regarding the choice of ADT in men with androgensensitive prostate cancer. ADT is one of the most effective palliat ive therapies for patients with metastatic prostate cancer, but not without drawbacks. While not as toxic as chemotherapy, ADT carries a significant risk of morbidity, including sexual dysfunction, fatigue, ane mia, accelerated bone loss and fractures, sarcopenia, increased risk of diabetes, and possibly, of cardiovascular events.1＇2 In addition, despite an initial response rate of more than 90%, most patients develop res istance to ADT, resulting in a median sur vival of 2.53 years. Predinical data suggest that continuous use of ADT may accelerate the emergence of resistance to this therapy, and that reexposure of prostate cancer stem cells to androgens can reinduce dif ferentiation and increase their apoptotic potential.3 These ADTassociated shortcom ings, in addition to treatment expense, havespurred the development of strategies to min imize the exposure to ADT, including the use of intermittent ADT. While several smaller randomized controlled clinical trials have compared the use of intermittent with con tinuous ADT, no definitive information is available for patients with metastatic prostate cancer. To fill this evidence gap, a large mul tinational randomized controlled trial led by Hussain et al.4 was designed in 1993, and out comes have been published recently in the New England Journal of Medicine. In a coprimary end point, the authors tested the hypotheses that （i） intermittent ADT is not inferior to continuous ADT with respect to survival in men with metastatic, hormone sensitive prostate cancer; and （ii） compared to continuous therapy, intermittent ADT improves quality of life. The primary finding from the study was inconclusive, that is, intermittent ADT was not proven to be as good as continuous ADT, and there was instead a trend to inferiority. While intermit tent ADT was associated with better erectile function and mental health, this benefit did not persist beyond 3 months. Due to the inconclusive finding of this noninferiority trial its findings may be difficult to interpret and apply to clinical practice. Therefore, we explore this trial in more detail. The study by Hussain et al.4 enrolled 3040 men from the Unite States, Canada and UK who had newly diagnosed prostate cancer with lymph node, visceral or bone metastases and a prostatespecific antigen （PSA） 〉 5 ng ml 1. Men received a 7month induction course with a luteinizing hormone releasing hormone agonist and antiandrogen （goser elin and bicalutamide, or equivalent） to select androgendependent disease, defined by a PSA G〈 4 ng ml 1 at induction end. One thou sand five hundred and thirtyfive men fulfilled this criterion and were then rando mized but not blinded to intermittent orcontinuous ADT, stratified by performance status, prior hormone therapy and extent of disease. Men assigned to continuous therapy continued, whereas men assigned to intermit tent therapy discontinued ADT at completion of the 7-month induction course. The
