Postulate 4: patient-risk reclassification

Choo et al. and Klotz et al. were the first groups to use a prospective active-surveillance protocol that incorporated a selective, delayed intervention for the patient subset with rapid PSA or grade progression on repeat biopsy. The eligibility criteria included patients with stage T1c or T2a prostate cancer who had a Gleason score of 6 or less and a PSA level of 10 ng/ml or less. For patients over 70 years of age, these criteria were relaxed to include a Gleason score of 7 (3 + 4) or less and/or a PSA value of 15 ng/ml or less. The cohort of active-surveillance patients comprised 299 patientsThe median age was 70 years (range 49–84 years); 80% of patients had a Gleason score of 6 or less, and the same proportion had a PSA level greater than 10 ng/ml (median 6.5 ng/ml). The median follow-up period was 72 months, during which time 101 (34%) patients came off active surveillance, whereas 198 patients remained on active surveillance. Of patients discontinuing surveillance, the reason was rapid biochemical progression in 15%, clinical progression in 3%, histologic progression in 4%, and patient preference in 12%. There was no correlation between grade progression and PSA doubling time. At a median follow-up of 7 years (range 2–11 years), the overall survival was 85% and disease-specific survival was 99%.

Only 3 out of 299 patients had died of prostate cancer at the time of writing this review. All three patients had PSA doubling times of greater than 2 years, and death occurred 3.0, 5.1 and 5.2 years after diagnosis. All three patients exhibited the same pattern of clinical progression: initial favorable prognostic factors; a rapid rise in PSA level, which led to treatment at 6, 9 and 11 months, respectively, after the initial diagnosis; and a further progressive rise in PSA level and clinically apparent bone metastases within 1 year of treatment, leading to androgen-deprivation therapy. All three patients died within 3 years of the initiation of hormone therapy. This very rapid progression after diagnosis indicates that these patients had occult metastases at the time of initial disease presentation and their outcome would not have been altered by earlier treatment. In the Swedish trial, there was almost no difference between the two groups before 5 years had elapsed.

In the Choo et al. study, the median PSA doubling time, calculated by logarithmic regression, was 7 years In total, 22% of patients had a PSA doubling time of greater than 3 years, whereas 42% had a PSA doubling time of over 10 years, which indicates an indolent course of disease in these patients. The Gleason score remained stable in 92% of patients; only 8% of patients demonstrated a marked rise in their Gleason score, classed as an increase of at least two points. In this group, 29 patients (10% of the cohort) had a radical prostatectomy as a result of a short PSA doubling time or tumor-grade progression. All these patients had an initial Gleason score of 5 or 6, a PSA value greater than 10 ng/ml and a tumor stage of pT1–2 at study entry. The final pathology was stage pT2 in 18 patients, stage pT3a in 11 patients, stage T3c in 1 patient and node-positive in 1 patient. Of the 18 patients with a PSA doubling time of greater than 3 years, only 7 patients had positive margins. This result suggests that even among the worst subset of the cohort, that is to say those reclassified as higher risk over time, the majority could be cured by delayed therapy.