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2010 THE AUTHORS. JOURNAL COMPILATION Urological Oncology 2010 BJU INTERNATIONAL INDEX LESION AND FOCAL THERAPY IN PROSTATE CANCER BOTT ET AL. BJUI The index lesion and focal therapy: an analysis of the pathological characteristics of prostate cancer BJU INTERNATIONAL Simon R.J. Bott, Hashim U. Ahmed*, Richard G. Hindley†, Ahmad Abdul-Rahman*, Alex Freeman‡ and Mark Emberton* Frimley Park Hospital NHS Foundation Trust, *Division of Surgery and Interventional Sciences, University College, Frimley, Surrey, London/NIHR University College Hospital Comprehensive Biomedical Research Centre, London, † North Hampshire and Basingstoke NHS Foundation Trust, Basingstoke, Surrey, and ‡Department of Histopathology, University College Hospital NIHR Comprehensive Biomedical Research Centre, London, UK Accepted for publication 18 February 2010 OBJECTIVE RESULTS To determine the pathological characteristics of radical prostatectomy specimens with respect to index and secondary lesions. Overall, 374 foci were examined. The median number of tumours per patient was 3.5 (range 1–15). The overall median tumour volume was 1.4 mL (range 0.1–18.2), the median volume of the largest (index) tumour was 0.95 mL (range 0.1–18.2) and the median volume of the largest secondary tumour was 0.2 mL (range 0.05–1.7). There were no patients in whom the index lesion was insignificant and secondary tumours were significant (by grade or extra-capsular disease). Seventy-seven fulfilled the clinical parameters of low-to-intermediate-risk disease. If focal therapy can be delivered with the aim of ablating all clinically significant disease, with untreated areas harbouring no cancer or clinically insignificant disease, between 58.5 and METHODS A total of 100 consecutive radical prostatectomy specimens examined at a single hospital were assessed. Patients undergoing salvage prostatectomy or those who had received neoadjuvant hormonal manipulation were excluded. Preoperative data and the number, volume and Gleason grade of each tumour focus were recorded. Criteria used to define a clinically significant lesion were tumour volume ≥0.5 mL and/or Gleason pattern 4 or 5 and/or extra-capsular disease. INTRODUCTION The incidence of prostate cancer has tripled in the last three decades as a result of greater public awareness, more men undergoing PSA testing and higher cancer detection rates from the intensification of biopsy strategies. The earlier detection has resulted in a well documented downward migration of both stage and grade [1,2]. The effect of this stage migration has been to reduce the burden of disease at the time of diagnosis. Men diagnosed as a result of a slightly higher PSA level are likely to have disease localized to the prostate and have an mean of between one and three cancer foci, of which the largest © accounts for 80–90% of the tumour volume. The total mean cancer volume occupies no more than 5–10% of the volume of the prostate [3]. This observation has led a number of investigators to evaluate the feasibility and utility of treating all the cancer as opposed to the whole of the prostate. This novel approach, which has been given the term focal therapy, has been proposed and discussed by several groups and has been accepted as one of the key research questions in the field of prostate cancer [4–7]. Several authors have already looked at radical prostatectomy specimens to determine what 67.5% might have been suitable for such a strategy. CONCLUSIONS The proportion of men with low-tointermediate-risk prostate cancer who may potentially be suitable for a focal therapy approach is unknown. The key question is whether the volume of individual lesions points to clinically significant cancer and whether ablation of these lesions alone would lead to cancer control. This research question is currently undergoing evaluation within a prospective clinical trial. KEYWORDS prostate cancer, risk stratification, multifocal, index lesion, focal therapy proportion of patients might be amenable to focal therapy [8]. Nearly all of these studies have taken a very absolute definition of focality and, as a result, have taken the view that any patient with a secondary or contralateral cancer focus would be ineligible for focal treatment. Our own analysis, presented in this paper, adds to this work by asking a similar question about eligibility, but departs from previous research by imposing thresholds of clinically important disease rather than taking the presence or absence of any measurable disease as the key determinants of who should and should not be eligible for a treatment that aims to preserve prostate tissue. 2010 THE AUTHORS JOURNAL COMPILATION © 2 0 1 0 B J U I N T E R N A T I O N A L | 1 0 6 , 1 6 0 7 – 1 6 11 | doi:10.1111/j.1464-410X.2010.09436.x 1 6 07 B OT T ET AL. METHODS The pathological details of 100 consecutive patients who underwent open radical prostatectomy were extracted from a radical prostatectomy database held in one centre between 2003 and 2004. Each radical prostatectomy specimen was embedded and processed as previously described [3]. Patients who had received neoadjuvant androgen suppression therapy or who had undergone salvage radical prostatectomy were excluded. The corresponding biopsy and radical prostatectomy reports and, where necessary, the whole mounts were extracted and reexamined. The preoperative features, including the PSA level, the percentage of biopsy cores and the biopsy Gleason score were collated. From the radical prostatectomy specimen, the total number of tumour foci and the volume, stage and Gleason grade of each focus were recorded. Significant tumour foci were defined using either tumour volume ≥0.5 mL, presence of any Gleason pattern 4 or 5 or evidence of extra-capsular disease [9]. To be able to generalize the results of the present study to other series, we undertook a separate analysis of patients who conformed to a low-to-intermediate-risk population based on preoperative variables (TRUS-guided biopsies and clinical/radiological staging). Patients who conformed to the following criteria on preoperative variables were attributed a low-to-intermediate risk: PSA ≤20ng/mL, Gleason score ≤7 or ≤66% of the cores declared positive [10,11]. RESULTS Table 1 lists the patient characteristics of the 100 men who underwent radical prostatectomy. A total of 374 tumour foci were examined. The median number of tumour foci per patient was 3.5 (range 1–15). The overall median tumour volume was 1.4 mL (range 0.1–18.2), the median tumour volume of the index tumour (largest focus) was 0.95 mL (range (0.1–18.2) and the median volume of the largest secondary tumour was 0.2 mL (range 0.05–1.7). The index lesion comprised a mean of 73% (SD 25) of the total tumour volume. Overall, clinically significant prostate cancer was found in 89% of patients. In addition, there were no cases where the index lesion was insignificant and the secondary tumours significant (by grade or extra-capsular disease). Specimen-confined 1608 TABLE 1 Baseline demographics and tumour characteristics at radical prostatectomy for 100 men with prostate cancer Variable Mean (SD) age, years Median (range) PSA, ng/mL Median (range) % of positive cores Biopsy Gleason grade Value 61 (±3.5) 8.0 (0.7–33) 25% (10–100%) 68 20 7 5 3.5 (1–15) 13 14 1.4 (0.1–18.2) 83 60 44 89 21 19 6 16 36 3+3 3+4 4+3 4+4 Median (range) number of tumours Overall tumours Secondary tumours Unilateral Unifocal Median (range) volume, mL Volume ≥0.5ml Grade >3 + 3 Stage >T3a Total significant index Median volume, mL Volume ≥0.5 mL Grade >3 + 3 Stage >T3a Total significant secondary disease was found in 70% (59/84) of patients with multifocal disease (46 with pT2 and 13 with pT3a-negative surgical margin disease). Including cases with unifocal disease, a total of 56 patients had organ-confined disease and 71 had specimen-confined disease. two by stage alone. There were no patients who had more than one significant secondary tumour. Fifteen patients had unilateral cancer with one or more foci. A single focus of adenocarcinoma (unifocal) was identified in 16 patients (one patient had unifocal disease where the tumour crossed the midline). The pathological stages in this unifocal group were pT2 (10/16), pT3a (4/16; two specimenconfined, two with positive postero-lateral surgical margins), pT3b (1/16) and pT4 (1/16) – 12/16 had specimen-confined disease. A total of 77 men fulfilled the criteria of lowto-intermediate-risk prostate cancer based on preoperative variables (Table 2). In low-tointermediate-risk patients, 51 had pT2 disease, 16 had pT3a disease (12 with negative surgical margins), three had pT3b disease and seven had pT4 disease. Overall, 63 (82%) had specimen-confined disease. The median number of tumours was four (range 1–11), which was similar to the whole cohort; 14 had unifocal disease and 13 had unilateral prostate cancer. Significant prostate cancer was found in 70 (90%) patients; the number of patients with significant secondary foci was 19 (25%) compared with 36 (36%) for the whole cohort. In 84 specimens with multifocal prostate cancer, 36 had significant secondary tumours. The secondary tumour was significant by volume (≥0.5 mL) in 21, by grade (any pattern 4 or 5) in 19 and by stage (extra-capsular extension) in six (Fig. 1). In five specimens, both the volume of the tumour and the Gleason grade were clinically significant; in three both the volume and stage were significant; and in one the volume, grade and stage were significant. In 12 patients, the secondary tumour was significant by volume alone, in 13 by Gleason grade alone and in LOW-TO-INTERMEDIATE-RISK GROUP A total of 11.7% (9/77) had unilateral disease with absence of any cancer on the contralateral side; 41/77 had multifocal disease, with 33/41 having an index lesion in one lobe with clinically insignificant secondary tumours in the contralateral lobe. In the 8/41 with clinically significant © JOURNAL COMPILATION © 2010 THE AUTHORS 2010 BJU INTERNATIONAL INDEX LESION AND FOCAL THERAPY IN PROSTATE CANCER FIG. 1. Significant secondary tumours by volume, grade and pathological stage. Tumour volume ≥ 0.5 mL n = 21 Gleason grade > 6 n = 19 secondary tumours, three (out of 13) were significant by volume alone (all three contralateral) and 10 were significant by grade alone (eight contralateral, two ipsilateral). DISCUSSION n=5 n = 12 SUMMARY OF RESULTS n = 13 Of 100 consecutive men who underwent radical prostatectomy for prostate cancer, 77 fulfilled the clinical variables of low-tointermediate-risk disease. Within this group, if only specimen-confined pT2 disease was considered, 11.7% (9/77) may have been suitable for hemi-ablation of the affected lobe with absence of any cancer in the contralateral lobe. This proportion was 15.6% (12/77) if specimen-confined pT2/T3a was considered for focal therapy. n=1 n=3 n=0 n=2 Stage > pT2 n=6 TABLE 2 Baseline demographics and tumour characteristics at radical prostatectomy for 77 men with low-to-intermediate-risk prostate cancer Variable Mean (SD) age, years Median (range) PSA, ng/mL Median (range) % of positive cores Biopsy Gleason grade 3+3 3+4 4+3 Median (range) number of tumours Unilateral Unifocal Volume ≥0.5 mL Grade >3 + 3 Stage >T3a Total significant index Volume ≥0.5mL Grade >3 + 3 Stage >T3a Total significant secondary Index tumour Secondary tumours secondary tumours, two were significant by volume (one contralateral, one ipsilateral) and six were clinically significant by Gleason score (four contralateral, two ipsilateral). None of the eight was clinically significant by both grade and volume. No secondary tumours were extra-capsular in the low-to- © Value 60 (± 0.7) 8.0 (0.7–17.9) 25% (8–60%) 62 12 3 4.0 (1–11) 13 14 57 41 26 70 9 12 4 19 intermediate-risk group with multifocal disease. Taking the group of patients with pT2/T3a disease that was specimen-confined, 51 had multifocal disease; 38/51 had insignificant secondary tumours. Of those with significant If a hemi-ablation plan was used to ablate the side in which the index lesion was situated and there was clinically insignificant disease on the contralateral lobe (absence of Gleason pattern 4; lesion volume ≤0.5 mL) with overall specimen-confined pT2 cancer, then 46.8% (36/77) would, in addition, be suitable for focal therapy. If specimen-confined pT2/T3a was considered, this proportion would be 51.9% (40/77). Focal therapy can be delivered with the aim of ablating all clinically significant disease, with untreated areas harbouring no cancer or clinically insignificant disease that would then undergo surveillance. In this retrospective cohort that have already undergone radical prostatectomy, we have found that, of the low-to-intermediate-risk group, between 58.5 and 67.5% may have been suitable for such a strategy. METHODOLOGICAL LIMITATIONS Before considering the implications of the findings of the present study in relation to the case selection for patients for focal therapy, a number of methodological issues require some attention. First, patients undergoing radical prostatectomy are not necessarily representative of all patients who are seeking treatment as a result of a diagnosis of prostate cancer. Patients who have radical prostatectomy have been selected as suitable for radical surgery. It is not clear whether they represent a spectrum of patients with more or 2010 THE AUTHORS JOURNAL COMPILATION © 2010 BJU INTERNATIONAL 1609 B OT T ET AL. less advanced disease than those who would be seeking a focal treatment as a result of today’s stage and grade migration. What we can say is that the characteristics of patients in our cohort are not too distinct from other published cohorts [9]. The second issue relates to the sampling frame. Although radical prostatectomy stepsection histopathology is regarded as the reference standard in studies such as this, it remains subject to sampling and processing error. In this series, step-sectioning of the prostate was performed at 5-mm intervals, in line with the standard method for assessing radical prostatectomy specimens [12]. Furthermore, during the preparation of a whole-mount slide, the tissue block is ‘trimmed’ to achieve a ‘full face’, with subsequent loss of prostate tissue for analysis. Both step-sectioning and trimming can result in an under-estimate of the number and volume of tumour foci. However, these inaccuracies are likely to be small and probably of little clinical consequence. The third methodological issue relates to inter-observer agreement on precisely what constitutes a tumour focus. There appears to be no agreement as to how the status of ‘focus’ should be conferred. On axial orientation the cross-sectional area of a ‘focus’ may be influenced by the presence of normal tissue within it. Contouring is the usual process whereby the pathologist defines the limits of the foci in the X- and Y-planes. This contouring is subjective and probably – as it has not been tested – varies between departments and between pathologists. The derivation of the Z-plane is subject to sampling error that is dependent upon the thickness of each section. The issue of adjacency remains problematic. In the present study, where one tumour focus overlay a focus on a more caudal or cephalic wholemount slice, a single focus was recorded, and where there was no overlay, the tumours would be counted as separate foci. All these errors influence the volume and number of foci that are declared in any one prostate. IMPLICATIONS Despite these limitations we feel that the findings of the present study do indicate that focal therapy may be feasible in a substantial proportion. Other series, when considering a hemi-ablative focal strategy, have concluded that about one-third of patients may be 1610 suitable [7,8]. Most studies of this type have limited their discussion to the presence or absence of any cancer. We have, instead, sought to define tumour volumes and Gleason grading in an attempt to classify lesions as either clinically important or otherwise. This approach is not unreasonable given what we know about the natural history of prostate cancer. Most men will develop prostate cancer in their lifetime [13] and the vast majority will harbour insignificant lesions. Men with insignificant disease are not likely to benefit from curative therapy and, as a result, will only experience harm if subjected to treatment. However, the definition of clinically significant disease has not been agreed. There are many definitions, most of which represent a small departure from that proposed by Epstein. For this definition, it was found that in those patients with organconfined disease at radical prostatectomy, a tumour volume <0.5 mL and a Gleason pattern ≤3 had a very low chance of future progression [10]. Other researchers have taken this further and proposed that the index lesion alone may drive progression [4,14]. Whilst much more work needs to be done to explore and understand the biology of the different tumour foci, clinical studies are also vital. Focal therapy that targets only the index lesion in addition to any other adjacent foci that are deemed to be clinically important, and leaves small ‘clinically insignificant’ lesions that may be sub-clinical in many cases, may allow a greater number of individuals to consider this kind of treatment [15]. The other implication of our findings has now been well recognised by others [16]. We have shown that the preoperative prediction of patients suitable for focal therapy is problematic when reliance is placed on standard TRUS-guided biopsies. Sampling error is greater if tumours are situated in the anterior or apical zones [17], where grade variation exists within a single focus and in multifocal tumours [13]. Attempts have been made to aid the prediction of multifocal disease using PSA level, but neither PSA level nor PSA density is able to predict unifocality or multifocality [18]. Accurately identifying all significant tumour foci using template-guided biopsies [19] and/ or multi-functional MRI [20] will be needed if patients are to be selected with any degree of precision for prostate tissue-preserving therapy. CONCLUSIONS The increasing incidence of men with low-tointermediate-risk prostate cancer, and the realization that in most men such disease is clinically insignificant and unlikely to have an impact on life expectancy, has meant a shift in emphasis from radical treatments to less invasive alternatives with less impact on quality of life. The multifocality of prostate cancer and the ability to identify and selectively treat prostate cancer foci have hampered focal therapy to date. Increasingly, imaging and biopsy strategies are evolving to accurately identify significant tumour foci within the prostate. Furthermore, tools to treat discrete areas of the prostate are being used to successfully ablate regions of the prostate, preserving normal adjacent structures critical to the preservation of urinary, bowel and erectile function. The present study shows that, while most radical prostatectomy specimens contain multiple tumour foci, a third have organ-confined disease and insignificant secondary tumour foci. Carefully designed clinical trials are needed to assess the long-term outcomes when either all significant lesions are targeted or an index-lesion-only ablative strategy is used with surveillance of clinically insignificant lesions. ACKNOWLEDGEMENTS Mark Emberton is funded in part by the NIHR UCLH/UCL Comprehensive Biomedical Research Centre. Hashim U. Ahmed holds an MRC Clinical Fellowship award. We are grateful to the Pelican Cancer Foundation, Prostate Research Campaign (Prostate UK), St Peters Trust and Prostate Cancer Research Centre charities for their financial support of work in focal therapy. CONFLICT OF INTEREST Hasmid U. Ahmed declares a conflict of interest due to USHIFU, MISONIX, UKHIFU and STEBA BIOTECH. Mark Emberton declares a conflict of interest due to funding from AMD, MISONIX, USHIFU and STEBA BIOTECH. Source of funding: MRC, Pelican Cancer Foundation, Prostate UK, St Peters Trust, Prostate Cancer Research Foundation, Prostate Cancer Research Centre (all charities). © JOURNAL COMPILATION © 2010 THE AUTHORS 2010 BJU INTERNATIONAL INDEX LESION AND FOCAL THERAPY IN PROSTATE CANCER REFERENCES 1 2 3 4 5 6 7 © 8 Gallina A, Chun FK, Suardi N et al. Comparison of stage migration patterns between Europe and the USA: an analysis of 11 350 men treated with radical prostatectomy for prostate cancer. BJU Int 2008; 101: 1513–8 Bott SR, Freeman AA, Stenning S, Cohen J, Parkinson MC. Radical prostatectomy: pathology findings in 1001 cases compared with other major series and over time. BJU Int 2005; 95: 34–9 Wise AM, Stamey TA, McNeal JE, Clayton JL. Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens. 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Clin Oncol 2009; 6: 197–206 Correspondence: Hashim Uddin Ahmed, Division of Surgery and Interventional Science, c/o National Medical Laser Centre, 67 Riding House Street, London, W1P 7NN. e-mail: [email protected] 2010 THE AUTHORS JOURNAL COMPILATION © 2010 BJU INTERNATIONAL 1 6 11