The ability of post-treatment surveillance to detect disease recurrence and/or persistence is critical in assessing treatment success and the planning of salvage therapy. Our study suggests that PSA alone does not accurately assess CaP activity in patients following RT. We observed that PSA prior to RCP was not significantly different between patients with and without histologically residual CaP in RCP specimens following definitive RT. Furthermore, 50% of patients had active CaP at the time of RCP despite meeting the Phoenix definition of biochemical success. Although, it is difficult to quantify the clinical significance of histologic CaP following RT, it is likely that the residual CaP represents persistent and/or under-treated disease. There are several possible explanations for poor predictive value of PSA for active CaP following RT. These include misclassification of active CaP, timing of CaP disease assessment, and the decreased ability of PSA to reflect locally persistent CaP following RT.
The differentiation between active CaP and post-RT changes may be histologically challenging. Ongoing controversy exists for determining the best way to follow patients who were initially treated with RT. This difficulty is in large part due to the prolonged effects of RT for destroying viable cancer cells, as well as the presence of residual prostate tissue architecture and glandular function, which can continue to produce PSA. Of primary importance is the ability to differentiate prostatic carcinoma from radiation treatment effects in the appropriate setting, and to identify small residual foci of disease. Pathologic examination of post-RT prostate specimens may demonstrate cellular atrophy, decreased number and size of glandular acini, and squamous metaplasia.9
The most common finding in irradiated prostate tissue is atypical basal cell hyperplasia, which can often be identified by cytoplasmic clearing and atypical nuclei in the same glandular acini that contain more typical appearing cells.9,10
Additionally, while vascular changes such as narrowing of vessel lumens from intimal hyperplasia may be seen in irradiated specimens, it is rare to identify vascular ectasia and fibrinoid necrosis which can be present in specimens with active CaP. Conversely, one of the hallmarks of malignancy is peri-neural invasion, which should not be seen in specimens with post-RT effects alone. In difficult cases, CaP can be identified with the finding of “retraction artifact” in high-power fields as well as the presence of intraluminal crystalloids and blue mucin, which are more common findings in malignant glands.10
Another confounding factor when evaluating CaP activity is the timing of disease assessment in relation to the completion of RT. Following RT, complete treatment effect is not expected for at least 12-18 months or longer, as radiation treatment does not kill cells immediately upon exposure. Prior series investigating the role of post-RT biopsy in evaluating CaP activity recommend waiting at least 24-36 months to avoid false positive biopsies. This point is supported by repeat biopsy data which demonstrated regression of disease on subsequent biopsies.6
The median duration of time between RT and RCP in the current series was 60 months. Additionally, with the known relationship between preoperative PSA and tumor volume in prostatectomy series, patients with clinically occult active CaP and a low PSA may simply have small volume disease .11-13
Such patients may go on to demonstrate biochemical failure with extended follow-up due to subsequent tumor growth. This concept is supported by the known natural history and PSA kinetics of small volume CaP observed in active surveillance series.14,15
There are several disparities in opinion on how to follow patients treated with definitive RT for CaP by serial assessment of PSA. Controversy surrounding the use of PSA monitoring post-RT is derived primarily from its inability to differentiate between local and distant disease recurrence, as well as the “bounce” effect commonly seen after RT. The ability of post-RT prostate biopsies to predict biochemical recurrence is a topic that has been previously investigated. Several series have demonstrated that patients meeting the criteria for biochemical failure have a higher rate of residual CaP on post-RT biopsy specimens.16-18
In a report defining biochemical recurrence by the Phoenix definition (PSA nadir + 2), it was found that 52% of patients without evidence of biochemical recurrence had an abnormal prostate biopsy 24 months following RT.7
Abnormal biopsies were defined as atypical cells (35%), malignant cells (15%), or biopsies with treatment effect (50%). The authors noted two important points. First, patients who were shown to have an abnormal biopsy had a significantly greater likelihood of developing biochemical recurrence compared to patients with a normal biopsy. Second, multivariate analyses showed that biopsy results were independent of PSA status in predicting biochemical recurrence. In a study by Crook et al., the incidence of active CaP following RT was 15%, despite meeting the 1996 ASTRO criteria for biochemical success.6
A third study by Pollack et al., revealed residual CaP in 30% of patients which were prospectively biopsied 2 years following RT without evidence of biochemical failure19
. Although the occurrence of active CaP following RT in patients who are biochemically NED following RT has been documented in the past, the reported rates are lower than the observed rate in the current series of 50%. The most likely explanation for this discrepancy is the manner in which residual CaP was evaluated. In our series, RCP specimens were evaluated which allowed complete histopathologic evaluation of the entire prostate, while the other described series relied on transrectal biopsy evaluation. The limitations of transrectal biopsy in evaluating the presence of CaP are well described, with sampling error being of significant concern.6
There are several limitations of the current series. Because a subset of patients had their CaP treated at outside institutions, complete clinical and pathologic data including the details of their radiation treatment were not available on all patients. In addition, our series was retrospective and made up of a relatively small population of patients. With the small sample size presented, the study may be underpowered to detect a significant difference between PSA values in patients with and without active CaP at the time of RCP. However, the need for RCP following RT for CaP is infrequent and a prospective approach to evaluating this question is impractical. Despite these limitations, our series provides a unique look at the occurrence of histological CaP following RT in patients who meet the current definition of biochemical success.