ADT-RT Results in Improved Outcomes for Locally Advanced PCa

This approach is, or should be, the standard of care for locally advanced PCa, some researchers say.
This approach is, or should be, the standard of care for locally advanced PCa, some researchers say.

Recently published studies provide additional evidence supporting the use of combination treatment with androgen deprivation and radiation in patients with locally advanced prostate cancer (PCa). 

The studies demonstrate that androgen deprivation therapy (ADT) plus radiation therapy (RT) is associated with superior cancer-specific and overall survival compared with ADT alone, prompting researchers to conclude that ADT plus RT is a reasonable option for treating locally advanced PCa. 

“For patients [with locally advanced PCa] who are treated by radiation, the standard of care should be ADT plus RT. Period,” said Justin E. Bekelman, MD, Associate Professor of Radiation Oncology at the University of Pennsylvania in Philadelphia. “The challenge is, there's never been a trial that has compared surgery to ADT plus RT for locally advanced prostate cancer. That trial is crucial. That would fill the evidence gap.” 

At his institution, RT plus long-term ADT is the standard recommendation for patients with locally advanced PCa who opt for RT, he said. 

Manageable side effects 

“I think that the important thing to note is that the combination of radiation with hormone therapy not only improves lives, but is tolerable, Dr. Bekelman said. “With modern radiotherapy techniques, studies have shown that the side effects of radiation with hormone therapy are manageable.” 

Dr. Bekelman led a study comparing ADT alone and ADT plus RT in 3 groups of men with locally advanced or high-risk PCa. These groups included a cohort of 4,642 men aged 65–75 years in a randomized controlled trial (RCT); an elderly cohort of 8,694 men older than 75 years with locally advanced PCa; and a cohort of 2,017 men aged 65 years and older with screen-detected high-risk PCa. 

In the RCT cohort, ADT plus RT was associated with a significant 57% decreased risk of cancer-specific mortality and 37% decreased risk of all-cause mortality compared with ADT alone in propensity score-adjusted analyses, Dr. Bekelman's group reported in the Journal of Clinical Oncology (2015;33:716-722). In the elderly cohort, ADT plus RT was associated with a significant 49% and 37% decreased risk of cancer-specific and all-cause mortality, respectively. In the screen-detected cohort, ADT plus RT was associated with a significant 75% and 50% decreased risk of cancer-specific and all-cause mortality, respectively. 

In a separate study, which was published in the Journal of Clinical Oncology (2015;33:2143-2150), Malcolm D. Mason, MD, of Cardiff University School of Medicine in Cardiff, UK, and colleagues reported on a study showing that men with locally advanced PCa treated with ADT plus RT had a significant 30% decreased risk of all-cause mortality and 54% decreased risk of PCa mortality compared with those who received ADT alone. The study included 1,205 men with locally advanced PCa who, from 1995 to 2005, were randomly assigned to receive ADT alone (602 men) or ADT plus RT (603 men). After a median follow-up time of 8 years, 465 patients had died, 199 from PCa. 

The researchers noted that patients in the combination arm experienced a higher frequency of adverse events related to bowel toxicity, but only 2 of 589 patients had grade 3 or higher diarrhea at 24 months after RT. 

Additionally, based on a recent systematic review and meta-analysis, researchers concluded that longer duration of ADT combined with radiotherapy is associated with better overall, disease-free, and disease- specific survival in patients with intermediate- and high-risk non-metastatic PCa. The researchers, who published their findings in the International Brazilian Journal of Urology (2015;41:425-434), analyzed pooled data from 6 randomized trials comparing different durations of hormone blockade. 

‘Sometimes a contentious area'

In an interview, Dr. Mason said he believes ADT plus RT is the standard of care for locally advanced PCa. “This is sometimes a contentious area in that the results of surgery in properly selected men treated in expert centers are undoubtedly excellent, too, though there is no level 1 evidence to support this,” he said. 

Dr. Mason added, “We badly need a trial of radiotherapy plus hormones versus surgery in locally advanced disease, but the challenges in doing such a trial are formidable. Our trial and others are sometimes interpreted as indicating that curative local therapy is effective in men with locally advanced disease, whatever form of curative therapy is employed. Now, this may be true, but it is an assumption, and it is not the only possible explanation for our study results.” 

In a study of men with clinically node-positive (cN+) prostate cancer (PCa), researchers led by Jason A. Efstathiou, MD, DPhil, of the Department of Radiation Oncology at Massachusetts General Hospital in Boston, found that ADT plus RT was associated with a significant 50% decreased risk of 5-year all-cause mortality compared with ADT alone in propensity score-adjusted analyses. 

This study, which was published in the Journal of the National Cancer Institute (2015;107:djv119), included 3,540 men with cN+ PCa identified using the National Cancer Data Base. Of these, 1,818 (51.4%) received ADT plus RT, 1,141 (32.2%) received ADT alone, 220 (6.2%) received RT alone, and 361 (10.2%) received neither ADT nor RT. The propensity score-adjusted analysis, which was performed to balance baseline characteristics, included 318 ADT-only recipients matched to 318 ADT plus RT recipients. 

Important clinical implications 

“As aggressive local management of cN+ prostate cancer may lead to durable disease control and even cure,” the authors concluded, “these data have important implications for clinical practice guidelines and staging systems.” 

Prior to propensity score matching, 47.1% of patients who received ADT alone and 25% of those treated with ADT plus RT died within the 5-year follow- up period. The crude 5-year overall survival rate was significantly lower in the ADT-only group compared with the ADT plus RT group (49.4% vs. 72.4%). 

The men had a median age of 66 years. The median follow-up time was 5.2 years for patients diagnosed from 2004 to 2006 and 2.7 years for those diagnosed from 2004 to 2011, the researchers reported. 

Data showed that the use of ADT alone decreased from 36.6% in 2004 to 32.2% in 2011, whereas use of ADT plus RT increased from 45.2% to 54.1%.

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