Management of PSA Recurrences After Radical Prostatectomy

Introduction

Following surgery for prostate cancer, approximately 30–35% of men will develop a rising prostate-specific antigen (PSA) level within 10 years. Considering that an estimated 138,000 radical prostatectomies were performed in the United States in 2010, approximately 41,400–48,300 men would be expected to have experienced a rising PSA after surgery, also known as biochemical recurrence (BCR). Furthermore, Pound et al. found the median time between BCR and metastasis was 8 years, suggesting that 331,200–386,400 men in the United States would harbor BCR with no evidence of metastasis at any given time.

Definition and natural history

Though rising PSA after RP is relatively common, the precise definition of BCR remains controversial. The European Association of Urology (EAU) and the American Urological Association (AUA) guidelines define BCR as a single PSA value above 0.2 ng/mL followed by a subsequent confirmatory PSA value above 0.2 ng/mL. The National Comprehensive Cancer Network (NCCN) defines BCR as either a failure of PSA to reach undetectable levels following surgery or an undetectable PSA after surgery with at least two subsequent increases in PSA level.

One reason for the different criteria for BCR is that not all men who have a PSA elevation after surgery will develop clinical progression. Pound et al. examined the natural history of disease for 304 men who experienced a PSA above 0.2 ng/mL during follow-up after RP. None of the men received postoperative radiotherapy or androgen deprivation therapy. The authors found a 5-year metastasis-free survival rate of 63% with a median metastasis-free survival of 8 years after BCR. In the analysis, not all men who experienced BCR had the same likelihood of metastasis, with higher likelihood in men with Gleason score 8–10, an interval between surgery and recurrence less than 2 years, and those with Gleason score less than 8 and a PSA doubling time (PSADT) of less than 10 months. Furthermore, another work has demonstrated that some men with a PSA above 0.2 ng/mL will have a stable PSA without subsequent rises. Amling et al. found that only 49% of men following RP with an increased PSA level in the 0.20–0.29 range progressed to a higher level and recommended using 0.40 ng/mL to define BCR. The authors suggested that benign prostatic glands may be left behind after surgery, or other tissue sites may produce PSA in some men.

As a result of the heterogeneity of outcomes among men with a PSA above 0.2 ng/mL, some authors have suggested changing the definition of BCR to better reflect likelihood of developing metastatic disease. Stephenson et al. evaluated 10 definitions of BCR to determine which had the highest association with metastatic disease in a multivariable model adjusting for postoperative Gleason score, preoperative PSA, surgical margin status, pathologic stage, and use of adjuvant therapies (radiotherapy or ADT). The authors found the definition of BCR that provided the best combination of sensitivity and specificity (based on the goodness-of-fit statistic) to be PSA ≥0.4 and rising. Thus, men would only be considered to have BCR if the PSA reached 0.4 and a subsequent PSA was higher. One interesting note from the article is that use of the American Society of Therapeutic Radiation and Oncology (ASTRO) definition of BCR (three consecutive PSA rises, with BCR backdated to the midpoint between the date of the last undetectable PSA and the date of the first of the three PSA rises) required a median time of 42 months, though as a result of back-dating, the time to recurrence would be considered 15 months. This delay in diagnosis may unnecessarily postpone salvage therapy, making the ASTRO definition an unattractive option following RP. Other authors found a similar delay using the revised ASTRO definition of nadir PSA +2 ng/mL.

The importance in choosing an appropriate definition of BCR lies in its ability to determine timing of salvage therapy after RP. In a retrospective study assessing the impact of salvage therapy on prostate-cancer-specific survival after BCR, Trock et al. demonstrated that an increased time between BCR and initiation of salvage therapy was associated with prostate-cancer-specific mortality (PCSM). The authors found the greatest inflection point to be at 2 years after BCR, with men treated greater than 2 years after BCR not benefiting from salvage radiotherapy (SRT). However, when comparing men treated within 1 year of BCR to those treated greater than 1 year after BCR, those treated earlier seemed to benefit more from salvage therapy (H.R. 0.15 vs. 0.22, respectively), though the difference was not statistically significant. Nonetheless, patients and clinicians would prefer to identify patients who will progress as early as possible, when SRT likely has the greatest chance to prevent PCSM. Ideally, one could use a definition of BCR that accurately identifies men likely to die of prostate cancer as early after RP as possible.

Due to the drawbacks of using PSA alone to determine who should undergo additional therapy, some authors recommend using variable definitions for BCR based on an individualized risk of cancer progression. Similar to Stephenson et al., Mir et al. examined 14 definitions for BCR for their association with subsequent disease progression. However, the authors stratified the patients into risk groups based on clinicopathologic factors known after RP. The authors found that for each definition of BCR, the likelihood of disease progression varied greatly based on these clinicopathologic risk factors. For instance, the likelihood of disease progression for a detectable PSA ≤0.1 ng/mL was 18–25% for men with good pathologic features and 73–88% for men with pT3b, pN1, or Gleason 8–10 disease. The investigators recommend using a single PSA ≥0.05 for men with the highest risk pathologic features (pT3b or pN1, or Gleason 8–10) as the definition of BCR versus PSA ≥0.4 and rising for those with lowest risk (pT2, Gleason 6 or 3 + 4, negative surgical margins). More generally, this work demonstrates that the use of any PSA rise after RP as the threshold for SRT in all patients is ill-advised. Instead, a PSA rise after RP must be considered in the context of disease risk when deciding whether SRT is likely to be advantageous. This notion is supported by the results reported by Karlin et al., who assessed the recurrence-free survival (RFS) rate for SRT after RP. The authors found that men with pathologic Gleason score 8–10 disease who underwent SRT at PSA level ≤0.33 ng/mL had a 77% RFS rate at 53 months compared to a 26% survival rate when SRT was initiated at a PSA between 0.34 ng/mL and 1.0 ng/mL.

Even if patients with a rising PSA are destined to progress, they may die of nonprostate cancer causes prior to the onset of morbidity from metastatic prostate cancer. Xia et al. used a competing risks model to assess the likelihood that men who experienced BCR would progress to metastatic disease before dying of nonprostate cancer causes. Since the median follow-up after BCR was 7.0 years, the authors had limited power to detect the incidence of metastases beyond 10 years. Instead, using US life tables adjusted for the good overall health of men undergoing RP, the authors calculated a lower bound for overdetection of BCR. Using this analysis, the authors estimate that at least 9.1% of men who experienced BCR within 5 years of RP and at least 15.6% of men with BCR between 5 years and 10 years after RP would never experience metastatic disease in their lifetime. For men who are older, sicker, and have lower stage or grade, SRT or hormonal therapy may be of no benefit.

For men with a rising PSA after RP, decisions regarding salvage therapies rely on careful consideration of the definition of BCR, how well BCR predicts oncologic outcome after RP, and the competing risk of death from nonprostate cancer causes before metastatic prostate cancer would arise. For men with low-risk pathology, a more conservative definition of BCR (with higher specificity) is appropriate, whereas those with aggressive features should choose low PSA thresholds before consideration of salvage therapy. Prior to initiation of salvage therapy, physicians and patients should consider the long natural history of recurrent prostate cancer, with median time between BCR and diagnosis of metastatic disease of 8 years. Only after considering these factors, as well as the patient’s comfort with risk of disease progression and PCSM, should physicians and patients choose a management course.