Comorbidity Can Confound Prostate Cancer Treatment

By Charles Bankhead
BOSTON, Jan. 22 -- The best-laid plans of therapy for localized unfavorable-risk prostate cancer can be upset by pre-existing comorbidities, investigators here found. For instance, adding six months of androgen suppression to radiation improves overall survival by a significant 80%, Anthony V. D'Amico, M.D., Ph.D., of Harvard, and colleagues reported in the Jan. 23 issue of the Journal of the American Medical Association. But the reduction in mortality risk was seen only in men without significant comorbid conditions. In fact, men with moderate or severe comorbidity scores fared better with radiation alone, they added.
"The clinical significance of this finding is that pre-existing comorbid illness may increase the negative effects of specific anticancer treatments such as [androgen suppression therapy]," the authors concluded.
"Therefore, future randomized studies evaluating the impact on survival of adding novel therapies to the current standards of practice in men with clinically localized or locally advanced prostate cancer should consider a pre-randomization stratification by comorbidity score."
Several randomized studies have demonstrated prolongation of survival when androgen suppression is added to external-beam radiation for unfavorable localized and locally advanced disease.
However, pooled analyses of other randomized and cohort studies have indicated that androgen suppression therapy increases the risk of fatal and nonfatal cardiovascular events in older men, the authors said.
One possible explanation for the association between androgen suppression and increased cardiovascular risk is that the emergence of comorbid conditions with age may increase the negative effects of specific anticancer therapies, such as androgen suppression.
Dr. D'Amico and colleagues reported long-term follow-up data from a randomized study comparing six months of androgen suppression with radiation therapy versus radiation alone. They also analyzed survival data in subgroups defined by patients' level of comorbidity at baseline.
The study involved 206 men (median age 72.5) with localized or locally advanced prostate cancer and at least one unfavorable prognostic factor, defined as:
PSA level >10 ng/mL
Biopsy Gleason score of 7 to 10
Evidence of extracapsular extension
Evidence of seminal vesicle invasion
Additionally, each patient was assigned a baseline comorbidity score based on assessment by the Adult Comorbidity Evaluation 27. A patient's overall comorbidity was graded on a scale of 0 (none) to 3 (severe), determined by the severity of individual organ system decompensation and prognostic impact.
All patients were given three-dimensional conformal radiation therapy and were randomized to no additional therapy or to six months of androgen suppression. Initially, the primary endpoint was time to PSA recurrence. However, the protocol was modified before the first planned interim analysis to extend follow-up to allow evaluation of the prespecified secondary endpoints of overall and prostate cancer-specific survival.
After a median follow-up of 7.6 years, there were 44 deaths in the radiation-only group and 30 in the androgen suppression group. The difference translated into a significant survival benefit among men treated with androgen suppression in addition to radiation (hazard ratio: 1.8, P=0.01). Estimated eight-year survival was 74% with androgen suppression and 61% without.
Patients given androgen suppression therapy also had a significant reduction in prostate cancer-specific mortality. There were 14 prostate cancer deaths in the radiation-alone group versus four among patients given androgen suppression (HR: 4.1, P=0.01).
Analysis of the data by baseline comorbidity score showed that the survival benefit conferred by androgen suppression applied only to patients who had low comorbidity scores at baseline. Among patients with no or minimal baseline comorbidity scores (0 to 1), there were 31 deaths in the radiation-only group versus 11 in the androgen-suppression group (HR: 4.2, P<0.001).
In contrast, men with moderate or severe comorbidity had a lower all-cause mortality when treated with radiation alone (13 deaths versus 19, HR: 0.54, P=0.08).
"Our study suggested that the relevant underlying comorbidity may have been a prior history of MI more than six months before randomization, but numbers were too small to exclude other comorbidities, such as diabetes," the authors concluded.
"Health-related quality-of-life outcomes require further study," they continued. "Specifically, it is possible that while life expectancy may not be altered, health-related quality of life may be affected more in men with certain underlying comorbidities when [androgen suppression therapy] is administered."
The authors had no disclosures.
Primary source: JAMASource reference:D'Amico AV, et al "Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial" JAMA 2008; 299: 289-295.