Radiation-Resistant Prostate Cancer and Salvage Prostatectomy

Routine Prostate Biopsy

There are currently no specific markers that can adequately diagnose partially treated versus untreated PCa after RT. While biopsy after prostate ablation is universally accepted to demonstrate successful treatment, the American Society for Radiation Oncology (ASTRO) consensus panel recommended against systematic prostate rebiopsy within 30 months after RT in the absence of a PSA recurrence, as negative prostate biopsy rates ranged from 62% to 80% for patients with stage T1 and T2 tumors. Conversion of gradable PCa to benign acting “treated” cancer can occur years after RT. Of men that underwent biopsy within 2 years from RT, almost one-third of biopsies that initially identified cancer were converted to a negative biopsy at 30 months. Given the low probability of finding cancer, serum PSA has been used as a surrogate marker for PCa viability to determine cure after RT.

Prostate-Specific Antigen

Prostate-specific antigen (PSA), expressed by benign and malignant prostate glands, is the most sensitive biomarker to determine recurrence after RT. Serial PSA measurements are taken every 3–6 months. Following RT, PSA slowly declines and reaches nadir 18 months or longer. Biochemical recurrence after radiotherapy is almost always asymptomatic and precedes clinical recurrence with an average time to relapse of 5 years. In 1996, the American Society for Radiation Oncology (ASTRO) consensus panel established a recurrence after RT as three consecutive increases in PSA after reaching nadir. This ASTRO definition of biochemical failure was revised by a second Consensus Conference sponsored in Phoenix, Arizona, on January 21, 2005. The panel recommended a rise by 2 ng/mL or more above the nadir PSA following RT as the standard definition for biochemical failure (known as the “Phoenix definition” of recurrence). While the Phoenix definition is highly specific to identify a recurrence, multiple studies have demonstrated earlier salvage treatment at lower PSA is associated with improved biochemical free survival (BFS) compared to delayed treatment and occult progression. The significant time and challenge required to identify a recurrence after RT may contribute to delayed identification of biochemical failure. The BFS after salvage prostatectomy for men with a PSA less than 4 ng/mL was 86%, 55% for a PSA of 4–10 ng/mL, and only 28% in those with a PSA greater than 10 ng/mL.

Even though the definition of failure after RT by the Phoenix criteria is defined as nadir +2.0 ng/mL, a prostate gland treated with RT may still have viable disease and not show a PSA that would prompt intervention. In a study of 78 patients with PCa who were treated with RT and then underwent a radical cystectomy at a later time for a bladder cancer, 45% of patients showed persistent gradable PCa when the prostate was removed. Sixty-nine percent showed Gleason grade ≥7 and 17% of specimens were at least pT3 disease. At the time of cystectomy, only 21% had a known PCa recurrence and there was no difference in mean PSA at the time of surgery between those with and without known recurrence (2.0 vs. 1.5 ng/mgL, p = 0.7). In those men without a known BCR, PCa was found in 37%. These data suggest that many PCas may not meet PSA criteria for intervention (PSA <2.0 ng/mL), but still remain viable after RT. Future studies should focus on identification of PCa biomarkers to identify early PCa recurrence.

PSA Nadir

The lowest PSA achieved after RT (the nadir) is prognostic of long-term PCa response to RT. In a retrospective study of 743 patients with localized PCa treated at the Memorial Sloan-Kettering Cancer Center with conformal RT, preoperative variables that predict PSA relapse were a PSA level higher than 10 ng/mL, a Gleason score of at least 7, and clinical stage T3 disease. Yet, the PSA nadir after RT was the strongest predictor, overshadowing the significance of the pretreatment PSA level. While no study has demonstrated a clear cut-off that absolutely predicts cure or failure of treatment, a trend toward lower PSA associated with treatment success has been demonstrated. Of 364 patients at a mean of 46 months after external beam RT, 93% of men with the lowest PSA nadirs (0–0.99 ng/mL) had no biochemical evidence of recurrence versus 49% with PSA nadirs of 1.0–1.99 ng/mL and 16% of those with a PSA nadir greater than 2.0 ng/mL ( p = 0.0001).