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Primary ADT failed to improve survival in prostate cancer
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Men with localized prostate cancer who received primary androgen deprivation therapy demonstrated no long-term or disease-specific survival benefit over those who received no treatment, according to results of a retrospective cohort study.
Although previous studies reported that primary ADT did not improve survival for men with localized moderately differentiated prostate cancer, a possible association with a borderline survival benefit for patients with poorly differentiated cancer during a 10-year period after diagnosis was noted.
Grace Lu-Yao
“Although there are no data to support the use of ADT for early stage prostate cancer, ADT has been widely used as a primary therapy for localized prostate cancer, especially among older patients,” Grace Lu-Yao, PhD, MPH, cancer epidemiologist at the Rutgers Cancer Institute of New Jersey, and colleagues wrote. “Because the cancers of most patients treated with ADT will become refractory within a few years and many adverse effects are associated with the use of ADT, the timing of ADT is crucial.”
To determine whether primary ADT provides a long-term survival advantage in older men with localized prostate cancer, the researchers assessed data from 66,717 Medicare patients aged at least 66 years diagnosed with clinical stage T1-T2 prostate cancer between 1992 and 2009.
Researchers used instrumental variable analysis to examine the effect of primary ADT and control for potential biases associated with unmeasured confounding variables. The instrumental variable included combined health services areas with various usage rates of primary ADT.
In addition, the analysis compared survival outcomes among patient populations in areas of the country where ADT was more often used as a sole treatment vs. areas where it was not.
Researchers observed that when ADT was administered as the primary treatment localized prostate cancer during the first 6 months after diagnosis, there was no association with improved 15-year overall or prostate cancer-specific survival, especially among the older patients in the study.
Among patients with moderately differentiated cancers, the 15-year OS was 20% in high primary ADT use areas vs. 20.8% in areas with low use (difference: 95% CI, –2.2% to 0.4%), and the 15-year prostate cancer survival was 90.6% in both high- and low-use areas (difference: 95% CI, –1.1% to 1.2%).
Among patients with poorly differentiated cancers, researchers found that the 15-year cancer-specific survival was 78.6% in high-use areas vs. 78.5% in low-use areas (difference: 95% CI, −1.8% to 2.4%), and the 15-year OS was 8.6% in high-use areas compared with 9.2% in low-use areas (difference: 95% CI, −1.5% to 0.4%).
“These findings, the fact that primary ADT does not delay the use of secondary cancer therapies, and the fact that randomized clinical trials show no survival benefit, demonstrate that there is a limited role for ADT as primary therapy for men with localized prostate cancer,” Lu-Yao and colleagues wrote. “Health care providers and their older patients should carefully weigh our findings against the considerable adverse effects and costs associated with primary ADT before initiating this therapy in men with clinically localized prostate cancer.”
Disclosure: The researchers report clinical research funding from Myriad; consultant roles with Merck; and employment relationships with Schering-Plough and Merck.
Perspective
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Daniel P. Petrylak, MD
Androgen blockade often has been used as an alternative treatment for those patients who either refuse or are deemed to be unfit for definitive local therapy, such as radical prostatectomy or external beam radiation therapy. The value of the use of this treatment has been questioned, as some retrospective studies have suggested an increase in all-cause as well as prostate cancer-specific mortality. Currently, neither the National Comprehensive Cancer Network nor the European Association of Urology include androgen deprivation therapy alone in their guidelines for the treatment of localized prostate cancer.Lu-Yao and colleagues used the SEER database to evaluate prostate cancer treatment for 66,717 men aged ≥66 years diagnosed with T1/T2 disease between 1992 and 2009. Of these patients, 25,125 (37.7%) received primary androgen deprivation therapy.
The researchers used a Cox multivariate analysis as well as an instrumental variable analysis, which adjusts for both measured and non-measured cofounders. This helps to eliminate the bias that an individual may be more likely to receive a treatment because that individual has one or more co-morbid conditions. The Cox multivariable analysis found that primary androgen blockade was associated with an increased risk for prostate cancer-specific and overall mortality. The fact that these findings were not confirmed by the instrumental variable analysis implies that there is significant bias in the Cox analysis toward patients with higher-risk disease.
Clearly, the only definitive way to answer this question would be a randomized controlled trial, which would be extremely difficult to administer given the multiple selection biases seen in local treatment. It is clear from this trial, as well as other trials, that primary androgen blockade should be avoided in these patients as monotherapy.
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