Radiation Therapy Failure in Prostate Cancer Patients: Risk Factors and Methods of Detection

MANAGEMENT OF RADIATION FAILURE IN PROSTATE CANCER Radiation Therapy Failure in Prostate Cancer Patients: Risk Factors and Methods of Detection Michael K. Brawer, MD Northwest Prostate Institute at the Northwest Hospital, Seattle, WA Radiation therapy for clinically localized prostatic carcinoma remains one of the mainstays among therapeutic approaches; however, patients continue to fail radiation therapy at too high a rate. This article reviews the risk factors and methods of detection for prostate cancer recurrence. The relative merits of the three major pre-therapy prognostic indicators—TNM staging, Gleason score, and serum prostate-specific antigen (PSA) levels—are discussed. The use of staging and Gleason score, as well as digital rectal examination, transrectal ultrasound, and post-radiation prostate biopsies in detecting failure of radiation therapy is reviewed. Challenges relating to the use of serum PSA levels as an indicator of recurrence are examined. Finally, this article makes recommendations as to procedure for evaluating patients suspected of failing radiation therapy. [Rev Urol. 2002;4(suppl 2):S2–S11] © 2002 MedReviews, LLC Key words: Prostate cancer • Prostate-specific antigen • Gleason score • Transrectal ultrasound • Biopsy, post-radiation prostate • Digital rectal examination R adiation therapy for clinically localized prostatic carcinoma has remained one of the mainstays among our therapeutic approaches. Indeed, the pendulum is recently shifting to increased use of radiation therapy, primarily by brachytherapy, for a variety of reasons. There have been significant improvements in methodology. For example, ultrasound guidance for brachytherapy appears to enable more precise and accurate volume distribution of the radiation. More sophisticated imaging and computer enhancement modalities for external beam therapy are now also widely utilized. However, patients continue to fail radiation therapy at too high a rate. S2 VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY Risk Factors for Radiation Failure in CaP Table 1 Biochemical Disease-Free Rates at 3 to 5 Years in Men Treated with Radiation Therapy as a Function of Pre-therapy PSA Level Author/Reference PreTx PSA (ng/mL) Kuban et al 5-y bNED (N = 652) Crook et al * 5-y bNED (N = 498) Zietman et al13 4-y bNED (N = 161) Hanks et al14 5-y bNED (N = 502) Lee et al9 3-y bNED (N = 500) Preston et al15 5-y bNED (N = 371) 0–4 4.1–10 10.1–20 20.1–50 >50 69% 58% 57% 20% — 90% 62% 26% 18% — 81% 43% 31% 6% 0 83% — 27% 13% — 85% 81% 59% 35% — 79% 67% 57% 27% 0 12 8 *Pretreatment PSA groupings 0–5 ng/mL, 5.1–10 ng/mL, 10.1–20 ng/mL, and >20 ng/mL. PreTx PSA, pre-treatment prostate-specific antigen level; bNED, no evidence of disease on the basis of the PSA value. Risk Factors for Failure of Radiation Therapy The etiology of failure to eradicate the cancer is obviously multifactorial. These factors include relative radioresistance of prostatic carcinoma, failure to administer a cytotoxic dose to the entire gland, and limitations in the ability to increase dose owing to potential injury to surrounding structures. A significant possibility is that as prostate cancer is being detected earlier and earlier, men are at risk for progression and/or development of secondary carcinomas for a much greater time. Clinical recurrence, whether detected as it is most commonly by biochemical evidence of failure based on prostate-specific antigen (PSA) assay, or on clinical grounds, has been demonstrated to predict ultimate disease dissemination.1,2 It has been demonstrated that patients with local persistance of cancer after definitive radiation therapy have shortened disease-specific survival as well as a four-fold increase for metastasis compared to patients with apparent local control. Morbidity owing to tumor progression may include pain, hematuria, bladder outlet obstruc- tion, ureteral obstruction, and resulting renal insufficiency, and may also be the source for metastasis. Therapy for local disease persistence, including transurethral resection of the prostate (TURP) or other forms of urinary diversion, is commonly required. TURP for bladder outlet obstruction in the setting of radiation failure is associated with significant morbidity, including incontinence in approximately 30% of patients.3 Pre-therapy Indicators of Prostatic Carcinoma Three major pre-therapy prognostic indicators are widely used. These are the clinical stage (tumor, node, metastasis [TNM]), the Gleason score, and the serum PSA level. Unfortunately, problems are associated with all these. The lack of prognostic information associated with clinical stage is perhaps best exemplified by the study by Pisansky et al.4 He reported on 500 patients with external beam radiation therapy. Twenty-three percent of patients who at diagnosis were clinical stage T2b had biochemical recurrence within 5 years. It should be noted that within subgroups of this cohort (based on grade and pretreatment PSA level), the risk of failure ranged from 0% to 88%. Thus, the importance of tables such as those developed by Partin and associates and others,5–8 which combined these three important prognostic factors. Subjectivity of palpation affording clinical stage determination, and indeed of the Gleason score, makes these two variables less robust when subjected to statistical testing analysis. In a number of series,9–11 when subjected to multivariate analysis, Gleason score and clinical stage were no longer significant. The objectivity associated with serum PSA remains predictive when subjected to multivariate analysis. Despite tremendous effort in establishment of new markers based on molecular, cytologic, or tissue findings, the heterogeneity observed in the prostate makes the accuracy of these problematic. This is depicted in Figure 1. New markers, such as expression of tumor suppression genes, the reverse transcriptase chain reaction, DNA ploidy, and neovascularity resulting from angiogenesis, are all undergoing extensive scrutiny. Unfortunately, none of these has been VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S3 Risk Factors for Radiation Failure in CaP continued demonstrated to provide unique independent prognostic information in widespread clinical series. Because of the heterogeneity and difficulty in establishing reliable markers based on biopsy material, most physicians have resorted to utilization of systemically expressed markers, the most widely utilized of course being PSA. Table 1 illustrates the prognostic information afforded by pretreatment, serum PSA levels in men treated with external beam radiation therapy. As is demonstrated, staggeringly different prediction of biochemical disease-free rate is observed across these six large series based on PSA level.8,9,12–15 Vicissitudes of determining the definition of biochemical failure following radiation therapy will be discussed below. It should be noted that the definition utilized in these papers varies tremendously. Kuban defined it as a PSA greater than 4.0 ng/mL,12 whereas Zeitman’s definition is PSA greater than 1.0 ng/mL 2 years or more following radiation therapy or an increase of greater than 10% in the first 2 years.13 Figure 1. Types of heterogeneity of expression in prostate cancer. Reproduced from Belldegrun A, Kirby RS, Newling DWW, editors. New Perspectives in Prostate Cancer, 2nd edition. Oxford, UK: Isis Medical Media, 2000, with permission from the publisher. Tumour A Tumour B Multifocal heterogeneity Sample B Sample A Detection of Radiation Failure The suspicion of persistent carcinoma following definitive radiation therapy can be raised in many ways. Clinically, it may present with signs and symptoms of bladder outlet obstruction or upper tract obstruction. In historical series it was often detected by an abnormality on digital rectal examination (DRE). The fibrosis and other changes that occur commonly following radiation therapy make DRE relatively crude in assessing persistent disease. Indeed, it has been demonstrated that between 20% and 80% of patients with positive post-radiation biopsies may indeed have a normal DRE.16,17 In general, DRE is only definitive in the setting S4 VOL. 4 SUPPL. 2 2002 the useful information represented in the Gleason system occurs primarily at the poles—those with Gleason scores less than 4 or greater than 6. Stamey and associates were the first to show that the percentage of Gleason grade 4 and 5 carcinoma is the best predictor of all in the Stanford series of radical prostatectomies.18 They noted that 89% of men were without biochemical failure following radical prostatectomy when less than 10% of the specimens revealed Gleason grade 4 or 5 carcinoma. In contrast, 88% of men progressed when 41% or more of their malignancy was high of extensive neoplasm. In recent times, the most common method for detecting the potential of radiation failure is rising PSA levels or failure to achieve a significant PSA nadir. Zagars11 combined clinical stage, serum PSA level, and Gleason score to afford 6 risk categories. Relapse rate among 938 men treated with external beam radiation therapy ranges from 6% for the lowest from this group to 88%, as shown in Table 2. The grading system devised by Gleason and colleagues has been shown in all studies to be the best predictor of pathologic stage.5 However, REVIEWS IN UROLOGY Regional heterogeneity Microdissected specimen Cellular heterogeneity Fibroblasts Inflammatory cells Microscope field of vision Cell A Cell B Tumour cellular heterogeneity Cancer cells Endothelial cells Risk Factors for Radiation Failure in CaP Table 2 Prognostic Catagories of Zagars et al11 Based on Multivariate Regression Analysis of 938 Men Category T stage PSA (ng/mL) Gleason Score Relapse Rate (%) 1 T1/T2 <4.0 2–6 6 2 T1/T2 ≤4.0 4.1–10.0 7–10 2–7 30 3 T1/T2 4.1–10.0 10.1–20.0 8–10 2–7 40 4 T3/T4 <10 5 T3/T4 10.1–20 2–7 57 6 any T >20.0 Any Gleason 88 10.1–20.0 8–10 grade. Extending this to patients treated with radiation therapy can be afforded by substantiating studies by Conrad and associates19 and Wills and colleagues,20 which demonstrated that the number of biopsies exhibiting Gleason 4 and 5 pattern of carcinoma was the best independent predictor of pelvic lymph node extension. Transrectal Ultrasound Following Radiation Therapy The use of transrectal ultrasound as a method of identifying persistent carcinoma has been debated. Initial studies demonstrated that the classic hypoechoic peripheral zone pattern persists after radiation, and areas with successful eradication of tumor become isoechoic.21,22 This has not been the universal experience. Kabalin and colleagues demonstrated lack of specificity of the sonographic appearance in post-radiation biopsies.16 The use of transrectal ultrasound to guide biopsies has been shown by Egawa23 to be important. He noted a detection rate in digitally guided biopsies of only 22% as compared to 67% detection of persistent carcinoma in those men undergoing sonographic biopsy guidance. 46 The Role of Post-Radiation Prostate Biopsies Prostatic biopsies following radiation therapy have been a standard procedure for a number of years. The ratio of positive biopsy varies tremendously between series (Table 3). Advances in biopsy technique, including transrectal ultrasound guidance and the spring-loaded biopsy devices, have considerably lessened biopsy-associated morbidity. The rationale for post-radiation biopsies is that microscopic evidence of disease persistence will occur at an earlier stage than clinical manifestation of same; earlier detection enables earlier institution of salvage therapy.24–26 Owing to the relatively cell-cycle–specific nature of radiation injury to carcinoma, the timing of radiation biopsy remains ill-defined. Indeed, it had previously been proposed that biopsies performed within 18 months of radiotherapy were of little biological significance, given that subsequent tumor kill could occur.27 However, in vitro studies have demonstrated the viability of post-radiated prostate cancer cells. Despite these factors, most reports have suggested that men with a positive biopsy post-radiation therapy have a significantly worse prognosis than those with negative biopsies (Table 4). Despite these observations, postradiation biopsy does not always predict eventual clinical recurrence. Approximately 20% of patients who have post-radiation biopsies will have no clinical evidence of disease at follow-up extending up to 10 years.17,28 Whether these biopsies either detected latent carcinoma or indeed were misinterpreted, “radiation atypia" remains obscure. Also of considerable importance is the fact that up to 30% of patients who have local or distant recurrence do so in the face of negative postradiation prostate biopsies. Some of these may have had occult micrometastasis at the time of presentation, and sampling errors in the biopsy procedure are notorious. The interpretation of post-radiation biopsies is one of the most difficult tasks of the surgical pathologist. Radiation atypia in benign prostate glands may mimic carcinoma.29 It has been demonstrated that utilizing immunohistochemical techniques with basal cell–specific keratin monoclonal antibodies is useful in differentiating benign glands from malignant ones. This is because only the benign glands display basal cell immunoreactivity.30,31 PSA in the Detection of Radiation Failure The definition of biochemical failure following definitive radiation therapy remains obscure. In men treated with radical prostatectomy, theoretically serum PSA should be zero or at the low-end sensitivity of the assay. The greatest variable is assay and laboratorian reliability in establishing the low-end sensitivity range. Although in theory extra-prostatic sites that elaborate a protein similar to PSA VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S5 Risk Factors for Radiation Failure in CaP continued Table 3 Results of Post-Radiation Therapy Prostatic Biopsies Author/Reference Technique N Positive Biopsy (%) Sewell et al35 EBRT 16 62 Cosgrove et al26 EBRT 9 56 Kurth et al EBRT 23 61 Nachstein et al37 EBRT 29 52 Lytton et al38 Brachytherapy 22 50 Kiesling et al39 EBRT 68 57 Jacobi et al40 EBRT Scardino et al52 Brachytherapy + 36 64 39 115 33 31 71 EBRT Babaian et al41 EBRT Freiha et al EBRT 64 61 Bosch et al43 EBRT + Brachytherapy 29 52 Scardino et al17 Brachytherapy + EBRT 124 35 Schellhammer et al44 EBRT or Brachytherapy 126 33 Bagshaw et al45 EBRT 64 61 Kabalin et al EBRT 27 93 Dugan et al46 EBRT 37 38 Kuban et al EBRT or Brachytherapy 94 18 Goad et al48 EBRT + Brachytherapy 49 55 Crook et al49 EBRT 226 30 Kaye et al Brachytherapy 71 18 (24% indeterminate) Radge et al51 Brachytherapy 77 5 (13% indeterminate) 42 16 47 50 EBRT, external beam radiation therapy. may cause false-positive test results, this does not appear to be relevant in clinical practice. Unfortunately, in the radiationtreated patients the scenario is considerably different. Not only is there an ongoing effect during the first several years of radiation injury to both the cancer and the benign prostatic elements, but in most series remaining benign elements that S6 VOL. 4 SUPPL. 2 2002 appear immunohistochemically to elaborate PSA are present. Evidence that new malignant cells may be associated with persistent PSA following radiation therapy may be found in the report by Willet and colleagues,32 who studied 36 men who had prostate radiation due to treatment for nonprostatic pelvic malignancies. Dose ranged from 45 to 65 Gy, and the mean PSA 3 years REVIEWS IN UROLOGY following radiotherapy was 0.6 ng/mL. However, 20% of the patients had readings greater than 1.5 ng/mL. No man had a clinical diagnosis of prostate carcinoma. Because of these issues, a number of definitions for biochemical failure following radiation have been utilized. This may well be the biggest factor in explaining the staggeringly different rates of biochemical failure in reported series (Table 5). In 1997, the American Society of Therapeutic Radiation and Oncology (ASTRO) developed a consensus guideline.33 The ASTRO consensus conference conclusion was that three consecutive rises in PSA is a reasonable definition of biochemical failure. They recommended that determinations be made 3 to 4 months apart in the first 2 years following radiation therapy and every 6 months thereafter. Three sources exist for PSA in patients following radiation therapy—residual benign prostatic epithelium, viable cancer within the prostate, and disseminated disease. Crook has summarized the typical response to therapy according to PSA nadir, time to nadir, and PSA doubling time. This is depicted in Table 6. Time to PSA nadir has been shown to correlate inversely with disease-free survival. Lee and colleagues34 noted that 75% of men whose PSA began to rise following the nadir in less than 12 months had disseminated disease, compared to only 25% of those who achieved their nadir more than 1 year following external beam radiation therapy. PSA doubling times tend to be longer in patients failing locally as compared to those with metastatic disease. Freedom from biochemical relapse at 3 to 5 years according to PSA nadir is shown in Table 7. It is obvious from this that the level of the PSA nadir and the length of nadir provide important prognostic information. Risk Factors for Radiation Failure in CaP Table 4 Prognostic Significance of Post-Radiation Therapy Prostatic Biopsy Author/Reference Technique Positive Biopsy Negative Biopsy Cosgrove et al26 EBRT 9 60% recurrence free at 5 years 100% recurrence free at 5 years Kurth et al36 EBRT 23 86% recurrence free at 1–4 years 100% recurrence free at 1–4 years Lytton et al Brachytherapy 22 91% recurrence free at 2 years 91% recurrence free at 2 years Kiesling et al39 EBRT 68 72% progression free in 5 years 96% progression free in 5 years Jacobi et al EBRT 64 36% recurrence free at 4 years 82% recurrence free at 4 years Scardino52 Brachytherapy + EBRT 50% recurrence free in 10–24 months 86% recurrence free in 10–24 months Babaian et al41 EBRT 31 89% with abnormal DRE 64% with normal DRE 11% with abnormal DRE 36% with normal DRE Freiha et al42 EBRT 64 28% progression free in 4.5 years 76% progression free in 4.5 years Scardino et al17 Brachytherapy + EBRT 124 35% recurrence free at 5 years 69% recurrence free at 5 years Schellhammer et al44 EBRT or Brachytherapy 126 Actuarial disease free survival 35% at 5 years Actuarial local failure rate 50% at 5 years Actuarial disease free survival 85% at 5 years Actuarial local failure rate 8% at 5 years Bagshaw et al45 EBRT 64 28% disease free survival at 15 years 76% disease free survival at 15 years Kabalin16 EBRT 27 100% with abnormal DRE 91% with normal DRE _ Kuban et al47 EBRT or Brachytherapy 94 Actuarial disease free survival 32% at 5 years, 18% at 10 years Actuarial local failure rate 44% at 5 years, 75% at 10 years Actuarial disease free survival 82% at 5 years, 62% at 10 years Actuarial local failure rate 8% at 5 years, 24% at 10 years Goad et al48 EBRT + Brachytherapy 49 70% progression free in 29.5 months 95% progression free in 29.5 months Crook et al49 EBRT _ 93% local progression free at 36 months 38 40 N 115 226 EBRT, external beam radiation therapy; DRE, digital rectal examination. Patient Evaluation Patients suspected of having persistent prostate cancer following radiation therapy owing to either an abnormality on DRE, clinical manifestation, or rising PSA should undergo an ultrasound-guided prostate needle biopsy. Although the best approach remains debatable, we currently per- form 10 biopsies including 6 systematic sector biopsies in the parasaggital plane and 2 additional biopsies extended extremely laterally in the gland to sample the so-called anterior horn region. In addition, metastatic workup is mandatory if salvage therapy is considered. This should include bone scan and computed tomography or magnetic resonance imaging of the abdomen and pelvis along with chest radiographs. The use of the ProstaScint scan remains controversial in this setting. The clinician should be cautioned that, whereas it is unusual in the pretreatment setting to have metastatic disease in the absence of PSA greater than 10.0 ng/mL, in VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY S7 Risk Factors for Radiation Failure in CaP continued Table 5 Actuarial Freedom from PSA and Clinical Failures Based on Definition of a PSA Nadir Author/Reference Technique N Definition of Failure Goad et al48 Brachytherapy + EBRT EBRT 76 2 consecutively rising PSA levels or a single rise > 2 ng/mL Increasing PSA level 36% at 5 years after treatment PSA > 0.5 ng/mL 30% at 5 years 6% at 10 years 67% at 5 years 24% at 10 years PSA > 1 ng/mL 20% at 5 years Kaplan et al53 Schellhammer et al54 EBRT 311 Brachytherapy Stamey et al55 117 123 Zagars et al56 EBRT (98) and 113 Brachytherapy (15) EBRT 314 Kavadi et al57 Zietman et al13 EBRT EBRT 182 161 Blasko et al58 Brachytherapy 197 Critz et al59 Brachytherapy + EBRT 239 Kaye et al50 Kuban et al12 Brachytherapy EBRT+ Brachytherapy EBRT 652 PSA = 4 ng/mL Rosenzweig et al60 EBRT 285 PSA > 4 ng/mL Zagars et al61 EBRT 461 Zagars et al11 EBRT 707 Lee et al34 EBRT 364 Stock et al62 Ultrasound-guided 97 transperineal seed implant EBRT 207 2 or more consecutive rising PSA levels or a second value higher than its predecessor by 1 ng/mL or factor of 1.5 2 or more consecutive rising PSA levels or a second value higher than its predecessor by 1 ng/mL or factor of 1.5 PSA > 1.5 ng/mL or 2 consecutive PSA elevations 2 consecutive increases in PSA above a nadir Crook et al63 45 31 Hanks et al64 Conformal 3-D 456 radiation therapy Radge et al51 Brachytherapy 126 2 or more consecutive rising PSA level or a second value higher than its predecessor by 1 ng/mL or factor of 1.5 PSA > 1 ng/mL PSA < 1 ng/mL or increase by >10% within the first 2 years PSA > 4 ng/mL or 2 consecutive PSA level rises or PSA > pre-implant value 2 consecutive PSA levels progressively greater than the lowest reading PSA > 4 ng/mL PSA ≥ 2 ng/mL and 1 ng/mL above the precedent value 2 consecutive increase in PSA levels that equals or exceeds 1.5 ng/mL PSA progression or failure to attain PSA value of 1.0 or 0.5 ng/mL PSA, prostate-specific antigen; EBRT, external beam radiation therapy. S8 VOL. 4 SUPPL. 2 2002 REVIEWS IN UROLOGY Actuarial Freedom from PSA Failure 66% at 29.5 months Actuarial Freedom from Clinical Failure 40% at 5 years 49% at 5 years 55% at 5 years 33% at 10 years 73% at 5 years 52% at 10 years _ 38% at 4 years _ 88% at 5 years 26% at 48 months 89% at 5 years 67% at 48 months 93% at 5 years _ 74% at 5 years, 66% at 10 years 92% at 5 years, 84% at 10 years 98% at 26.3 months 95% at 26.3 months 51% at 26.3 months 63% at 26.3 months 35% at 5 years 13% at 10 years 53% at 5 years 28% at 10 years 70% at 5 years 43% at 5 years 31% at 10 years 60% at 5 years 42% at 10 years _ 66% at 5 years 67% at 5 years 56% at 5 years _ 76% at 2 years _ 82% at 36 months 75% at 36 months 61% at 5 years 57% at 7 years _ 79% at 7 years 77% overall 7-year survival Risk Factors for Radiation Failure in CaP 7. Table 6 Failure Pattern According to Level of PSA Nadir, Time to Nadir, and PSA Doubling Time 8. PSA Nadir (ng/mL) Time to Nadir (months) PSA Doubling Time (months) NED 0.4–0.5 22–33 NA Local failure 2.0–3.0 17–20 11–13 Distant failure 5.0–10.0 10–12 3–6 9. 10. PSA, prostate-specific antigen; NED, no evidence of disease. Data from Crook et al.65 11. Table 7 Freedom from Biochemical Relapse (bNED) at 3–5 Years After Radiotherapy According to PSA Nadir 12. Author / Reference 13. PSA nadir Crook et al8 (N = 489) Kestin et al66 (N = 871) Zietman et al67 (N = 314) Lee et al34 (N = 364) <0.5 75% 78% 90% 93% 0.6–1.0 50% 60% 55% 34% 1.1–1.9 32% 50% 2.0–3.9 0 20% >4 14. 49% 16% 15. 9% bNED, no evidence of disease on the basis of PSA value; PSA, prostate-specific antigen. 16. the post-radiation cohort this cutoff does not apply. Cystoscopy may be useful to evaluate bladder or bladder neck involvement. References 1. 2. Conclusion Patients electing radiation therapy need to be followed indefinitely for treatment failure. 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Prostate-specific antigen after external beam radiotherapy Main Points • Factors in the failure to eradicate prostate cancer include relative radioresistance of prostatic carcinoma, failure to administer a cytotoxic dose to the entire gland, and limitations in the ability to increase dose owing to potential injury to surrounding structures. • Three major pre-therapy prognostic indicators are widely used: clinical stage (tumor, node, metastasis [TNM]), the Gleason score, and the serum prostate-specific antigen (PSA) level. Subjectivity of palpation affording clinical stage determination and of Gleason score makes these two variables less robust when subjected to statistical testing analysis; the objectivity associated with serum PSA remains predictive when subjected to multivariate analysis. • Persistent carcinoma following definitive radiation therapy may present with signs and symptoms of bladder outlet or upper tract obstruction. In historical series it was often detected by an abnormality on digital rectal examination (DRE), but DRE is relatively crude in assessing persistent disease. • The Gleason grading system has been shown in all studies to be the best predictor of pathologic stage; however, the useful information represented in the Gleason system occurs primarily at the poles—in those with Gleason scores less than 4 or greater than 6. • Prostatic biopsies following radiation therapy have been a standard procedure for a number of years, and advances in biopsy technique, including transrectal ultrasound guidance and the spring-loaded biopsy devices, have considerably lessened biopsyassociated morbidity. • Of considerable importance is the fact that up to 30% of patients who have local or distant recurrence do so in the face of negative post-radiation prostate biopsies. • Regarding serum PSA levels and disease recurrence, the American Society of Therapeutic Radiation Oncology consensus conference conclusion was that three consecutive rises in PSA is a reasonable definition of biochemical failure. • Patients suspected of having persistent prostate cancer following radiation therapy should undergo an ultrasound-guided prostate needle biopsy. 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