Practical application of biochemical failure definitions: what to do and when to do it

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Purpose: The posttreatment prostate-specific antigen (PSA) profile can often be difficult to interpret after external beam radiotherapy for prostate cancer. We performed an extensive analysis of post-radiotherapy PSA measurements to determine the clinical significance of biochemical failure (BF) and the correlation of BF with clinical failure (CF) and cause-specific death (CSD).Materials and Methods: Between 1987 and 1997, 727 patients with clinical stage T1–T3 N0 M0 prostate cancer were treated with definitive external beam radiotherapy at William Beaumont Hospital and had at least five post-radiotherapy PSA levels and did not receive hormonal therapy for post-radiotherapy PSA elevations only (before evidence of CF). All patients received external beam radiotherapy alone (no adjuvant hormonal therapy) to a median total prostate dose of 66.6 Gy. More than 20 BF definitions were tested for their correlation with CF (any local failure or distant metastasis) and CSD. All BF definitions were tested for sensitivity, specificity, accuracy, and positive and negative value of predicting subsequent CF and CSD. The median follow-up was 5.0 years.Results: Three consecutive PSA rises yielded a 73% sensitivity, 76% specificity, and 75% overall accuracy for predicting CF. The 10-year CF rate (from the completion of radiotherapy) for those 251 patients demonstrating three consecutive rises (BF) was 64% vs. 14% for those patients who did not have three rises (biochemically controlled). Defining BF as a post-nadir increase to ≥3 ng/ml above the nadir yielded the highest accuracy of 87%. In addition, this definition also seemed to provide the greatest separation in CF rates: 82% for BF vs. 5% for biochemically controlled at 10 years after radiotherapy. CF rates were also calculated from the date of BF (e.g., date of third rise). The CF rates at 6 months and 2 years after the third PSA rise were 9% and 27%, respectively. The CF rates at 6 months and 2 years after an increase to ≥3 ng/ml above the nadir were 23% and 54%, respectively. Once a patient was classified as a BF, regardless of the BF definition, the CF rate varied markedly, depending on the pretreatment characteristics. For each BF definition, younger age at diagnosis, higher pretreatment PSA, and higher Gleason score independently predicted for CF after BF on Cox multiple regression analysis. For instance, patients with a pretreatment PSA <4.0 ng/ml demonstrated an 11% CF rate at 2 years after the third PSA rise vs. 46% after three rises with a pretreatment PSA ≥20.0 ng/ml. Similarly, patients with Gleason 2–4 had a 2-year CF rate of only 3% after a nadir ≥1.0 ng/ml vs. 47% for Gleason 8–10 at 2 years after a nadir ≥1.0 ng/ml. Although the CF rate also coincided with pretreatment characteristics when using ≥3 ng/ml above the nadir, CF rates remained high even for low-risk patients (e.g., 2-year CF of 48% for PSA <10.0 ng/ml, 41% for Gleason 2–4). In addition, a shorter time interval from nadir to nadir + 1 ng/ml or from nadir to nadir + 3 ng/ml (corresponding to a steeper slope in the PSA profile) independently predicted for CF.Conclusion: Once the post-radiotherapy PSA profile reaches ≥3 ng/ml above the nadir, there is a high risk of clinical failure within a relatively short time period, for which treatment intervention may be considered, regardless of pretreatment characteristics. After a nadir ≥1.0 ng/ml or three consecutive rises, some patients (especially with low-risk pretreatment characteristics) may be considered for further PSA observation before treatment intervention.