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(Radiology. 2000;215:757-760.)
© RSNA, 2000

Radiation Oncology

Prostate-Specific Antigen: Effect of Pelvic Irradiation1

Stephan Gripp, MD, J. Christoph Haller, MD, Jürgen Metz and Reinhardt Willers, PhD

1 From the Departments of Radiation Oncology (S.G., J.C.H., J.M.) and Biostatistics (R.W.), Klinik für Strahlentherapie und Radiogische Onkologie, Heinrich-Heine-Universität Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf, Germany. Received October 4, 1999; revision requested October 20; revision received December 3; accepted December 17. Address correspondence to S.G. (e-mail: stephan.gripp@uni-duesseldorf.de).


   Abstract
TOP
 Abstract
Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
PURPOSE: To study the effect of pelvic irradiation on the level of serum prostate-specific antigen (PSA).

MATERIALS AND METHODS: Of 33 patients treated with pelvic irradiation to the prostate and seminal vesicles for anal and rectal cancer, 26 received 50.4 Gy or more (1.8 Gy per fraction), and seven received 25.0 Gy (5.0 Gy per fraction). PSA levels were measured before (n = 33), during (n = 26), and after radiation therapy (n = 33). In 24 patients, follow-up (mean, 15.7 months) PSA data were obtained. Actual and pretreatment PSA levels were compared (Wilcoxon rank test).

RESULTS: During the first 3 weeks in all patients, PSA levels rose steeply, culminating in a 3.7-fold increase (P = .02). At the end of radiation therapy (7 weeks), the PSA level was no longer significantly different from the pretreatment value. In the long term, the PSA level decreased to 77% of the pretreatment value (P = .04).

CONCLUSION: Irradiation of the prostate initially elevates serum PSA levels. Apparently PSA release is determined by the duration of radiation therapy, while the accumulated dose has a minor effect. In the long term, PSA production is impaired after radical radiation therapy. PSA reference concentrations should be adjusted to these reduced levels.

Index terms: Anus, therapeutic radiology, 757.1299 • Prostate, 844.1299 • Prostate neoplasms, therapeutic radiology, 844.1299 • Radiations, injurious effects, 844.1269, 844.458 • Rectum, therapeutic radiology, 757.1299


   Introduction
TOP
 Abstract
 Introduction
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 
Prostate-specific antigen (PSA) is a 34-kd serine protease that was isolated 20 years ago from extracts of human prostatic tissue (1). It is exclusively secreted by the epithelium of the prostatic ducts to lyse seminal vesicular protein. Disruption of the epithelial layers of the prostatic ducts, for example by prostatic cancer, leads to an elevation in serum PSA. In the absence of prostatic disease, the concentration in the prostatic fluid is 106 times higher than in the blood. Serum PSA exists as both uncomplexed enzyme (4%–50% of total PSA) and bound to {alpha}1-antichymotrypsin (60%–95% of total PSA) and {alpha}2-macroglobulin, respectively (2). Free and {alpha}1-antichymotrypsin–bound PSA are detected with commercial tests.

PSA has emerged to be the most important tumor marker in prostatic cancer with regard to early detection and screening (3), tumor stage (4), residual tumor after radical prostatectomy (5), and response of prostatic cancer to radiation therapy (6–8). After prostatectomy, PSA decreases exponentially, with a half-life of 2–3 days, within several weeks to female levels (0.0–0.2 ng/mL). Rising or persistently elevated PSA concentration indicates relapse or residual disease (9,10). The PSA change after radiation therapy is more complex, however, and its interpretation poses a serious problem. After radiation therapy, serum PSA decreases to low but still detectable concentrations. Both the healthy prostatic epithelium and residual prostatic cancer may contribute to the postirradiation PSA secretion into the blood. Although several factors that may interfere with PSA determinations have been identified, the influence of therapeutic irradiation of the normal prostate on the PSA level is poorly understood. To ascertain the effect of radiation therapy on serum PSA in male patients with no clinical evidence of prostatic disease, we performed serial measurements before, during, and after radiation therapy to the pelvis.


   MATERIALS AND METHODS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 References
 
Between July 1997 and January 1999, 33 consecutive eligible men receiving pelvic radiation therapy for nonprostatic malignancies were enrolled in this study. Patients were considered eligible if they had no clinical evidence of prostatic disease and there was no indication of prostatic infiltration by the tumor. Three different therapeutic regimens were administered. (a) Postoperative adjuvant radiation therapy for colorectal cancer (n = 22) with daily fractions of 1.8–50.4 Gy and a supplemental presacral boost of 5.4–9.0 Gy (ie, 6–7-week treatment time) and, simultaneously, two concomitant cycles of chemotherapy with 5-fluorouracil (group A). (b) Primary radiation therapy for anal cancer (n = 4) with daily fractions of 1.8–50.4 Gy and a supplemental anal boost of 9.0 Gy (ie, 6–7-week treatment time) and, simultaneously, two concomitant cycles of chemotherapy with 5-fluorouracil and mitomycin C (group B). (c) Preoperative hypofractionated accelerated radiation therapy for locally advanced rectal cancer (n = 7) with daily fractions of 5.0–25.0 Gy (ie, 1-week treatment time) (group C).

Radiation therapy to the pelvis was accomplished with three- and four-field box techniques. The prostate and the seminal vesicles were included in all fields and thus received approximately the dose specified to the reference point of the International Commission on Radiation Units and Measurements, or ICRU (ie, intersection of beam axes). The final boost fields did not completely cover the prostate.

Serum samples were obtained with regular blood counts according to our routine clinical practice. Any manipulation of the prostate before venous puncture was strictly avoided. Total PSA levels were measured with an immunoassay with monoclonal anti-PSA antibodies (Elecsys; Roche Diagnostics, Mannheim, Germany). The sensitivity of the PSA test is specified as 0.006 ng/mL. The first blood sample was taken on the 1st day of irradiation. Additional samples were obtained during radiation therapy in groups A and B but not group C owing to the brief therapy course in the latter group. Finally, another PSA value was determined at long-term follow-up several months after radiation therapy.

The PSA values were grouped according to the elapsed time in weeks from initiation of radiation therapy. The Table shows the number of blood samples taken in the corresponding weeks. Absolute PSA values may vary considerably between individuals in a normal population. Since the objective of this study was the PSA change with radiation therapy rather than absolute PSA values, we normalized the actual PSA values (PSA) by the pretreatment value (PSA0): PSA/PSA0. In this way, interindividual differences were reduced. The data were analyzed after logarithms were taken, as we were interested in proportions, and the logarithm reduces the influence of extreme values and makes the distribution more robust. To test the significance of changes in the means for each group as compared with the mean pretreatment level, the Wilcoxon rank test was applied after adjusting for multiple tests (Bonferroni method). To take account of the very different dose schedule, data for group C were evaluated separately.


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  		Mean PSA Values Relative to Pretreatment Level according to Elapsed Time after Radiation Therapy
 

   RESULTS
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 References
 
In 33 of the 33 patients, PSA values were available before and immediately after radiation therapy. In addition, at least one PSA value was obtained during radiation therapy for each patient in groups A and B (n = 26). At long-term follow-up (more than 6 months after initiation of radiation therapy [range, 6.7–25.0 months; mean, 15.7 months]), data were available for 24 patients. Four patients died, and five were lost to follow-up. The mean PSA levels during and immediately after radiation therapy and at long-term follow-up are listed in the Table. The corresponding graph is shown in the Figure.



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  		Figure 1. Change in normalized serum PSA during fractionated radiation therapy with daily doses of 1.8 Gy. After an initial increase, serum PSA level culminates after 4 weeks, which corresponds to an accumulated dose of about 36.0 Gy. With continuing radiation therapy, the PSA level slopes to the pretreatment value. • = mean value, error bars indicate variance.

 
During the first 4 weeks of conventionally fractionated radiation therapy (groups A and B), the PSA level increased steadily (Figure). It culminated 3–4 weeks after initiation of radiation therapy in a 3.7-fold statistically significant (P = .02) increase as compared with the pretreatment mean, which corresponds to a logarithmic normalized PSA of 0.566. When hypofractionated accelerated radiation therapy was administered for 1 week (group C), the PSA values also increased, but owing to the small number of patients, the significance was marginal (P = .06). The magnitude of increase (0.20) was almost the same as that in groups A and B after the same period of time (0.182), although the accumulated doses differed considerably (5.0 x 5.0 Gy vs 5.0 x 1.8 Gy). However, the PSA level decreased even as radiation therapy continued. Toward the end of radiation therapy, the logarithmic normalized PSA was 0.15, which corresponds to a 1.4-fold increase from the beginning level. This change was no longer significantly different from the initial PSA values (P = .63).

At long-term follow-up after a mean of 15.7 months, the logarithmic normalized values decreased slightly by 0.112, which corresponds to a factor of 0.77 as compared with the pretreatment values. This decrease was also significant (P = .04).


   DISCUSSION
TOP
 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
References
 
The PSA concentration in serum is widely used in diagnosis, staging, and follow-up of prostatic cancer. It has evolved as the single most important tumor marker in prostatic cancer. Below a cutoff level of 4.0 ng/mL, serum PSA concentrations are considered unsuspicious. However, two-thirds of men with higher PSA levels have no prostatic cancer, and, in turn, 20% with clinically localized prostatic cancer have normal PSA levels (11,12). Serum PSA levels increase a little with advancing age (13,14). Besides prostatic cancer, benign prostatic hyperplasia, inflammation, and ejaculation affect PSA concentration (15,16). In addition, mechanical manipulations with transurethral resection and biopsy also increase serum PSA levels (17,18). Digital rectal examination has a minor effect if any (19,20).

Several studies have addressed the kinetics of postirradiation PSA levels in patients with prostatic cancer. After radical radiation therapy for localized prostatic cancer, PSA levels tend to normalize within 6 months, with a median half-life of 1.6 months (21). PSA levels lower than 4 ng/mL obtained 6–60 months after radiation therapy were found to be associated with a high likelihood of long-term disease-free survival (22). Lower postirradiation PSA levels predict an even better prognosis (23), whereas persistently elevated levels indicate a poor outcome (24). Even though a postirradiation decrease in PSA level was supposed to reflect tumor cell clearance rather than direct effect on PSA production (25), the normal prostatic tissue also contributes an unknown amount to postirradiation PSA levels.

The change in PSA after irradiation of the normal prostatic gland has been barely investigated. In an attempt to address this issue, 36 men were studied 1–5 years after pelvic irradiation for nonprostatic malignancies with 45.0–65.0 Gy (26). Since preirradiation PSA levels were not available, those patients were compared with a retrospectively recruited control group. The median PSA value in the irradiation group was lower than that in the control group (0.65 vs 1.1 ng/mL), and PSA values less than 0.5 ng/mL were observed significantly more frequently in the control group. However, owing to the lack of pretreatment PSA values, no individual PSA courses were assessable, and the comparison of different patient cohorts is susceptible to selection bias. Nevertheless, findings in our study confirmed these results. We found a modest decrease in postirradiation PSA level to 0.77-fold of the pretreatment level after a mean of 1.3 years, which coincides with the results of Willet et al (26), who observed a 0.59-fold (0.65/1.1) lower mean PSA level after irradiation as compared with the control after a mean of 3 years after treatment. In a recent update (27), the postirradiation PSA levels continued to decline, and only three of 24 patients displayed small rises over the observation period of 3.3 years. High doses of ionizing radiation are actually well known to decrease permanently protein synthesis of exocrine and endocrine glands such as thyroid, salivary, and pituitary glands (28–30). Therefore, recovery of the exocrine function of the irradiated prostate seems to be an unlikely event.

Until now, to our knowledge, the course of PSA during irradiation has not been studied at all. We observed a significant increase in serum PSA to the 3.7-fold level within the first 3 weeks after radiation therapy. There was only a slight difference between both fractionation schedules with single doses of 1.8 and 5.0 Gy, respectively. It seems that the PSA release is determined by the time after initiation of radiation therapy rather than by the accumulated dose (25.0 vs 9.0 Gy after a week). Similarly, a transient excessive release of thyroid hormones during radiation therapy that finally changes to a persistent insufficiency was observed with irradiation of the thyroid (31,32). We hypothesize that damage to the epithelium of the prostatic ducts entails a release of PSA into the blood. In the long term, the epithelial damage is repaired, but the exocrine function is irreversibly impaired, which results in decreased serum PSA levels.

However, the significant transient increase in serum PSA level during radiation therapy will not influence the assessment of treatment response. The first PSA check is usually performed several months after radiation therapy is completed. At this time, the PSA level has returned to normal. Actually, we observed that the PSA level decreased slightly in comparison with the pretreatment level. Therefore, postirradiation PSA reference levels should be adjusted to the reduced PSA production.


   Acknowledgments
 
The authors thank Prof James Kilbury from Heinrich-Heine-Universität Düsseldorf for invaluable assistance in preparation of the manuscript. We also thank Dr Wolfgang Kiemstedt from Roche Diagnostics for providing detailed information about the Elecsys PSA test.


   Footnotes
 
Abbreviation: PSA = prostate-specific antigen

Author contributions: Guarantor of integrity of entire study, S.G.; study concepts, S.G., J.M.; study design, S.G., R.W., J.M.; definition of intellectual content, all authors; literature research, S.G.; clinical studies, S.G., J.M., J.C.H.; data acquisition, S.G., J.M., J.C.H.; data analysis, S.G., R.W., J.C.H.; statistical analysis, R.W., S.G.; manuscript preparation and editing, S.G.; manuscript review, S.G., J.C.H.


   References
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 Abstract
 Introduction
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 References
 

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