Prostatic Biopsy after Radiotherapy: When and How

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1 European Urology Supplements European Urology Supplements 1 (2002) 83±88 Prostatic Biopsy after Radiotherapy: When and How P. Hammerer *, M. Graefen, J. Palisaar, H. Huland Department of Urology, University Hospital Hamburg Eppendorf, Hamburg, Germany Abstract Objectives: External beam radiotherapy and seed implantation are treatment options for clinically localized prostate cancer. Post-radiation biopsies may assess the ef cacy of radiation in locally eradicating prostate cancer cells. Aim of this overview was to analyze the role of prostate rebiopsies after radiation to evaluate treatment success. Methods: A Medline searchwas performed from 1980 to 2001 for articles in English. Results: Based on the available data a positive prostate rebiopsy can be found in 18±90% for patients with stage T1± T3. Pretreatment PSA, pretreatment Gleason score, clinical stage and digital rectal examination (DRE) after radiotherapy correlate with biopsy results. A positive post-treatment biopsy is associated with a higher nadir PSA serum level and a higher rate of local recurrence compared to patients with negative biopsies. However, systematic prostate biopsies after radiation therapy are not necessary in the standard follow-up because a rising PSA after radiation therapy is a more rigorous end-point for evaluation of treatment ef cacy. However, patients with rising PSA after irradiation without evidence of systematic disease and positive prostate biopsies may be candidates for salvage treatment. Conclusions: Prostate biopsies after radiation therapy are not necessary as a standard procedure for followup. Prostate rebiopsies may be an important research tool to evaluate histological changes within the prostate and may indicate local recurrence. # 2002 Elsevier Science B.V. All rights reserved. Keywords: External beam radiotherapy; Seed implantation; Prostatic biopsy 1. Introduction Radiation therapy is an effective therapeutic modality for patients withcarcinoma of the prostate [1,2]. Evaluating local control after external beam radiotherapy or interstitial brachytherapy for early stage prostate cancer is based on digital rectal examination (DRE), transrectal ultrasound (TRUS), prostate-speci- c antigen (PSA), and prostate biopsies [3±6]. DRE is useful in detecting recurrent or persistent disease in patients withpalpable tumors, however, in men with normal DRE the speci city is low [4]. TRUS permits the evaluation of the complete prostate gland. The correlation of speci c ultrasound ndings like hypoechoic lesions with biopsy results is poor and positive biopsies can be detected in normal appearing areas [4]. * Corresponding author. Tel ; Fax: address: hammerer@uke.uni-hamburg.de (P. Hammerer). Nadir PSA after irradiation has a strong correlation withthe probability of post-irradiation failure. Several different post-irradiation serum PSA levels are used to de ne recurrent disease suchas 0.5, 1, and 1.5 ng/ml [7±9]. Because of uctuations in PSA levels the American Society of Therapeutic Radiology and Oncology (ASTRO) consensus was formulated which requires three consecutive rises, and the date of failure should be the midpoint between the post-irradiation nadir PSA and the rst of the three consecutive rises [10]. A rising PSA indicates recurrence but does not differentiate between local failure and systematic disease [9]. The use of routine post-irradiation biopsies is controversial. The association of local and distant failure rates withpositive biopsies has been reported by several authors (Table 1) [3,5,6,11]. Pretreatment tumor stage, tumor grade, technique of irradiation and tumor dose as well as post-radiation biopsy technique may in uence biopsy results. Despite the statement by Cox and Stoffel [12], that there seemed to be no further justi cation to continue to pursue post-irradiation biopsies the /02/$ ± see front matter # 2002 Elsevier Science B.V. All rights reserved. PII: S (02)

2 84 P. Hammerer et al. / European Urology Supplements 1 (2002) 83±88 Table 1 Correlation of post-radiation biopsy results withoutcome Negative biopsy Positive biopsy Reference 38% progression 81% progression [16] 24% local recurrence 75% local recurrence 18% progression 88% progression [3] 30% local recurrence 72% local recurrence [23] 24% progression 60% progression [21] discussion still continues. Is it possible that histologically present tumor is biological inert? Although this idea has been contested, studies have shown that patients withtumor positive biopsy specimens may show no clinical signs of disease recurrence even after years of follow-up [6]. In addition, the interpretation of a post-irradiation biopsy of the prostate is dif cult and the possible signi cance and implication for treatment remains controversial [13±15]. In 1999, the ASTRO challenged a multidisciplinary consensus panel to develop evidence-based guidelines for prostate rebiopsy after radiation therapy [5]. 2. Positive biopsies after external beam radiation The rate of positive post-irradiation biopsy varies signi cantly and is related to patient selection, timing of the biopsy after radiotherapy, the clinical status at the time of the biopsy and the method of biopsy [3±6,12,16]. Studies, which exclude patients with signi cant obstructive symptoms and palpable suspicion of clinical local failure, will have a low positive biopsy rate. In patients withsuspicious DRE, a positive biopsy rate can be found in 55±100% [3,4]. In the report by Kabalin et al. [4], a mean number of eight biopsies were taken under ultrasound guidance which allowed adequate tissue sampling. Of 27 patients, 25 (93%) had post-irradiation biopsies positive for prostate cancer witha mean interval from radiation therapy to biopsy of 5.2 years. All patients withsuspicious DRE had positive rebiopsies. The use of TRUS guidance as well as extensive sampling and patient selection may have in uenced this high detection rate. Scardino [3] reported a progressive increase in histological con rmation of disease after radiation by stage from stage B1 (28%) to stage B2 (41%) to stage C (62%). Improvement in radiation techniques and patient selection has resulted in a decreased positive biopsy rate. At the Memorial Sloan-Kettering Cancer Center prostate biopsies after radiation therapy were done to correlate PSA pattern withhistologic criteria [5,17]. Sextant biopsies were performed in 38% of 370 patients without evidence of local or metastatic disease. Biopsies were classi ed as showing no cancer, prostatic adenocarcinoma without radiation-induced changes or residual tumor cells with cytoplasmatic and nuclear radiation changes. The positive biopsy rate correlated withradiation dose level. A positive biopsy was seen in 57% of patients who received 64.8 Gy, in 44% of patients who received 70.2 Gy and in 7% of patients receiving 81 Gy. In patients where biopsies showed no cancer, median nadir PSA was 0.3 ng/ml and median PSA level 1 ng/ml. In patients withpositive biopsies median nadir PSA was 1.35 ng/ml and median PSA level 4.85 ng/ml. A total of 84% of patients withpositive biopsy specimens had rising PSA pro les. If patients reached a nadir of 1 ng/ml and had a non-rising PSA pro le at the time of the biopsy, only 6% had histologic evidence of prostate cancer. They concluded that a PSA nadir of 1 ng/ml witha non-rising PSA is the best indicator of a complete response, and this could be used as a surrogate for negative biopsies in clinical trials [5,17]. Forman et al. [18] analyzed rebiopsy ndings in 49 patients withlocally advanced prostate cancer who received a median radiation dose of 80 Gy. More than half of these patients received neoadjuvant hormonal therapy. Biopsy specimen were graded as either negative, marked, moderate, or minimal therapeutic effect or positive. Post-treatment biopsies after 12 months were negative in 55% or showed marked therapeutic effects in 16% of patients. Negative biopsies or biopsies with marked effects were seen more often after 82 Gy (91%) compared to dose levels of 78 Gy (60%). The strongest predictor of a positive biopsy was the PSA level at the time of rebiopsy. In patients with PSA levels <1.5 ng/ml positive rebiopsy rate was 17% compared to 50% in patients withpsa levels 1.5 ng/ml. In this series, pretreatment PSA levels predicted outcome as good as the rebiopsy results. The authors concluded that post-treatment rebiopsies were not uniquely useful in predicting tumor regression [5]. In 2000, Crook et al. [6] published their prospective study results on 978 sequential prostate biopsies after external beam radiotherapy in 498 men. This study was done to determine the time to histologic regression and to correlate biopsy results withpsa and clinical outcome. Six biopsy cores were taken 1 year after radiation therapy and repeated every 6±12 months if residual tumor was present. In patients withnegative rebiopsies, the rebiopsy was repeated after 3 years. A positive biopsy in conjunction witha rising PSA was considered

3 P. Hammerer et al. / European Urology Supplements 1 (2002) 83±88 85 as local failure and no further biopsies were performed. In patients where systematic failure was observed no rebiopsies were repeated. Median time of the rst biopsy was 13 months (n ˆ 498), for the second biopsy 28 months (n ˆ 342), for the third biopsy 36 months (n ˆ 110), for the fourth biopsy 44 months (n ˆ 28) and for the fth biopsy 55 months (n ˆ 4). Biopsies were evaluated with immunohistochemistry for PSA, high molecular weight keratin and proliferative cell nuclear antigen (PCNA) or Mib-1. Radiation therapy effects on residual tumor cells were graded as negative, positive or intermediate. Failures were classi ed as local, distant, biochemical or biopsy only. In patients withnegative post-radiotherapy biopsies, 19% progressed to local failure on subsequent rebiopsies. This reversion from negative back to positive was detected at a mean time of 43 months after radiotherapy. A false positive biopsy withdelayed tumor regression was observed in 81 patients who showed residual tumor on their rst post-treatment biopsy with conversion to a negative biopsy and NED at a mean time of 30 months. The proportion of intermediate biopsy results decreased from 33% at the rst biopsy to 7% for the fourth biopsy. The histological degree of radiation therapy effects did not predict outcome in intermediate biopsies. In patients withintermediate biopsies, 30% cleared to NED, 18% progressed to local failure and 34% remained as biopsy failure; in the remainder, intervention for distant failure curtailed further observation of the local situation. Positive staining for proliferation markers was associated withsubsequent local or distant failure. Crook concluded that systematic post-radiotherapy biopsies help to de ne failure patterns, however, routine post-radiotherapy biopsies should not be considered necessary in the follow-up of individual patients and are only indicated if radical local salvage is an option [6]. In a small series published by Dugan et al. [19], 37 men withinitially stage T3 prostate cancer and interval since treatment of 24 months or more underwent postirradiation biopsy. Patients withevidence of local failure or hormonal therapy were excluded from this study. Thirty-one patients received one biopsy per lobe; six patients had multiple biopsies. Of 37 patients 38% had positive post-irradiation biopsies. In respect to pretreatment tumor grade 22% of patients withwell or moderately differentiated cancers had positive biopsies compared to 64% in patients withpoorly differentiated cancers. Serum PSA level at the time of the post-irradiation biopsy had a strong impact on biopsy results. In patients witha PSA serum level of 2.5 ng/ml 21% of biopsies were positive compared to 71% positive biopsy rate in patients withserum PSA level 2.5 ng/ml (p < 0:02). In patients withpsa serum levels <1.0 ng/ml the positive biopsy rate was 8%. 3. Positive biopsies after seed implantation In 1992, Kuban et al. [11] reported the results on post-treatment biopsies in patients treated by iodine- 125 interstitial implants and external beam irradiation. Ninety-four of the patients with clinically negative post-treatment examination and no symptoms for local recurrence underwent needle biopsies at least 18 months after treatment. Positive biopsies were found in 10 of 55 patients and correlated withstage and grade. Clinical local failure developed in 53% of patients with a positive biopsy compared to 24% of patients in whom the biopsy was reported as negative. This high false negative rate may be due to inhomogeneous dose distribution of the implantation technique allowing for a greater sampling error. Distant metastasis developed in 71% of patients witha positive biopsy compared to 35% of patients witha negative biopsy. Prestidge et al. [20] analyzed 361 biopsy specimens taken after 12 months post iodine-125 or palladium- 103 or a combination of implants withexternal beam radiation. Patient selection included early stage, low volume disease and excluded stage T3 disease. A total of 201 out of 402 treated patients were biopsied. Of the biopsies performed, 78% of biopsy specimens were negative, 20% had histological features of residual prostate cancer, but withradiation effect and were therefore classi ed as intermediate, and 2% were positive. At the time of the last biopsy 80% had achieved a negative pathology with a median followup of 30.8 months. Of 16 patients with biochemical progression who underwent rebiopsies, only 5 were graded as positive, 1 as intermediate and 10 as negative. This may re ect some false negative biopsies or systematic relapse withlocally controlled disease. Pretreatment Gleason score or stage were not signi cantly different in patients withpositive or negative biopsies. PSA correlated withpost-implant biopsy status. Median PSA at rebiopsy, nadir PSA and time to nadir for patients withnegative biopsies was 0.2 ng/ ml, 0.1 ng/ml and 30.5 months, respectively compared to 8.1 ng/ml, 1.6 ng/ml and 16.6 months, respectively in patients withpositive biopsies (Table 2). Stock et al. [21] reported on 268 patients treated with permanent implants for T1 to T2 prostate cancer. Postimplant biopsies with6±8 cores were performed after 2 years. Pretreatment Gleason score 6 was observed in 92% of patients. Hormonal therapy was administered to

4 86 P. Hammerer et al. / European Urology Supplements 1 (2002) 83±88 Table 2 Correlation of post-treatment biopsy results withpsa levels and PSA nadir levels Median PSA/median nadir PSA (ng/ml) Negative biopsy Positive biopsy 0.2/ /1.6 [20] 1/ /1.3 [17] 0.9/± 14.2/± [19] ±/0.65 ±/1.1 [6] 98 patients with high risk features. Biochemical failure rate at 2 years was 18% for the entire group. The authors found a positive biopsy rate of 11%. Patients with a positive biopsy had a 60% biochemical failure rate compared to 24% for patients withnegative biopsies. In the univariate and multivariate analysis was shown that pretreatment Gleason score, stage and PSA as well as hormonal therapy and implant dose affected biopsy results. Patients receiving high dose radiation had a signi cant lower rate of positive biopsies compared to patients receiving a low dose radiation (5% versus 23% positive biopsies). A multivariate analysis demonstrated that risk group, Gleason score and D90 signi cantly correlated withbiopsy results. The use of hormonal therapy was associated with a 2% positive biopsy rate compared with16% for seeds alone. Similar results were reported by Sharkey et al. [22] who found an 11% positive biopsy rate at 2 years in 151 patients treated with103pd implants. These data show that positive post-irradiation biopsies are associated withprogression and PSA recurrence in the majority patients. 4. Effect on timing of rebiopsy results Reference In 1977, Cox and Stoffel [12] reported that the incidence of positive biopsies decreased withan increasing interval of time, from 60% at 6 months post-treatment to 19% at 30 months post-treatment. This observation was con rmed by Scardino and Wheeler [23]. Scardino reported on 140 patients who had one or more needle biopsies after radiation witha mean follow-up of 8.6 years. Thirty-two percent of his patients with a positive biopsy at 12 months had a negative biopsy at 24 months. In the series published by Crook et al. [14] on 861 sequential prostate biopsies after external beam radiotherapy repeated biopsies were performed in patients withevidence of residual cancer on biopsies after 12± 18 months. In two-thirds of these patients repeated biopsies at 28 months showed no signi cant proliferation based on immunohistochemical staining. Forman et al. [18] performed rebiopsies at 6 and 12 months post-radiation. They could show that 50% of patients had a positive rebiopsy rate at 6 months, whereas this rate dropped to 30% after 12 months. It was therefore recommended that biopsies after irradiation should be performed at least 18±24 months post-treatment to be prognostically signi cant [5]. 5. Effect of neoadjuvant androgen deprivation In most series use of hormonal treatment affected post-radiation biopsy results [5,18,21,24]. Laverdiere et al. [24] analyzed biopsy results in a prospective trial comparing external beam radiation therapy (EBRT) alone (group 1), with 3 months of neoadjuvant hormonal therapy prior to EBRT (group 2) or in combination withneoadjuvant and adjuvant hormonal therapy (group 3). Positive biopsy results after 12 months were found in 62, 30 and 4%, respectively ( p ˆ 0:00005). Similar results were reported by Zelefsky et al. [17] and the Wayne State group who found a signi cantly decreased positive rebiopsy rate in patients treated with hormonal therapy whereas the rate of biochemical failure was similar [5]. Gaudin et al. [25] compared post-radiation biopsy ndings in patients receiving 3D conformal external beam radiation therapy (3DCRT ) with or without 3 months of neoadjuvant androgen deprivation therapy (ADT). The use of neoadjuvant ADT had a signi cant impact on the results of post-radiation biopsy. Of the 31 patients treated withneoadjuvant ADT, 28 (90%) had post-radiation biopsies showing radiation therapy effect compared to only 62 of 106 men (59%) treated with3dcrt alone ( p ˆ 0:004). Stock et al. [21] found a positive biopsy rate of 2% in patients receiving hormonal therapy. However, these positive biopsy rates are lower compared to the progression rate. Hormonal therapy may alter the architecture of residual prostate cancer, which will in uence pathological evaluation. Whether adjuvant or neoadjuvant hormonal treatment might alter overall survival remains controversial [26,27]. 6. Histological and cytological grading after radiation The degree of radiation therapy effect may help to interpret the biopsy ndings. Because of dif culties in interpreting post-irradiation biopsies, use of staining

5 P. Hammerer et al. / European Urology Supplements 1 (2002) 83±88 87 against high molecular weight keratin, PSA or proliferative cell nuclear antigen has been proposed [13,14,25]. The Gleason scoring system may be inappropriate to describe the degenerated tumor remnants [14]. In biopsies withmoderate to marked radiotherapeutic effects Gleason scoring should be avoided because the observed glandular disintegration may mimic a high Gleason score. Radiation appears to cause enlarged or pyknotic nuclei withrupture of cell membranes [13,28]. Th e number of glands may be decreased witha more haphazard gland arrangement. Similar changes may be observed after hormonal treatment, which also will induce cytoplasmatic vacuolation and nuclear pyknosis. Radiation effect can be classi ed according to cytoplasmatic and nuclear changes. Dhom and Degro [28] analyzed 1138 prostate biopsies after radiation therapy of hormonal therapy and applied a score of 10 points to divide the histopathologic regression into three gradings: pronounced, moderate, and poor or no regression. Crook et al. [14] published their results on 89 selected patients withresidual tumor in one or more biopsies at 10±78 months of follow-up. They performed a separate grading from 0 to 3 for cytoplasmatic and nuclear changes and added both scores together to give a combined score from 0 to 6 (Table 3). In patients withpositive biopsies, a mean score of 3.3 was found which did not change with time. However, in 19% of patients an increase of the radiotherapy effects was noted, 35% remained stable and a decrease was observed in 46%. The observed decrease in histological radiotherapy effects was seen in adjacent areas within the same biopsy. Patients withsuchvariable scores had a local failure rate of 41% compared to 18% of those with stable histopathological scoring [14]. 7. Possible implications for positive post-radiation biopsies PSA progression following radiotherapy indicates local recurrence, metastatic disease or both. In patients withno evidence of systematic disease and residual carcinoma in a post-irradiation biopsy performed after 24±36 months local failure can be assumed. The surgical treatment options for clinical local failure include radical prostatectomy, cystoprostatectomy or pelvic exenteration, however associated morbidity remains high [29,30]. Other treatment Table 3 Grading scheme for cytoplasmatic and nuclear radiation therapy (RT) effect [14] Cytoplasmatic changes 0 No identi able RT effect 1 Swelling and microvesicular changes 2 Extensive vacuolation, voluminous cytoplasm 3 Indistinct or ruptured cytoplasm, lipofuscin pigment accumulation Nuclear changes 0 No identi able RT effect 1 Some swelling or smudging of nuclei 2 Smudged and distorted chromatin rare nucleoli, large nuclei 3 Pyknotic, small nuclei options are salvage cryotherapy or endocrine treatment [15,31]. Since local failure occurs more often in patients with advanced stage and higher tumor grades, the chance of cure by salvage treatment is low [15]. However, for patients withclinically localized disease and a life expectancy of 10 years or longer early proof of local recurrence may identify a subgroup of patients who could be cured by salvage surgical treatment. Preradiation PSA as well as post-radiation PSA serum level before salvage surgery correlate with pathological stage and progression-free survival, but no clear cut-off serum level has been established [15]. The rate of organ-con ned disease after salvage surgery has ranged from 30 to 67% with disease-free survival rates of 30±60% [15,29,32]. Within the last years the incidence of complications like rectal injury, postoperative urinary incontinence or anastomotic strictures after salvage surgery has decreased [15,29,32]. Salvage surgery should therefore be considered in appropriate patients withradioresistant prostate cancer and biopsy proven local recurrence (Table 3). 8. Conclusion Systematic prostate rebiopsies are not necessary in the follow-up of prostate cancer patients after radiation therapy. Results from prostate rebiopsies do not add additional information to the data provided by PSA measurements. However, in patients withrising PSA who are candidates for local salvage treatment, local persistence of cancer can be evaluated by rebiopsies. In addition, prostate rebiopsies may be an important researchtool to analyze progression markers to study development of distant metastasis or resistance to local therapy.

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