Charles R. Pound

CONTEXT: In men who develop an elevated serum prostate-specific antigen level (PSA) after having undergone a radical prostatectomy, the natural history of progression to distant metastases and death due to prostate cancer is unknown. OBJECTIVE: To characterize the time course of disease progression in men with biochemical recurrence after radical prostatectomy. DESIGN: A retrospective review of a large surgical series with median (SD) follow-up of 5.3 (3.7) years (range, 0.5-15 years) between April 1982 and April 1997. SETTING: An urban academic tertiary referral institution. PATIENTS: A total of 1997 men undergoing radical prostatectomy, by a single surgeon, for clinically localized prostate cancer. None received neoadjuvant therapy, and none had received adjuvant hormonal therapy prior to documented distant metastases. MAIN OUTCOME MEASURES: After surgery, men were followed up with PSA assays and digital rectal examinations every 3 months for the first year, semiannually for the second year, and annually thereafter. A detectable serum PSA level of at least 0.2 ng/mL was evidence of biochemical recurrence. Distant metastases were diagnosed by radionuclide bone scan, chest radiograph, or other body imaging, which was performed at the time of biochemical recurrence and annually thereafter. RESULTS: The actuarial metastasis-free survival for all 1997 men was 82% (95% confidence interval, 76%-88%) at 15 years after surgery. Of the 1997 men, 315 (15%) developed biochemical PSA level elevation. Eleven of these underwent early hormone therapy after the recurrence and are not included in the study. Of the remaining 304 men, 103 (34%) developed metastatic disease within the study period. The median actuarial time to metastases was 8 years from the time of PSA level elevation. In survival analysis, time to biochemical progression (P<.001), Gleason score (P<.001), and PSA doubling time (P<.001) were predictive of the probability and time to the development of metastatic disease. An algorithm combining these parameters was constructed to stratify men into risk groups. Once men developed metastatic disease, the median actuarial time to death was 5 years. The time interval from surgery to the appearance of metastatic disease was predictive of time until death (P<.02). CONCLUSIONS: Several clinical parameters help predict the outcomes of men with PSA elevation after radical prostatectomy. These data may be useful in the design of clinical trials, the identification of men for enrollment into experimental protocols, and counseling men regarding the timing of administration of adjuvant therapies.

In a series of 1623 men with a follow-up of 5 +/- 3 years (range 1-13) after anatomic RRP for clinically localized prostate cancer, 17% (276/1623) have shown recurrence. A detectable PSA was the only evidence of recurrence in 7.9%, whereas 2.5% have recurred locally and 5.4% have developed distant metastases. The overall actuarial progression-free rate for these men at 10 years was 68%. Actuarial rates at 10 years were 18% for development of an isolated PSA recurrence, 8% for local recurrence, and 9% for distant recurrence. The actuarial likelihood of a postoperative recurrence increased with increasing clinical stage, Gleason score, preoperative PSA level, and pathologic stage. Although not shown in our previous report, the actuarial rate of recurrence of tumors with a Gleason score of 7 was statistically different from that of tumors of higher Gleason score (8-10). As well, men with preoperative PSA levels of 10.1 to 20 ng/mL experienced recurrence at a significantly lower rate than did men with preoperative PSA levels greater than 20 ng/mL. By using a combination of Gleason score, pathologic stage, and surgical margin status, we demonstrated that the presence of a positive surgical margin did not dramatically affect recurrence in tumors of Gleason scores 2 to 6 with capsular penetration. Surgical margin status was important in high-grade tumors with capsular penetration. In fact, tumors with capsular penetration, Gleason score of at least 7, and a positive surgical margin behaved similarly to tumors with invasion of the seminal vesicles. Preservation of potency did not adversely influence cancer control. The Gleason score, presence or absence of seminal vesicle or lymph node involvement, and the timing of PSA recurrence are all important variables in predicting eventual local versus distant failure associated with an isolated rise in serum PSA. Overall actuarial cause-specific survival at 5 and 10 years was 99% and 93%. Although there was no difference in survival among men grouped by TNM stage or preoperative PSA, advancing histologic grade and pathologic stage did have an effect on actuarial cause-specific survival. Men undergoing RRP for clinically localized prostate cancer showed a 16% actuarial rate of development of metastatic disease at 10 years. This is considerably better than conservative therapy and justifies RRP as the treatment of choice for men with clinically localized disease who are otherwise healthy and have a greater than 10-year life expectancy.

1. With an average follow-up of 53 months (range 12-120 months), 19.4% (185/955) of men have had a cancer recurrence after radical prostatectomy for clinically localized prostate cancer. A detectable serum PSA was the only evidence of recurrence in 11.2%, whereas 2.2% have had a recurrence locally and 6% with distant metastases. 2. The actuarial status at 10 years was 70% for undetectable serum PSA; 23% for isolated serum PSA elevation only; 7% for distant metastases; and 4% for local recurrence. 3. In our study, no patient demonstrated disease progression (local or distant) without detectable serum PSA. 4. The actuarial likelihood of an elevated serum PSA increased with increasing clinical stage, Gleason score, preoperative serum PSA concentration, and pathologic stage. 5. The actuarial recurrence rate for tumors with a Gleason score of 7 was not statistically different from the recurrence rate for lesions of Gleason score 8-10. 6. There exist marked differences in actuarial recurrence-free probabilities for men with tumors of low Gleason score (< 7) compared with those with tumors of high Gleason score (> or = 7) when there is pathologically established capsular penetration. 7. Patients with preoperative serum PSA concentrations greater than 10.0 ng/mL are at a statistically increased risk of recurrence. 8. Men who have detectable serum PSA within the first year after surgery are at a significantly higher risk of disease progression than those men who have measurable serum PSA in postoperative years two and three. 9. Men with an isolated elevation of serum PSA after radical prostatectomy have a 25% likelihood of harboring an occult local recurrence. However, radiation therapy produces a sustained suppression of PSA to undetectable levels for 2 years or more in only 10% of men. This suggests that radiation therapy is not effective in sterilizing occult local residual tumor in many men. 10. Valuable information concerning disease recurrence and progression can be obtained through early postoperative measurement of serum PSA. This article demonstrates the long-term value of serum PSA as a measure of progression after anatomic radical prostatectomy.