Faculty Bibliography

PURPOSE/OBJECTIVE:To identify predictors of distant metastases (DM) among patients who develop an isolated prostate-specific antigen (PSA) relapse after definitive external-beam radiotherapy for clinically localized prostate cancer. MATERIALS AND METHODS/METHODS:A total of 1,650 patients with clinical stage T1 to T3 prostate cancer were treated with high-dose three-dimensional conformal radiotherapy. Of these, 381 patients subsequently developed three consecutive increasing PSA values and were characterized as having a biochemical relapse. The median follow-up time was 92 months from the completion of radiotherapy. RESULTS:The 5-year incidence of DM after an established PSA relapse was 29%. In a multivariate analysis, PSA doubling time (PSA-DT; P < .001), the clinical T stage (P < .001), and Gleason score (P = .007) were independent variables predicting for DM after established biochemical failure. The PSA-DT for favorable-, intermediate-, and unfavorable-risk patients who developed a biochemical failure was 20.0, 13.2, and 8.2 months, respectively (P < .001). The 3-year incidence of DM for patients with PSA-DT of 0 to 3, 3 to 6, 6 to 12, and more than 12 months was 49%, 41%, 20%, and 7%, respectively (P < .001). Patients with PSA-DT of 0 to 3 and 3 to 6 months demonstrated a 7.0 and 6.6 increased hazard of developing DM or death, respectively, compared with patients with a DT more than 12 months. CONCLUSION/CONCLUSIONS:In addition to clinical stage and Gleason score, PSA-DT was a powerful predictor of DM among patients who develop an isolated PSA relapse after external-beam radiotherapy for prostate cancer. Patients who develop biochemical relapse with PSA-DT < or = 6 months should be considered for systemic therapy or experimental protocols because of the high propensity for rapid DM development.

PURPOSE/OBJECTIVE:To study the radiation dose-response as determined by Kaplan-Meier prostate-specific antigen (PSA) disease-free survival (PSA-DFS) estimates in patients with stage T1-T2 prostate cancer treated within a 2-year period (1994-1995). METHODS:Nine institutions combined data on 4839 patients with stage T1 and T2 adenocarcinoma of the prostate who received > or =60 Gy external beam radiation therapy (RT) as sole treatment. No patient received neoadjuvant androgen deprivation or planned adjuvant androgen deprivation. Of the 4839 patients, 1325 were treated in 1994 and 1995; 1061 were treated with <72 Gy and 264 with > or =72 Gy. The median RT doses for the <72 Gy and the > or =72 Gy groups were 68.4 Gy and 75.6 Gy, respectively. The median follow-up for the <72 Gy and the > or =72 Gy groups were 5.8 and 5.7 years, respectively. Risk groups, defined on the basis of T stage, pretherapy PSA level, and biopsy Gleason score (GS), were as follows: low risk--T1b, T1c, T2a, GS < or =6 and PSA < or =10 ng/mL; intermediate risk--T1b, T1c, T2a, GS < or =6 and PSA >10 ng/mL but < or =20 ng/mL or T2b, GS < or =6 and PSA < or =20 ng/mL or GS 7 and PSA < or =20 ng/mL; high risk--GS 8-10 or PSA >20 ng/mL. The endpoint for outcome analysis was PSA-DFS at 5 years after therapy using the American Society for Therapeutic Radiology and Oncology failure definition. RESULTS:Patients receiving > or =72 Gy had significantly more advanced cancers. The proportion of stage T2b/T2c cancers in the > or =72 Gy group was 42% compared with 32% in the <72 Gy group (p = 0.027). The mean pretherapy PSA was 11.4 ng/mL in the > or =72 Gy group compared with 10.7 ng/mL in the <72 Gy group (p = 0.001). The proportion of GS > or =8 cancers in the > or =72 Gy group was 9% compared with 7% in the <72 Gy group (p = 0.309). Overall, 15% of patients receiving <72 Gy had high-risk disease, compared with 22% of patients receiving > or =72 Gy (p = 0.034). The > or =72 Gy group had a greater number of follow-up PSA levels (mean 10.6/patient) compared with the <72 Gy group (mean 9.6/patient) (p = 0.007). For all 1325 patients, the 5- and 8-year PSA-DFS estimates were 64% and 62%, respectively. The 5-year PSA-DFS estimates for <72 Gy vs. > or =72 Gy were 63% vs. 69%, respectively (p = 0.046). Multivariate analysis for factors affecting PSA-DFS was performed for all cases using the following variables: pretherapy PSA (continuous), biopsy GS (continuous), stage (T1 vs. T2), radiation dose (continuous), and radiation technique (three-dimensional conformal vs. conventional). Pretreatment PSA (p < 0.001, chi-square 112.2), GS (p < 0.001, chi-square 12.8), radiation dose (p < 0.001, chi-square 13.5), and stage (p = 0.007, chi-square 7.2) were independent predictors of outcome. Radiotherapy technique was not (p = 0.50). CONCLUSION/CONCLUSIONS:Differences in PSA-DFS estimates observed in multiple retrospective series have been attributed to differences in follow-up duration between patients treated to conventional doses (longer follow-up intervals) and those treated to higher doses (shorter follow-up intervals). In this report, the median follow-up duration in the > or =72 Gy group was essentially identical to the <72 Gy group, because the study included a large number of patients treated consecutively during a narrow time range (1994-1995). With similar follow-up duration, higher than conventional radiotherapy doses were associated with improved PSA-DFS when controlled for the influence of pretreatment PSA levels, biopsy GS, and clinical T stage.

PURPOSE/OBJECTIVE:To compare long-term outcome using alternative failure definitions after external beam radiation for localized prostate cancer. METHODS AND MATERIALS/METHODS:Data from 4839 patients with stage T1b, T1c, and T2 adenocarcinoma of the prostate who were treated solely with external beam radiation between 1986 and 1995 at nine U.S. institutions were analyzed. Outcome using the following prostate-specific antigen (PSA) failure definitions was compared: (1) three consecutive PSA rises backdated (American Society for Therapeutic Radiology and Oncology [ASTRO]), (2) two PSA rises of at least 0.5 ng/mL each, backdated (0.5 x 2), (3) three consecutive PSA rises with failure recorded at the call date (ASTRO call date), (4) PSA > or =current PSA nadir + 2 ng/mL (Houston + 2), (5) PSA > or =current PSA nadir + 3 ng/mL (Houston + 3), (6) PSA >0.2 ng/mL, or (7) PSA >0.5 ng/mL. For definitions 3-7, the failure date was recorded as the date the criterion was met, without backdating. RESULTS:PSA disease-free survival (PSA-DFS) varied according to the failure definition used with differences of up to 13% with PSA rise definitions and up to 44% with absolute nadir value surgical-type definitions within the first 5 years post-therapy as compared with the ASTRO definition. PSA-DFS was 66%, 66%, 68%, 72%, 15%, and 25% at 5 years postradiation for definitions 2-7, respectively, vs. 59% for the ASTRO definition. Sensitivity and specificity of definitions 2, 4, and 5 were better than for the ASTRO definition, whereas, for definitions 6 and 7, the sensitivity was at least 90% but the specificity was only 9% and 26%, respectively. This analysis shows that the ASTRO definition does not overestimate outcome, particularly in the first 5 years after therapy, as compared with other definitions appropriate to irradiated patients. CONCLUSION/CONCLUSIONS:There are notable differences in both short- and long-term outcomes after definitive radiation for prostate cancer depending on the failure definition applied. Failure definitions must be tested objectively for sensitivity and specificity in predicting clinical outcome, and it is only in this manner that reasonable choices can be made. Although traditional surgical-type failure definitions do not seem applicable to patients treated with external beam radiation, further analysis of definitions across multiple therapeutic modalities is necessary to determine whether a universal failure definition might be feasible, at least for research and comparative purposes.