The Use of Early Postoperative Prostate-specific Antigen to Stratify Risk in Patients With Positive Surgical Margins After Radical Prostatectomy

Stepan Vesely; Ladislav Jarolim; Katerina Duskova; Marek Schmidt; Pavel Dusek; Marko Babjuk

Disclosures

BMC Urol. 2014;14(79) 

In This Article

Discussion

The removal of the entire prostate gland is a primary goal of radical prostatectomy. A positive surgical margin is defined as the presence of tumor at the inked surface of the resected specimen and as such implies inadequate cancer clearance. Despite advances in surgical techniques and the significant stage shift in newly diagnosed prostate cancer in the last decade, PSM are still reported in 11–38% of patients who have undergone RP.[1,2] Comparable results were found in the present study, where PSM was diagnosed in 21% of patients after radical prostatectomy.

Although the true impact of a PSM remains controversial, many authorities agree it presents a significant risk of biochemical and subsequent clinical relapse. Authors from Johns Hopkins Hospital reported 79% of men with negative margins were progression-free over a 10 year period compared with 55% of those with positive margins.[18] Others have demonstrated similar findings.[3,19] However not every patient will suffer eventual disease recurrence and the policy of adjuvant radiotherapy could result in considerable over-treatment. In the observation arms of large randomized trials where high-risk patients were involved, up to 52% did not show a BCR during the follow-up.[20] However, some results of these trials are conflicting due to the differences in the number and type of adverse pathologic characteristics included.[21] It has been demonstrated that in daily clinical practice, positive surgical margins present an independent predictor of secondary prostate cancer treatment.[7] Therefore, in our study we based the analysis only on a cohort of patients with the diagnosis of PSM and we found out that potential adjuvant radiation would result in overtreatment in the majority of the patients (53%).

Several explanations may explain why a positive margin is not always associated with the recurrence of cancer. It has been proposed that ischemia and fibrosis as a consequence of the surgery may destroy small areas of residual carcinoma.[22] Possible disruption of additional tissue covering cancer cells during all the handling of the specimen by surgeons, nurses and pathologists may result in inadvertent damage leading to the false impression of PSM. Finally the experience of the reading pathologist and the type of classification may influence the accuracy of surgical margin diagnostics. Nevertheless, the question remains how to reliably identify patients with residual prostate cancer cells in the surgical bed who would be the best candidates for immediate adjuvant treatment.

The ability of imaging modalities in the staging process of prostate cancer remains limited. Current imaging devices are not endowed with sufficient resolution to detect extraprostatic extension, which is often microscopic.[8] Several groups have highlighted potential prognostic value of additional pathological factors such as the location, extent and number of positive margins.[19,23] However, the subclassification of positive margins has not been standardized and there is no general consensus in the literature on how specific PSM-associated prognostic variables influence BCR or assist in clinical decision-making.[2] Intraoperative frozen section biopsy has been recommended in radical prostatectomy. However, routine use of frozen section on all cases to be "sure" of getting negative margins has not fulfilled its dream.[9,10] A number of authors have described prognostic significance of PSM after adjusting for other clinical and pathological variables. The Johns Hopkins group demonstrated the effect of Gleason grade on outcome in men with positive margins. They reported positive surgical margins had no impact on 10 y probability of biochemical recurrence in men with Gleason score less than 7.[24] Conversely, in our series of men with PSM, we have not noted any impact of age, Gleason score and/or the extraprostatic extension of the prostate cancer on the frequency of BCR. Ultrasensitive PSA assessed early after the operation was the only variable predicting the disease progression.

With removal of all the prostate cancer tissue, the serum PSA should rapidly decline to zero, or at least very close to zero within 2 to 6 weeks following radical prostatectomy. However, general recommendation advises to perform the first PSA check at 3 months after the surgery, although a significant decline in PSA and even the PSA nadir may be reached a few weeks prior to this point.[11] These results prompted us to investigate the PSA kinetics early after the surgery, starting with the first measurement at day 14. Our data demonstrate that PSA at day 14 is not offering valuable prognostic information regarding the outcome of the surgery. However, as time from surgery increased, the predictive power of ultrasensitive PSA measurements increased. For example, the calculated AUR for day 30 and day 60 were 74% and 84%, respectively. Serum PSA at early moments after the surgery may be influenced by the clearance of PSA, which was produced by the tissue of ablated prostate. This is compatible with our finding that preoperative PSA correlated only with postoperative PSA at day 14 and at day 30.

It has been shown that retained benign prostatic elements are an unlikely source of elevated PSA levels in men who have undergone radical prostatectomy. In a study of Godoy et al. only 0.3% out of 331 men with low-risk prostate cancer had developed a measurable PSA level after radical prostatectomy.[16] Odisho et al. have reviewed 274 patients with benign glandular tissue at the surgical margin after radical prostatectomy. They concluded that this finding was not associated with postoperative elevation of PSA.[15] Thus, it seems that the only significant source of PSA after radical prostatectomy may be retained malignant cells and PSA kinetics early after the surgery are key to identification of patients with prostate cancer who have received failed prior therapy. In a series of Hong et al. there were 106 (27.6%) subjects who had a positive surgical margin after radical prostatectomy. Among these men, 45 patients, who showed undetectable ultrasensitive PSA nadir (PSA < 0.001 ng/ml) during the postoperative follow-up, demonstrated a significantly higher rate of 3-year biochemical recurrence-free survival compared with 61 men who did not (94.1% vs 57.1%, P < 0.001). In line with these results we observed that only 1 of 16 patients who reached PSA ≤0.01 ng/ml at the first month after the surgery experienced BCR during the follow-up.

This study has several potential limitations. These include limitations inherent to any retrospective study. There were no strict criteria for subjecting the patients with PSM after radical prostatectomy to adjuvant therapy during the whole study period. It may be argued that by doing so some patients with PSM who received adjuvant treatment were at high risk of the recurrence and they were excluded from the analysis. However, the comparison of clinicopathological characteristics did not reveal any significant difference between studied group of patients and those who underwent immediate secondary therapy after the surgery. Another limitation of our study was the relatively short mean follow-up of 31 months. Several investigators have reported that most biochemical recurrences are detected within the first 3 years after radical prostatectomy.[25] Nevertheless, presented results should be analyzed with caution, as patients with BCR do not necessarily share the same long-term cancer outcomes. Our results will need re-evaluation as our follow-up matures to yield meaningful data on cancer specific survival, as the most relevant endpoint.

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