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Dose-escalated external beam radiation treatment (EBRT) ?75.6 Gy is associated with improved overall survival in men with intermediate and high-risk prostate cancer although not in men with low-risk disease, a retrospective comparative effectiveness study suggested.

In a cohort of 12,229, 16,714, and 13,538 patients with low, intermediate and high-risk prostate cancer, respectively, investigators found that dose-escalated EBRT was associated with a statistically significant 16% decreased hazard of death at an inverse probability weight propensity score (IPW-PS) adjusted hazard ratio (HR) of 0.84 (95% CI: 0.80-0.88; P<0.001) for men with intermediate-risk prostate cancer compared with patients who received standard-dose EBRT.

Among men with high-risk disease, dose-escalated EBRT was associated with a statistically significant decreased hazard of death at an IPW-PS adjusted HR of 0.82 (95% CI: 0.78-0.85; P<0.001) compared with standard-dose EBRT.

In contrast, the association between dose-escalated EBRT and reduced hazard of death was not significant in men with low-risk disease at an IPW-PS adjusted HR of 0.98 (95% CI: 0.92-1.05; P=0.54).

"Our findings are concordant with the growing literature that most men with low-risk prostate cancer have excellent survival without radical treatment," Anusha Kalbasi, MD, Hospital of the University of Pennsylvania, Philadelphia, and colleagues wrote in JAMA Oncology.

"And our results add to the body of evidence questioning aggressive local treatment strategies in men with low-risk prostate cancer but supporting such treatment in men with greater disease severity."

Investigators identified 360,142 patients with prostate cancer reported to the National Cancer Data Base (NCDB) between 2004 and 2006.

Patients who received EBRT with or without androgen-deprivation therapy (ADT) were included in the analysis.

Each of the low, intermediate, and high-risk groups were separated into men who had received EBRT at a dose of less than 75.6 Gy and those who received EBRT at a dose of 75.6 Gy or greater.

As the authors note, the dose of 75.6 Gy was chosen as a cut-off point to reflect the division between high and low-dose arms of randomized clinical trials of EBRT in prostate cancer.

The median follow-up for surviving patients was 85 to 86 months for all risk cohorts.

"For the low-risk cohort, incremental increases in dose were not associated with a difference in survival," the authors note.

However, for the intermediate-risk cohort, every approximate 2-Gy dose increase was associated with a 7.8% reduction in the hazard of death at an IPW-PS HR of 0.92 (95% CI: 0.90-0.95; P<0.001).

For men in the high-risk disease group, every approximate 2-Gy increase in dose was associated with a 6.3% reduction in the hazard of death at a HR of 0.94 (95% CI: 0.91-0.97; P<0.001).

Furthermore, dose categories of 81 Gy and greater than 81 Gy were each associated with a statistically significant improvement in survival compared with 70.2 Gy, investigators added.

The authors acknowledge their study has limitations.

"First, we cannot establish a causal relationship between dose-escalated EBRT and overall survival based on our observational cohort," they caution.

Secondly, even after traditional regression and propensity score methods, they cannot rule out residual bias from unknown variables.

Thirdly, the NCDB does not record data on ADT duration nor treatment toxic effects and NCDB EBRT dose records are subject to heterogeneity as the dose prescribed by radiation oncologists can vary considerably.

Lastly, the NCDB collects data only from Commission on Cancer-approved facilities.

"Thus our results are generalizable to patients treated at facilities that tend to be larger and urban," investigators note.

In an accompanying editorial, Phillip Gray, MD, and Anthony Zietman, MD, Harvard Medical School, Boston, observe that the lack of benefit seen in patients with low-risk disease is "hardly surprising" because the risk of cancer-specific death in this patient group is already very low.

"Indeed, mounting evidence suggests that for many, if not most, low-risk patients, the most appropriate dose of radiation may in fact be 0 Gy," they state.

For patients with more aggressive disease, on the other hand, death from prostate cancer is of significant concern.

"In such patients, local failure is strongly associated with subsequent cancer-related death," Gray and Zietman observe.

"And it is these patients who stand to derive the most benefit from intensification of therapy."

The research was supported by the National Cancer Institute and the David and Leslie Clarke Fund.

Kalbasi disclosed no relationships with industry.

Gray and Zietman disclosed no relationships with industry.

• Reviewed by F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine

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