The clinical characteristics of the 1833 patients are summarized in . As expected from the risk group stratification criteria, the high risk cohort had significantly higher T-categories, iPSAs, and Gleason scores than the low risk group (P<.0001 for all three variables). The intermediate risk group similarly had higher iPSAs and Gleason scores (P <.0001 for both). Median age differed by only one year, although the age difference was statistically significant. Fewer patients in the low risk group received a radiation dose ≥76 Gy. Median follow-up for the low and intermediate risk groups was identical at 65 months. The high risk group had longer median follow-up (79 months, P<.0001). A greater percentage of patients received neoadjuvant or adjuvant AD in the intermediate (P=.02) and the high risk (P<.0001) groups.
Patient characteristics according to risk group*
Biochemical failure using the ASTRO definition was documented in 447 (24%) of the 1833 study patients. The majority of these failures were registered early due to backdating, with 390/447 (87%) in years 0–4 post-RT. The 5-year actuarial ASTRO BF rates increased from 16% to 54% with higher risk group stratification and the difference in ASTRO BF among risk groups was statistically significant on univariate (P<.0001, ) and multivariate analysis (P<.0001, ). Univariate analyses revealed that higher T-category, Gleason score and iPSA, and use of neoadjuvant/adjuvant AD were significantly associated with a higher ASTRO BF rates (P<.0001, ). Conversely, higher RT doses were significantly related to lower ASTRO BF rates (P<.0001). Multivariate analysis (MVA) for all patients confirmed that higher Gleason score, iPSA, and risk group, along with lower RT dose, were independently associated with increased ASTRO BF (). An MVA was also performed for each risk group individually ().
Biochemical failure, distant metastasis, salvage androgen deprivation, and mortality by risk group
Multivariate analyses of potential predictors of biochemical failure and distant metastasis*
Univariate analyses of potential predictors of biochemical failure and distant metastasis
Biochemical failure using the Nadir+2 definition was documented in 396 (22%) of the 1833 study patients. These failures were recorded at call (time of event) following treatment, with 170/396 (43%) occurring >4 year after RT. The 5-year actuarial Nadir+2 BF rates increased from 9% to 43% with higher risk group stratification. The difference in Nadir+2 BF rates among the risk groups was statistically significant on univariate (P<.0001, ) and multivariate analyses (P<.0001, ). As with ASTRO BF, univariate analyses revealed that higher T-category, Gleason score, and iPSA, and use of neoadjuvant/adjuvant AD were significantly associated with higher Nadir+2 BF rates (P<.0001, ). Multivariate analyses confirmed that higher iPSA, higher Gleason score, lower RT dose, and some other covariates, were independently associated with increased Nadir+2 BF (P<.0001; ).
Using the ASTRO and Nadir+2 definitions, the hazard rates of BF for each 2-year time interval of follow-up after treatment are shown in . Due to backdating, ASTRO BF was documented at earlier times than Nadir+2 BF. ASTRO BFs are nearly absent in years 8–12. The most revealing findings are derived from the examination of interval hazard rates using the Nadir+2 definition. The hazard of Nadir+2 BF persisted in years 8–12 in all risk groups. For low risk patients there was a peak incidence at 6–8 years post-treatment. For intermediate risk patients, Nadir+2 BF continued to gradually increase throughout the period of the study. For high risk patients, there was an early peak at 4–6 years, followed by a decline. The decline in Nadir+2 BF in the 10–12 year range was undoubtedly affected by the lack of patients at risk; but prior to that the decline is probably real. The difference in the BF hazard function between the low, intermediate, and high risk groups was statistically significant using the log-rank test for overall differences (ASTRO BF, P<.0001; Nadir+2 BF, P<.0001) and the Wilcoxon statistic for early differences (ASTRO BF, P<.0001; Nadir+2 BF, P<.0001).
FIGURE 1 Interval hazard rates for biochemical failure during 2-year time intervals after radiotherapy, according to the ASTRO definition (3 consecutive rises in PSA, backdated)8 and the Nadir+2 definition (PSA ≥ nadir + 2 ng/mL).9-14
Distant metastasis was documented in 87 (5%) of the 1833 study patients. The 5-year actuarial DM rates increased from 1% to 8% with increasing risk group stratification (P<.0001, ). The 10-year actuarial DM rates were higher and were consistent with this pattern. Univariate analyses revealed that higher T-category, Gleason score, and iPSA were significantly associated with higher DM (P<.0001 for each, ). RT dose as a categorical variable did not reach significance (P=.2917). On MVA, the significant associations of T-category, Gleason score, and iPSA with DM were confirmed (). Moreover, increasing RT dose as a continuous variable was significantly associated with reduced DM (P=.025); the effect of dose was most apparent in the intermediate risk patients. The risk of DM was decreased by 6% with each additional Gy of radiation administered, within the dose range of the study (51–82 Gy).
The interval hazard rates for DM are shown in . The distribution of DM over time was biphasic in the intermediate and high risk groups, with an early wave peaking at 0–4 years and a late wave at 8–12 years. The waves in the high risk group had greater magnitude and began about 2 years earlier than in the intermediate risk group. In the low risk group, the pattern of DM was not biphasic, due to the absence of a distinct early wave; the risk of DM remained low after RT until a late wave of DM was seen in years 10–12. The difference in the DM hazard function between the risk groups was statistically significant using the log-rank test for overall differences (P<.0001) and the Wilcoxon statistic for early differences (P<.0001).
Interval hazard rates for distant metastasis during 2-year time intervals after radiotherapy.
One potentially confounding factor in an analysis of the timing of failure, particularly DM, is the use of androgen deprivation therapy. In this study, 194 patients (11%) received AD in the neoadjuvant or adjuvant setting for ≤6 months duration. A significantly higher percentage of men in the intermediate and high risk groups received neoadjuvant/adjuvant AD (). When patients who received neoadjuvant/adjuvant AD were excluded from the DM hazard analysis (), the timing of DM was largely unchanged compared to the entire study group, with the exception of the late wave of DM peaking at a slightly earlier time during the 8–12 year period among high risk patients.
Interval hazard rates for distant metastasis during 2-year time intervals after radiotherapy alone, excluding patients who received neoadjuvant/adjuvant androgen deprivation (AD).
Salvage AD initiated after RT is another confounding factor. 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 210 (11%) of the 1833 study patients. If the salvage AD was initiated after a diagnosis of DM, the DM hazard function would not be affected. However, 163 (9%) of the study patients had hormone therapy initiated for a rising PSA, at a time when no DM had been identified. Half of these patients (n=82) were in the high risk group. shows that with increasing patient risk, there is an increase in the use of salvage AD before the diagnosis of DM (4%, 7% to 21% for low, intermediate to high risk). Thus, the greatest potential effect on the shape of the interval hazard curves would be in the high risk group; yet, this was the group showing the earliest onset of DM in the early and late waves.
Regarding mortality, a total of 404 deaths occurred, including 47 prostate cancer cause-specific deaths (). Multivariate analysis demonstrated that higher age, Gleason score, and risk group, along with lower RT dose, were significant predictors of increased OM (P<.01 for each). For CSM, higher iPSA, Gleason score, and T-stage were significantly associated with increased cause-specific death (P≤.01 for each). The interval hazard rates for OM and CSM are shown in . The preponderance of deaths was from intercurrent disease, with the hazard of OM increasing steadily from time 0 out to 12 years in every risk group. A small wave of CSM is seen in the 10–12 year time interval in the intermediate and high risk groups, which was less apparent in the low risk patients. These data suggest that the early wave of DM does not translate into mortality from prostate cancer until 5–8 years later.
Interval hazard rates for overall mortality (OM) and cause specific mortality (CSM) during 2-year time intervals after radiotherapy.