Craig G. Rogers, M.D. The James Buchanan Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Cancer 2004;101:2549. 
 

Between 1989 and 2002, 160 men failed to achieve an undetectable PSA level ( 0.1 ng/mL) after undergoing RRP for clinically localized prostate carcinoma. No patient received adjuvant therapy before documented metastasis. The probability of distant metastasis-free survival at 3 years, 5 years, and 10 years was reported to be 68%, 49%, and 22%, respectively. Seventy-five men (47%) developed distant metastases after RRP (median time to metastases of 5.0 years; range, 0.5-13 years). The combination of RRP Gleason score, seminal vesicle status, and lymph node status resulted in 3 risk groups for the prediction of distant metastasis-free survival (hazards ratio [HR] = 1.6; P < 0.01). The slope of PSA changes approximately 3-12 months after RRP at a cutoff value 0.05 was found to be even more predictive of distant metastasis-free survival (HR = 2.9; P < 0.01). he PSA slope 3-12 months after undergoing RRP was found to be the most powerful predictor of distant metastasis-free survival, followed by biopsy Gleason score and clinical stage (HR = 2.9, 2.6, and 2.0, respectively).

CONCLUSIONS: Many patients remained free of metastatic disease for an extended period despite failing to achieve an undetectable PSA level after undergoing RRP for clinically localized prostate carcinoma. However, other patients experienced rapid disease progression to distant metastasis. The authors defined clinical (PSA slope) and pathologic (Gleason score) prognostic variables to help identify those patients with a higher risk of developing distant metastasis after undergoing RRP.

What does a persistently detectable PSA level after RRP mean? Two potential explanations for a PSA level that does not become undetectable within 6 weeks after a successful RRP include the presence of systemic, micrometastatic disease that went undetected preoperatively, and the presence of residual benign prostate tissue left behind at surgery (i.e., overpreservation of the bladder neck, incomplete prostatectomy with residual capsular tissue at the apex, and capsular incisions exposing benign tissue). Men with a PSA level in the early postoperative period that is detectable but stable often do not have disease progression. Benign glandular tissue at the margins of surgical resections is a possible explanation for stable postoperative PSA levels 0.3 ng/mL. The misinterpretation of persistent, low levels of serum PSA caused by the presence of unresected benign glands as systemic disease could lead potentially to unnecessary, aggressive adjuvant treatment in these patients. If PSA fails to reach undetectable levels after surgery but remains stable at levels < 0.4 ng/mL for 3 years after surgery, it is reasonable to consider retained benign tissue as a potential source of detectable PSA. However, if a patient's detectable PSA level increases above 0.4 ng/mL within 3 years after surgery or never decreases below 0.4 ng/mL, the presence of systemic disease should be strongly considered. One possible method to monitor this possibility of residual micrometastatic disease might be the use of technology that detects circulating prostate cells, preferably cancer cells, in the blood. More recently, a new commercially available technique already has been quite successful in breast carcinoma cases and could prove of value in patients with prostate carcinoma.

The current study analysis demonstrates that some men who fail to achieve an undetectable PSA level will experience slow disease progression and remain free of distant metastasis for an extended length of time. In the current study, 38% of patients had no evidence of metastases for 7 years. The median time from surgery for all patients to disease progression to distant metastases was 5 years. A significant number of men who fail to achieve an undetectable PSA level will experience rapid disease progression. In the current study, 32% of the patients were reported to develop metastases within 3 years. It is important to direct efforts at the early identification of those patients who will develop disease progression more rapidly. PSA kinetics, such as PSA velocity, PSA density, and PSA doubling time, have proven valuable in estimating the aggressiveness and location of disease in patients with biochemical disease recurrence. It is interesting to note that PSA density was not found to be predictive of subsequent distant metastasis in the current study. However, we observed that the kinetics of change in PSA level from 3-12 months after RRP (represented by a slope) was strongly predictive of earlier time to distant metastasis in the current analysis. Our analysis demonstrates that it might be clinically useful to monitor these treatment failures at more frequent intervals (3 months) for the first 18 months after undergoing RRP to calculate PSA slopes earlier in the disease process.

The risk of developing distant metastatic disease when PSA persists in the detectable range after RRP is performed was shown to correlate with biopsy and RRP Gleason scores. Men with RRP Gleason scores < 8 had a 62% chance of remaining free of metastasis 5 years after surgery compared with a 30% probability in men with higher grade tumors (Gleason score of 8-10). The risk of developing metastatic disease when PSA persists after RRP also was shown to correlate with clinical stage. The reason for presenting two different models of outcome was to compare postoperative pathology  and PSA kinetic data in predicting distant metastasis-free survival. Also, only a subset of patients had at least two PSA measurements available for calculation of PSA slope, whereas postoperative pathology reports were available for all patients. However, all variables were analyzed simultaneously using multivariate analysis and both RRP Gleason score and post-RRP PSA slope were found to be independent prognostic variables. We believe that both models are informative and provide important clinical information related to patient risk. However, it appears that PSA slope after undergoing RRP was a better predictor of distant metastasis-free survival time in this cohort of patients.

Pound described the natural history of disease progression to distant metastasis after biochemical disease recurrence. They demonstrated that time to biochemical disease progression ( 2 years), prostatectomy Gleason score (> 7), and PSA doubling time ( 10 months) was predictive of the probability as well as the time to the development of metastatic disease. One potential limitation of the study was that two to three predictive variables were time dependent. The concept of immediate adjuvant therapy for patients who are most likely to harbor aggressive disease and are at increased risk of developing metastatic disease recently has gained interest and has been shown to provide some benefit. The ability to classify patients with a persistently detectable PSA into risk groups for the development of distant metastasis could be useful in helping physicians and patients decide who should be treated early with hormonal therapy or investigational protocols and who should undergo surveillance. The PSA slope 3-12 months after RRP was found to be a significant predictor in the current study, but this variable is time dependent.

The limitations of the current study included the retrospective design and limited follow-up in some patients. Follow-up was limited for 47 of the patients in this study (30%) who had only 1-2 years of follow-up after undergoing RRP. Only six of these patients had developed distant metastasis at the last date of follow-up. The poor correlation between biopsy and prostatectomy Gleason scores in the patient sample in the current study made it difficult to use this critical pretreatment pathology variable to predict distant metastasis. However, the phenomenon of histologic upgrading from biopsy to prostatectomy specimen, which most likely accounts for the lack of correlation in the current study, is to our knowledge well established. The findings of the current study will require external validation.

In the current study, we report on the natural history of disease progression to distant metastasis in men with a failure to achieve an undetectable PSA level after undergoing RRP for clinically localized disease. Many patients remained free of metastatic disease for an extended period without other forms of therapy despite failing to achieve an undetectable PSA level, whereas another group of patients experienced rapid disease progression. Postoperative pathology provides some guidance in the identification of patients who do not achieve an undetectable PSA level after RRP who are at a higher risk for eventual distant disease metastasis. However, the post-RRP PSA slope, as calculated using PSA levels 3-12 months after surgery, was found the best predictor of time to distant metastasis in this cohort of men. The latter finding would indicate that men at high risk for prostate carcinoma progression based on preoperative and postoperative pathology should be monitored more frequently in the first 3-18 months after undergoing RRP to allow kinetic analysis of their PSA levels. Finally, it would appear that a Partin-like table, nomogram, or computer program could be constructed with the inputs derived from the current study to manage men at high risk for disease progression.