Of 1,530 patients in this analysis, 43 were treated with <70 Gy (median follow-up of 85.9 months), 552 patients with 70–74.9 Gy (median follow-up of 67.8 months), 568 patients with 75–79.9 Gy (median follow-up of 54.6 months), and 367 with ≥80 Gy (median follow-up of 45.6 months). The AJCC clinical stage was T1–T2 in 96%, and the Gleason scores were 2–6, 7, or 8–10 in 72%, 24%, and 4% respectively. The iPSA levels were <10 ng/mL in 62%, 10–20 ng/mL in 27%, and >20 ng/mL in 11% of patients. Patients were classified as low-risk in 45%, intermediate-risk in 39%, or high-risk in 16% of cases.
shows the distribution of patients by age, T-stage, Gleason score, iPSA, and risk group for the four dose groups. The median age was 73 years for the low-dose cohort, and 68–69 years for the three higher dose cohorts. Median follow-up ranged from 46 to 86 months, reflecting longer follow-up for patients treated with lower doses. The highest dose group was biased toward higher Gleason scores, with 51% of the cohort with a GS of 7, compared to 18% and 15% in the 70–74.9-Gy and 75–79.9 Gy cohorts, respectively. Clinical stage and iPSA were similar between the four dose groups. This difference in GS was also reflected in an increase in intermediate-risk patients in the highest dose group (67%).
Salvage androgen deprivation was initiated in 151 of 338 patients with an ASTRO biochemical failure. There were 61 patients with distant metastases. Androgen deprivation was not started before the diagnosis of distant disease in 39 patients (64%). The numbers of patients treated with androgen deprivation before distant metastases, compared to those who did not receive androgen deprivation before distant metastases, were 0:1, 9:24, 11:7, and 2:7 for the <70-Gy, 70–74.9-Gy, 75–79.9-Gy, and ≥80-Gy dose groups, respectively.
Multivariate analyses of biochemical failure are shown in . For the ASTRO definition, increasing dose (relative risk [RR] = 0.92, continuous variable), T-stage (RR = 2.27, dichotomous variable), Gleason score (RR = 2.07, dichotomous variable), and increasing iPSA (RR = 1.02, continuous variable) were significant independent predictors of BF. For the Phoenix definition, dose (RR = 0.94), T-stage (RR = 2.37), Gleason score (RR = 2.07), and iPSA (RR = 1.02) were significant independent predictors of BF. When the median dose in each cohort was used to define categorical variables, dose remained a significant predictor of FFBF with both the ASTRO and Phoenix definitions.
Multivariate analyses of biochemical failure
shows FFBF and FFDM rates by dose group, adjusted for T-stage, GS, and iPSA. The adjusted ASTRO FFBF rates were lower than the Phoenix FFBF rates at 5 years, and higher at 8 years. shows the adjusted Kaplan-Meier estimates of FFBF for the ASTRO definition () and the Phoenix definition () for each dose group. A comparison of adjusted curves reveals that the ASTRO definition has a steeper initial slope, and plateaus at approximately 7 years, compared to the Phoenix definition. This reflects the effect of backdating failures in the ASTRO definition. By the Phoenix definition, there is a higher FFBF rate initially, and a steady rate of decline over time, without a noticeable plateau. These patterns are reflected in the dose–response functions for FFBF at 5 and 8 years shown in .
Patient outcomes adjusted for T-stage, iPSA, and GS
(a) The ASTRO FFBF adjusted Kaplan-Meier estimates for each dose group.
(a) Adjusted dose–response functions at 5 years for FFBF and FFDM. (b) Adjusted dose–response functions at 8 years for FFBF and 10 years for FFDM. FFBF = freedom from biochemical failure; FFDM = freedom from distant metastases.
displays the results of multivariate analysis using FFDM as the endpoint. Dose (RR = 0.92, p = 0.0224), T-stage (RR = 2.42, p = 0.0152), GS (RR 4.41, p < 0.0001), and iPSA (RR = 1.02, p < 0.0001) were independent predictors of DM. For median doses of 69 Gy, 72 Gy, 76 Gy, and 82 Gy, the adjusted 5- and 10-year FFDM estimates were 96% and 93%, 97% and 93%, 98% and 95%, and 98% and 96%, respectively. and display the 5- and 10-year dose–response function for FFDM. The number of events remains low, even at 10 years, but the relationship of FFDM to dose is nonetheless robust.
Multivariate analysis of distant metastasis
The effect of higher RT doses on improved FFDM appeared to translate into a survival advantage. Overall mortality, when adjusted for age, T-stage, iPSA, and GS at 10 years, was 49%, 37%, 31%, and 26% for the <70-Gy, 70–74.9-Gy, 75–79.9-Gy, and ≥80-Gy dose groups, respectively (p = 0.0023).