While many older patients and their oncologists typically opt for androgen-replacement therapy (ADT) without radiation for locally advanced or screening-detected high-risk prostate cancer, those treated with both regimens appear to have longer survival, according to an observational analysis of studies included in the National Cancer Institute's Statistics, Epidemiology, and End Results (SEER) database (JCO 2015;33:716-722).
Prostate cancer patients over age 75 have not been well represented in clinical trials, noted the researchers, led by researcher Justin E. Bekelman, MD, Associate Professor of Radiation Oncology at the University of Pennsylvania Perelman School of Medicine's Abramson Cancer Center.
The study compared outcomes for men receiving androgen-replacement therapy (ADT) alone or with radiotherapy treated between 1995 and 2007 in patients under or over age 75 followed through 2009. Both cause-specific and all-cause mortality was significantly less among older patients who received both types of therapy.
Three groups were compared in the randomized clinical trial, which included men age 65 to 75, determined to be most consistent with participants in all randomized trials. The older group included those over 75 with locally advanced prostate cancer, and a screen-detected group of men between 65 and 75.
“Two recent landmark randomized clinical trials found that ADT plus RT resulted in a large and significant reduction in overall and cause-specific mortality compared with ADT alone, but elderly men and patients with screen-detected high-risk cancers were under-represented or excluded,” Bekelman said. “What we have found is this also holds true for older men with locally advanced or screen-detected high-risk prostate cancer.”
In the clinical trial group, ADT plus RT was associated with reduced cause-specific and all-cause mortality relative to ADT alone, with a cause-specific propensity adjusted ratio of 0.43 and an all-cause propensity score of 0.63—which is not significantly different from ratios from other randomized trials, he said.
Lack of Evidence to Guide Treatment Decisions
“Despite this, ADT alone is a common treatment, especially in elderly patients in their 70s and 80s. Among men over 75 diagnosed with locally advanced or high-risk screen-detected cancers, an estimated 40 percent receive ADT alone, even though it is not curative and many patients risk adverse effects.”
The lack of evidence to guide prostate cancer treatment decisions among older men and those with screen-detected high-risk tumors stands as a special priority among the many evidence gaps in the treatment of prostate cancer, Bekelman continued.
He and his colleagues investigated nonrandomized observational studies to examine whether the strong survival advantage of ADT plus RT relative to ADT alone reported in the two efficacy trials also holds in real-world clinical practice among these older patients.
“Although clinically localized prostate cancers, in general, often present as indolent malignancies in the prostate-specific antigen era, locally advanced prostate cancers are more aggressive. Ten-year cause-specific mortality approaches 25 percent in men with locally Stage T3 advanced disease.”
For many years clinicians have been uncertain whether or not to add radiation therapy to systemic ADT improved survival for older patients with locally advanced cancers, he explained. But the team found that in the elderly cohort, ADT plus RT was associated with reduced cause-specific mortality, with a hazard ratio (HR) of 0.51, and all-cause mortality at 0.63. In the screen-detected group, ADT plus RT was associated with reduced cause-specific mortality (HR 0.25) and all-cause mortality (HR 0.50).
In secondary analyses of the screen-detected cohort restricted exclusively to men between the ages of 76 and 85, the results were similar to the main findings.
In an accompanying editorial (JCO 2015;33:676-677), Dean A. Shumway, MD, and Daniel A. Hamstra, MD, of the University of Michigan, said the study suggests that there may be what they call “ageism” in treatment decisions for older men with prostate cancer, and that data show that undertreating high-risk prostate cancer is a growing problem, with increased reliance on primary ADT monotherapy.
“Given that an average 75-year-old man in the United States has a remaining life expectancy of 11 years, and that the 10-year cause-specific mortality from conservatively treated high-risk prostate cancer is approximately 26 percent, this represents a serious potential for age-dependent bias against therapy,” they wrote.
Clinical trials have consistently shown that long-term ADT plus RT for locally advanced prostate cancer improves survival, they noted, as well as improvements in clinical/biochemical progression–free survival and metastasis-free survival.
“On the basis of these three trials, there is little question that for patients with locally advanced prostate cancer, use of ADT alone provides inadequate treatment, with inferior outcomes in comparison to ADT with RT. These findings are now reflected in guidelines from the European Association of Urology, the American Urological Association, and the National Comprehensive Cancer Network.”
These organizations recommend that primary therapy with ADT alone should be restricted to only patients who are not candidates for more comprehensive treatment with RT.
“How these results apply to older men who are not well represented in [such] prospective clinical trials is an area of critical unmet need that is in part addressed by the population-based observational study performed by Bekelman and colleagues,” Shumway and Hamstra continued.
“This is an intuitive and reassuring finding: that the results observed in selected patients enrolled onto RCTs seem applicable to a similar group of men receiving care in the community. However, more importantly, the authors then extend their analysis to assess the generalizability of these findings to two groups who are not well represented in the RCTs: men with screen detected high-risk prostate cancer and men older than 75.
The editorial notes that much of the public discourse on prostate cancer emphasizes that there is overtreatment of low-risk prostate cancer in men who are least likely to die as a result of the disease. With so much evidence supporting the addition of radiation therapy to ADT for high-risk disease, “one must question why, in the population analyzed, 49 percent of men older than 65 with locally advanced or high-risk prostate cancer were treated with ADT monotherapy, a rate that increased to 61 percent in those age 75 years or older.”
The findings underscore the importance of making treatment decisions based not on chronological age but rather on each patient's physical condition: “In elderly men who are sufficiently healthy to tolerate ADT, careful consideration should be given to also treating with radiation therapy, which is associated with substantial improvements in disease-specific and overall survival and can be delivered with minimal morbidity using modern treatment,” the writers concluded.
Physical Assessment, Not Age
Asked for his perspective, William Dale, MD, PhD, Chief of the Section of Geriatrics & Palliative Medicine and Director of the Specialized Oncology Care & Research in the Elderly Clinic at the University of Chicago Medicine, said: “I think the paper shows what many of us in geriatric oncology have always said, that treatment should depend not on chronological age but on each individual's overall health and physical condition. It confirms that if an older person is more or less healthy and able to function they probably have reasonable life expectancy.”
Still, he said he has concerns that the functional status of older adults is often not assessed and that physical ability is not a factor in most oncology clinical trials and even in large data sets like SEER: “Studies in older adults need to include their functional status and cognitive state, not just their age—how well and how fast they can walk, and strength assessment.
“Some of this data is out there, and the authors made an attempt, but if there is a lot of difference in functional status, and it changes whether or not these patients are good candidates for ADT and RT. This is especially important when it comes to reviews of large data bases.”
Dale said there is a need to look at current data in this group differently—for example, with regard to loss of muscle mass. “Every physician can access existing CT scan data that can provide a more accurate appraisal of each patient's physical and cognitive status. There is some of this in the SEER data base, and I think the researchers need to go back and look a little harder instead of just considering standard comorbid factors.”
The good news, though, he said, is that there is not much evidence that hormonal treatment or even radiation has much of an effect on the brain, and many subjects with cognitive difficulties are excluded from most clinical trials.