The clinical characteristics of the 667 patients are summarized in . Patient age and clinical T-stage were well matched among the three RT dose groups. Initial pretreatment PSA and Gleason score distributions were similar in the >74 and 74-76 Gy groups, however the >76 Gy group had more favorable iPSA (P<.0001) and more adverse Gleason score (P<.0001). Median follow-up was also shorter in the >76 Gy group (65 months), compared with 85-87 months in the lower dose groups (P<.0001).
Biochemical failure was examined using two definitions, one encouraged by a consensus conference sponsored by ASTRO (16
) and the other from a joint ASTRO-RTOG conference in Phoenix (22
). The Phoenix definition, the PSA nadir + 2 ng/mL after RT, is a better approximation of eventual clinical failure (17
). A primary reason for making the comparison here is that, because the ASTRO definition incorporates backdating, the interval hazard function for ASTRO BF will not be an accurate reflection of the risk of BF at a given interval of time, while the Nadir+2 definition will.
Biochemical failure using the ASTRO definition was documented in 227 (34%) of the 667 study patients. The majority of these failures occurred early, with 194/277 (85%) in years 0-4 post-RT. The 5-year actuarial ASTRO BF rates decreased from 50% to 30% with increasing RT dose (P<.0001, ). Univariate analysis revealed that higher T-stage and iPSA were significantly associated with an increased ASTRO BF rate (P≤.0001, ). Conversely, higher RT doses were significantly associated with lower ASTRO BF rates (P<.0001). Multivariate analysis confirmed that higher RT dose as a continuous variable was independently associated with decreased ASTRO BF (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.88 to 0.95; P<.0001, ). Thus the risk of ASTRO BF was reduced by 8% for each additional Gray of radiation administered, within the dose range of the study (67-82 Gy). Gleason score 7-10, stage T3-T4 and higher iPSA were also significantly associated with increased ASTRO BF in the MVA.
Biochemical Failure, Distant Metastasis, and Salvage Androgen Deprivation
Univariate Analysis of Potential Predictors of Biochemical Failure and Distant Metastasis
Multivariate Analysis of Potential Predictors of Biochemical Failure and Distant Metastasis
Biochemical failure using the Nadir+2 definition was documented in 208 (31%) of the 667 study patients. These failures were not restricted to the early years following RT, with 94/208 (45%) occurring at year 5 or later. The 5-year actuarial Nadir+2 BF rates decreased from 32% to 18% with increasing RT dose (P=.040, ). Univariate analysis revealed that higher T-stage, Gleason score, and iPSA, as well as lower RT dose were all significantly associated with increased Nadir+2 BF (). These variables remained significant on MVA ().
The interval hazard rates of BF using the ASTRO and Nadir+2 definitions are shown in for each 2-year time interval of follow-up after RT. In general, ASTRO BF was documented at earlier times than Nadir+2 BF because of backdating in the former. There were similar changes in the interval hazard functions with increasing RT dose. First, the risk of BF was reduced in magnitude overall. Second, higher RT doses were associated with a shift in the risk of BF to the later time intervals. This effect is particularly evident using the Nadir+2 definition, where the peak hazard rate for BF was at 4-6 years in the <74 Gy group and was at 8-10 years in the 74-76 and >76 Gy groups. It should be noted, however, that in the >76 Gy group, the large spike in the Nadir+2 BF hazard function observed in the 8-10 year interval was based on only 3 patients at risk. The difference in the BF hazard function between RT dose <74, 74-76, and >76 was statistically significant using the log-rank test for overall differences (ASTRO BF, P<.0001; Nadir+2 BF, P=.040) and the Wilcoxon statistic for early differences (ASTRO BF, P<.0001; Nadir+2 BF, P=.018). When the BF hazard functions for men with intermediate and high risk disease were analyzed separately, the overall patterns of failure and response to RT dose escalation described above persisted in each risk group.
Fig. 1 Interval hazard rates for biochemical failure during each 2-year time interval after radiotherapy, according to the ASTRO definition (3 consecutive rises in PSA, backdated) (16) and the Nadir+2 definition (PSA ≥ nadir + 2 ng/mL) (17-22).
Distant metastasis was documented in 47 (7%) of the 667 study patients. The 5-year actuarial DM rates decreased from 8% to 2% with increasing RT dose (P=.010, ). The 10-year actuarial DM rates were 16%, 7%, and 3% for RT dose <74, 74-76, and >76 Gy groups, respectively. Univariate analysis revealed that higher T-stage, Gleason score, and iPSA, as well as lower RT dose were all significantly associated with increased DM (). These significant associations were confirmed on MVA (). The hazard ratio was .88 (95% CI, .80 to .96; P=.006) for RT dose as an increasing continuous variable. Thus the risk of DM was decreased by 12% with each additional Gy of radiation administered, within the dose range of the study (67-82 Gy).
The interval hazard rates for DM are shown in . Because only 5 DM events occurred in patients receiving >76 Gy, hazard analysis of this subgroup would be based on only 1-2 events in each time interval. We therefore compared all patients who received ≥74 Gy (DM events = 20) to those who received <74 Gy (DM events = 27). For the entire study cohort, the distribution of DM over time was biphasic, with an early wave peaking at 0-4 years and a late wave at 8-10 years. This biphasic pattern was driven primarily by the <74 Gy group. In patients receiving ≥74 Gy, the incidence of both early and late DM was reduced. The difference in the DM hazard function between RT dose <74 and ≥74 Gy was statistically significant using the log-rank test for overall differences (P=.003) and the Wilcoxon statistic for early differences (P=.0027). The percentage men with intermediate risk disease (67%) and high risk disease (33%) was identical in the <74 and ≥74 Gy groups. When the DM hazard functions for intermediate and high risk patients were analyzed separately, the biphasic pattern of DM persisted in each risk group and RT dose escalation reduced both the early wave (0-4 years) and the late wave of DM (8-10 years), as observed in the entire study cohort in .
Interval hazard rates for distant metastasis during each 2-year time interval after radiotherapy.
One potentially confounding factor in an analysis of DM is the use of salvage androgen therapy. Androgen deprivation given to patients for a rising PSA could postpone or eliminate the subsequent appearance of DM, thus altering the DM interval hazard function. Salvage AD was administered to 108 (16%) of the 667 study patients (). Salvage AD was initiated after a diagnosis of DM in 28 men (4%). This would not affect the DM hazard function. The remaining 80 patients (12%) had hormone therapy initiated for BF, at a time when no DM had been identified. However, these patients were distributed fairly evenly among the RT dose groups (range 9-14%) and a similar percentage went on to develop subsequent DM in each dose group (range 2-3%, ).