Serum PSA, Gleason Score and Clinical Staging in Predicting Biochemical (PSA) Failure After Radical Prostatectomy for Carcinoma of Prostate

Article ID: WMC003222 ISSN 2046-1690 Serum PSA, Gleason Score and Clinical Staging in Predicting Biochemical (PSA) Failure After Radical Prostatectomy for Carcinoma of Prostate Corresponding Author: Mr. Anthony Kodzo - Grey Venyo, Urologist, Urology Department. North Manchester General Hospital - United Kingdom Submitting Author: Mr. Anthony Kodzo - Grey Venyo, Urologist, Urology Department. North Manchester General Hospital - United Kingdom Article ID: WMC003222 Article Type: Audit Submitted on:10-apr-2012, 03:21:05 AM GMT Article URL: http://www.webmedcentral.com/article_view/3222 Subject Categories:UROLOGY Published on: 10-Apr-2012, 05:42:19 PM GMT Keywords:Adenocarcinoma, Prostate, Radical Prostatectomy, PSA, Gleason score, Stage, Biochemical Failure How to cite the article:venyo A, Imran S, Shah S, Gordon R, Barnes D. Serum PSA, Gleason Score and Clinical Staging in Predicting Biochemical (PSA) Failure After Radical Prostatectomy for Carcinoma of Prostate. WebmedCentral UROLOGY 2012;3(4):WMC003222 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: 0 Competing Interests: None Additional Files: Serum PSA, Gleason Score and Clinical Staging in p WebmedCentral > Audit Page 1 of 26

Serum PSA, Gleason Score and Clinical Staging in Predicting Biochemical (PSA) Failure After Radical Prostatectomy for Carcinoma of Prostate Author(s): Venyo A, Imran S, Shah S, Gordon R, Barnes D Abstract Introduction Background: It has been suggested that pre-operative serum PSA, Gleason Score of the tumour as well as stage of the tumour may predict the possibility of PSA (Biochemical) recurrence after radical prostatectomy for localized prostate cancer. Aims: To investigate and to confirm the relationship between biochemical failure rates with regard to: serum PSA levels; Gleason score of prostate biopsy and radical prostatectomy specimens; and Stage. Patients and Methods: Records of the first 50 patients who had undergone radical prostatectomy for localised prostate cancer between December 1999 and January 2006 were reviewed to ascertain the PSA failure rates of the aforementioned groups. Analysis of outcome was done using sure start to determine if the differences in outcome were significant. Results: Total 11 out of 50 patients (22%) had PSA failure. PSA: 11%, 40%, and 60% of patients in the 10-20 ug/l, and >20ug/L groups respectively developed PSA failure. Gleason score of prostate biopsy specimens: 21.9%, 13.3%, and 100% of patients with tumours scored as Gleason?6, 7, 8-10 respectively had PSA failure. Gleason score of radical prostatectomy specimens: 17%, 20%, and 50% of patients with tumours scored as Gleason?6, 7, 8-10 respectively had PSA failure. Stage of tumour: 4%, 0%, and 43% of patients whose tumours were staged T1-2a, T2b,and T2c-T3 had PSA failure. Statistical analysis has shown that the differences in the outcome of the PSA, stage, and Gleason score of the using the radical prostatectomy specimens was significant. Conclusions: PSA failure rate is higher with higher: serum PSA; Gleason score; and stage. However, individually serum PSA, Gleason score and stage of tumour cannot be used to clearly predict PSA failure. Radical prostatectomy is one of the treatment modalities available for localized prostate cancer with curative intent. Radical prostatectomy which has been available for many years now, is the widely accepted gold standard treatment modality for localized adenocarcinoma of prostate. Radical prostatectomy is usually carried out in specialised Urology Centres. Prior to 1999 Radical Prostatectomy had not been carried out in North Manchester General Hospital in the United Kingdom (The first Radical Prostatectomy was performed in North Manchester General Hospital in 1999). Despite the aim of curative intent of radical prostatectomy some patients subsequently develop biochemical failure post radical prostatectomy and would require further additional alternative treatment. It is generally accepted that individually pre-operative serum Prostate Specific Antigen (PSA) levels, the Gleason score, and clinical stage of the tumour are predictors of PSA / Biochemical recurrence in that patients with localized prostate cancer who have high serum PSA, high Gleason score or higher stage of tumour would be the patients who are likely to develop biochemical failure pursuant to their operations. Patients Materials and Methods Patient population The study population comprised of the initial 50 consecutive men who underwent radical retro-pubic prostatectomy and bilateral pelvic lymph node dissection at North Manchester General Hospital in United Kingdom between 1999 and 2006. Serum PSA levels of all the patients were quantitated using the Abbot Architech assay technique before their pre-operative trans-rectal ultrasound scan biopsies and post operatively after one month, 3rd month and at 6 monthly intervals just before or at each out patients clinic follow-up attendance. In cases of possible post operative serum PSA elevations the serum PSA levels were determined at more frequent WebmedCentral > Audit Page 2 of 26

intervals. Pre-treatment staging A clinical stage was originally assigned pre-operatively in accordance with the 1992 version of unified tumour node metastasis (TNM) system [1]. All patients underwent digital rectal assessment of their prostates in the out-patient clinic and in the day-service unit at the beginning of their trans-rectal ultrasound scan and biopsies of their prostate glands. Details of the trans-rectal ultrasound of prostate findings were carefully recorded; details of the histology reports as well as details of the patients CT scan/magnetic Resonance Imaging (MRI) scans were also recorded and taken into consideration in the staging of the tumours. Pathological examination All hematoxylin and eosin (H&E) pathological slides of radical prostatectomy specimens were examined by a consultant pathologist with an interest in Urology. The tumour grading was determined based upon the Gleason grading system. The extent of the tumour was determined according to the recommendations of the Royal College of pathologists of the United Kingdom. The capsule of the prostate on each side was carefully examined microscopically for evidence of penetration of cancer through the surface of the prostatic capsule (extra-capsular extension). The seminal vesicles were examined for evidence of tumour involvement; the nodes were examined to confirm or negate nodal involvement of tumour. The status of the surgical margin was also assessed for presence or absence of tumour. Follow-up After the radical prostatectomy, all the patients were reviewed initially in the out-patients clinic within two to four weeks by which time the histology reports of the radical prostatectomy specimens have been received and discussed at the Urology Multi-Disciplinary Team meeting. At the first post-operative review the histology report was discussed with the patients including further follow-up and management plan that was recommended by the Multi-Disciplinary Team. All patients had their serum PSA checked. The patients were then reviewed at 3 months and then at 6 monthly intervals after that. At each review the patients clinical histories were taken to ascertain whether or not they had any complications including voiding symptoms; erectile dysfunction; incontinence and back ache. The serum PSAs were also checked at each visit. The plan for all patients was in case any patient had a serum PSA greater that 20 ug/l then isotope bone scan was done. However, no patient had PSA level higher than 20 ug/l. Post operative serum PSA values were considered elevated (PSA failure / biochemical failure) if values of 0.2 ug/l or greater were obtained on two consecutive visits 1 month apart. In the case when the serum PSA never became undetectable post-operatively, then biochemical failure was considered to have occurred at time zero. Data Collection The 4th author was the only surgeon who performed all the retro-pubic radical prostatectomy operations. The first author assisted in less than 10 of the operations. The audit study was designed by the first and 3rd authors. The first author explained the Gleason grading system and staging of adenocarcinoma of prostate to the 2nd and third authors who then entered the following data into the audit proforma: patient identity details; presenting symptoms; clinical findings including digital rectal examination findings on first consultation and subsequent follow-ups; the serum PSA results at first consultation and at each follow-up; the trans-rectal ultrasound scan findings and histology results of the prostate biopsies; results of CT/MRI scans done in the pre-operative assessment; records of the intra-operative findings; the histology reports of the radical prostatectomy specimens; the post-operative clinical findings including all serum PSA results at each follow-up and any further investigations and further management; the Gleason score and clinical staging of the trans-rectal prostate biopsy specimens; the Gleason score and clinical staging after taking into consideration the histology report and clinical findings of the prostatectomy specimens and findings. All the recorded data entered by the 2nd and 3rd authors were cross checked in the presence of both the second and 3rd authors after checking the patients case records, serum PSA results and dates as entered in the computerized data, the radiological reports entered in the computerized PACS system, clinical findings entered in the clinical notes and in all letters stored in the computerized ALS system. The Gleason score and clinical stage were accepted by all three authors to be correct as well as outcome of patients with regard to PSA (biochemical failure or non-failure and further management. The duration of follow up of each patient was recorded. All the collected data were submitted to the clinical audit department where analyses of data were done without the knowledge of any of the four authors. Analysis of results: The audit department analyzed the results with regard to outcome in relation to percentage of patients without PSA (biochemical) non failure and PSA failure and further management in: 3 different pre-operative serum PSA groups (PSA< 10 ug/l; PSA >10 20 ug/l; WebmedCentral > Audit Page 3 of 26

3 Gleason score groups of the pre-operative biopsy specimens (Gleason?6, Gleason 7, Gleason 8-10); Gleason score groups of the radical prostatectomy specimens (Gleason?6, Gleason 7, Gleason 8-10); Clinical staging groups of the radical prostatectomy specimens (stages T1 T2a, T2b, T2c-T3); Form of treatment and follow-up time and outcome of all PSA failures were summarized Results 50 patients underwent Radical prostatectomy for localized prostate cancer. They had a follow-up ranging from 4 months to 7 years with a mean follow-up of 28.7 months. The average age range of the patients was 62 years; 1 patient was aged >70 years; 14 patients were aged between 66 and 70 years; 15 patients were aged between 61 and 65 years;13 were aged between 56 and 60 years; 6 were aged between 50 and 55 years; 1 was less than 50 years old. During the period of follow-up 11 patients (22%) developed PSA failure and one of these patients died of his prostate cancer but the remaining 10 patients were free of clinical disease and they were either referred for adjuvant therapy or have been receiving adjuvant therapy. The only patient who died of his prostate cancer was initially treated with radical radiotherapy prior to his radical prostatectomy however, he developed PSA (Biochemical) failure and he then opted to undergo radical prostatectomy. He also continued to be on hormonal treatment but died. With regard to the ten patients who developed PSA failure the outcomes were as follows: One patient developed PSA failure by the 6th post operative period with PSA values of 0.681 ug/l, [ng/ml], and 1.95 ug/l, [ng/ml. He was referred to the Oncologist and has been treated by radical radiotherapy and he is also receiving hormonal therapy. One patient developed PSA failure at 4 months with serum PSA level recorded as: 0.22 ug / L. He was referred to the oncologist and he had undergone radical radiotherapy and is receiving hormonal treatment as well. His last serum PSA was < 0.050 at the time of the study. One patient developed PSA failure at 33 months and has received radical radiotherapy as well as he is on hormonal treatment. His last 3 serum PSAs were One patient developed PSA failure at 4 months post operatively and was referred to the oncologist following which he received radical radiotherapy. His last serum PSA was >0.050 ug/l. One patient developed PSA failure 7 years post operatively and had just been referred to the oncologist. One patient developed PSA failure 4 years post operatively and had just been referred to the oncologist. One patient developed PSA failure 3 years post operatively and was referred to the oncologist following which he received radical radiotherapy. His last 3 serum PSA levels have been: One patient developed PSA failure 8 months post operatively; he was referred to the oncologist and he received radical radiotherapy; his last 2 serum PSA levels were One patient developed PSA failure 2 months post operatively; he was referred to the oncologist and he received radical radiotherapy and is also on hormonal treatment. His last 3 serum PSA levels were One patient developed PSA failure 2 years post operatively; he was referred to the oncologist and he received radical radiotherapy. His last serum PSA was Out of 35 patients with PSAs?6 ug/l, 4 patients (11%) had PSA (biochemical failure) and 35 patients were in the non PSA failure group. Out of 10 patients with pre-operative serum PSAs between 10 and 20 ug/l, 4 had (40%) PSA (biochemical failure and 6 were in the non PSA failure group. Out of 5 patients with pre-operative serum PSAs greater than 20 ug/l 3 (60%) had PSA (biochemical failure) and 4 did not develop PSA (biochemical) failure at follow-up. With regard to outcome and the Gleason score of the pre-operative Trans-rectal ultrasound biopsy of the prostate, out of 32 patients with Gleason score?6, 7 patients (21.9%) had PSA (biochemical) failure and 25 patients did not develop any PSA (biochemical failure);out of 15 patients with Gleason score of 7, 2 patients (13.3%) had PSA (biochemical) failure and 13 did not develop PSA (biochemical failure); out of 3 patients whose tumours were scored as Gleason 8 to 10, all the three patients (100%) had PSA (biochemical) failure (2 patients had PSA failure and 1 patient died as a result of his prostate cancer) With regard to outcome and clinical staging of the radical prostatectomy specimens: out of 25 patients whose tumours were staged as T1-T2a, 1 patient (4%) had PSA (biochemical) failure and 24 patients did not develop any PSA (biochemical) failure; out of two patients with stage T2b tumours none developed PSA (biochemical failure); out of 27 patients with tumours assigned to the T1-T2b stage group only one developed PSA (biochemical failure); out of 23 patients whose tumours were staged as within the T2c and T3 group, 10 (43%) developed PSA (biochemical) failure (one of them died of his tumour)and 13 did not develop PSA (biochemical failure) PSA (biochemical) failures occurred in; 6 out of the 50 WebmedCentral > Audit Page 4 of 26

patients (12%) in less than one year, 4 (8%) out of the 50 patients between 1 and 5 years; and in one patient (2%) out of the 50 patients after 7 years. Out of the 11 patients who had PSA failure one patient died as a result of his tumour. (This patient had already been treated by radical radiotherapy and he developed PSA failure post radiotherapy he was informed that it was most likely that he might still continue to have biochemical failure after radical prostatectomy but he was of the opinion that the only other treatment of curative intent was radical prostatectomy. He was therefore treated by radical prostatectomy but developed PSA (biochemical) failure at day zero. There was evidence of up staging to stage T3 in his radical prostatectomy specimen). He received hormonal treatment but died. The remaining 10 patients who developed PSA (biochemical) failure did not develop any evidence of metastasis during the follow-up period. Discussion PSA (biochemical) failure pursuant to definitive treatment with curative intent for localized prostate cancer has been documented to precede clinical evidence of tumour recurrence by a number of months to years [2-4]. Association has been reported between PSA (biochemical) failure pursuant to definitive radiotherapy and increased mortality within the first 10 years after treatment [4]. It was also reported that a trend toward worse outcome exists after 8 years in those with PSA (biochemical) failure [4]. Jhaveri and associates [3] concluded in their study that patients with biochemical failure following radical prostatectomy have excellent over-all survival, equivalent to those without a detectable PSA at 10 years. D Amico and associates [5] reported that patients at high risk for biochemical failure after radiation therapy are also at high risk for death from prostate cancer despite competing causes of morbidity. Prostate-specific antigen has been used as surrogate to measure individual success with regard to failure of surgical treatment [2; 6; 7; 8]. Nevertheless, the natural history of the patient with biochemical failure after radical prostatectomy remains poorly defined, and no criteria for implementing treatment for such patients are uniformly accepted [9]. Pound and associates [2] reported that in patients who have had radical surgery the median time to the discovery of distant metastases is 8 years from the time of isolated biochemical failure and the median actuarial time to death is five years there- after. Hence those with biochemical failure after radical surgery may have a reasonably long life expectancy. An elderly man may die from an unrelated cause before he develops symptoms that require treatment. Results of other studies [2, 3] support the findings of Pound and associates [2]; these indicate an excellent overall survival, equivalent to those without detectable or increasing PSA after definitive therapy. It has been stated that this lack of biochemical failure impact on overall survival in the surgical series may partially reflect more favourable tumour characteristics and lead time [3, 4], but the 10-year actuarial overall survival curves for patients with and without biochemical failure were found to be similar even in high-risk patients (T2b or greater, PSA greater than 10 ng/ml or specimen Gleason score 7 or greater) [3]. Kupelian and associates [4] found a trend toward worse prognosis in those with biochemical failure after 8 years in the radiotherapy series [4]. This would indicate that longer follow-up may show biochemical failure becoming of increasing significance in the prediction of overall survival. It has been observed that some patients with biochemical failure have inferior prognosis than others. Pound and associates [2] proposed an algorithm to predict a man s likelihood of developing metastatic disease following biochemical failure that was based upon the specimen Gleason score (? 7 vs? 8), the time of initial biochemical failure (? 2 years vs? 2 years) and PSA doubling time (PSADT,? 10 months vs? 10 months). Egawa and associates [9] observed the existence of a significant correlation between biochemical failure and overall survival in their study. 11 (22%) out of 50 patients in our study developed PSA (biochemical) failure. 11%, 40% and 60% of patients developed PSA (biochemical) failure respectively in the PSA < 10 ug/l; PSA >10-20 ug/l groups. This observation confirms that localized prostate cancers with higher PSA values are likely to have higher incidence of biochemical failure after radical prostatectomy. Furthermore statistical analysis was done using sure stat to determine whether or not the differences in the biochemical failure rates were significant or not; in view of the fact that the number patients was only 50 varoius tests statistical analysrs were done including: Nominal Independence; Anova; Linear Trend; Nominal Association; and Ordinal. The results of these tests confirm that differences in outcome are significant. Details of the statistical analyses are as follows: With regard to the Gleason score of the trans-rectal ultrasound scan prostate biopsy specimens in our WebmedCentral > Audit Page 5 of 26

study, 21.9%, 13.3% and 100% of patients whose tumours were assigned respectively to Gleason? 6; 7; 8-10 groups developed PSA (biochemical) failure after radical prostatectomy. This observation would indicate that patients whose tumours are assigned to the Gleason 8-10 group have a much higher chance of developing PSA (biochemical) failure than those patients whose tumours have been assigned to Gleason scores less than 8. With regard to the Gleason score of the radical prostatectomy specimens in our study, 17%, 20% and 50% of patients whose tumours were assigned respectively to Gleason?6; 7; 8-10 groups developed PSA (biochemical) failure. The difference observed in relation to the outcome of radical prostatectomy and trans rectal ultrasound scan biopsy specimens would be explained by the down/up grading of tumours in the radical prostatectomy specimens which would be more representative of the patients tumours. Various statistical analyses were done using sure Stat including: Nominal Independence, Anova, Linear Trend, Nominal Association, and Ordinal. Even though the results of outcome of PSA failure were noted to be higher with higher Gleason score the differences were not noted to be statistically significant. The ensuing data of the statistical analyses would explain the results: With regard to the Gleason score of the trans-rectal ultrasound scan prostate biopsy specimens in our study, 21.9%, 13.3% and 100% of patients whose tumours were assigned respectively to Gleason? 6; 7; 8-10 groups developed PSA (biochemical) failure after radical prostatectomy. This observation would indicate that patients whose tumours are assigned to the Gleason 8-10 group have a much higher chance of developing PSA (biochemical) failure than those patients whose tumours have been assigned to Gleason scores less than 8. With regard to the Gleason score of the radical prostatectomy specimens in our study, 17%, 20% and 50% of patients whose tumours were assigned respectively to Gleason?6; 7; 8-10 groups developed PSA (biochemical) failure. The difference observed in relation to the outcome of radical prostatectomy and trans rectal ultrasound scan biopsy specimens would be explained by the down/up grading of tumours in the radical prostatectomy specimens which would be more representative of the patients tumours. Various statistical analyses were done using sure Stat including: Nominal Independence, Anova, Linear Trend, Nominal Association, and Ordinal. Even though the results of outcome of PSA failure were noted to be higher with higher Gleason score the differences were not noted to be statistically significant. The ensuing data of the statistical analyses would explain the results: With regard to clinical staging of the radical prostatectomy specimens and outcome in relation to PSA (biochemical failure) 3.7% of patients whose tumours were assigned to stages T1 to T2b developed PSA (biochemical failure); 4% of patients whose tumours were assigned to stages T1-T2a developed PSA (biochemical) failure; there were only 2 patients whose tumours were assigned to stage T2b and none of them developed PSA (biochemical) failure [this number of two is too small to give any meaningful outcome]; 43% of patients whose tumours were assigned to stages T2c-T3 group developed biochemical failure. These results indicate that patients with tumours assigned to stages T1-T2a and T2b have a less chance of developing (PSA) biochemical failure in comparison with patients whose tumours eventually get assigned to the T2c to T3 group. An important finding of clinical significance is the fact that statistical analyses of the outcome with regard to PSA failure and non failure was done which showed that the differences in outcome were significant whether not the patients were divided into either (a) 3 groups [stages T1-T2a, T2b, T2c-T3] or 2 groups [stages T1-T2b, T2c-T3]. Data of the statistical analyses which confirm the above findings are as follows: The results indicate that individually pre-operative serum PSA, Gleason score and clinical stage of the tumours can be used to predict PSA (biochemical) failure in that higher pre-operative serum PSA levels, higher Gleason score, and higher clinical stages are more likely to be associated with PSA (biochemical) failure in comparison with lower serum PSA, lower Gleason score and lower clinical stage. But the fact that PSA (biochemical) failure was found in each PSA subgroup, Gleason score subgroup and clinical stage subgroup would indicate that the individual parameters of serum PSA, Gleason score and clinical stage may be useful in predicting outcome, perhaps it may be a good idea to combine the individual parameters of serum PSA, Gleason score and clinical stage which should be used to divide the patients into 3 separate risk stratification groups to see if risk group stratification would be a more useful way in predicting outcome after radical prostatectomy. The observation that 10 out of 11 patients, who developed PSA (biochemical) failure without any evidence of recurrent tumour and are alive, would be consistent with what WebmedCentral > Audit Page 6 of 26

others have previously observed; that patients with PSA (biochemical) failure would live for a number of years without evidence of metastases. Conclusions The results of our study confirm that pursuant to radical prostatectomy for localized adenocarcinoma of prostate: The likelihood of subsequent development of PSA (Biochemical) failure is higher for patients with high pre-operative serum PSA in comparison with those patients whose serum PSAs are low. However pre-operative PSA alone cannot be used to predict which patients would subsequently develop PSA (Biochemical) failure from those who would not develop PSA (Biochemical) failure. The likelihood of PSA (Biochemical) failure is higher for patients with high Gleason score; however the Gleason score of the radical prostatectomy specimen is more reliable than the Gleason score of the trans rectal ultrasound scan biopsy specimen in view of up or down grading of the tumour that may occur in the radical prostatectomy specimen (The radical prostatectomy specimen is more representative of the tumour characteristics in comparison with biopsy specimens). Higher staged tumours especially tumours that are staged higher than T2b are associated higher incidence of subsequent PSA (Biochemical) failure. Nevertheless, the stage of the tumour alone is not enough to adequately predict which patients would subsequently develop PSA (Biochemical) failure from those who would not develop PSA failure. Twenty two percent of our initial 50 patients who underwent radical prostatectomy for localized prostate cancer subsequently developed PSA (Biochemical) failure. The results of our initial experience would suggest that there is the need to combine various risk factors into risk stratification groups to see if risk group stratification would clearly differentiate patients who would develop PSA failure from those who would not develop PSA failure. Acknowledgement References 1. International Union against cancer, TNM Atlas, 3rd edn., 2nd revision, Springer: New York 1992; pp 241-250 2. Pound C R, Partin A W, Eisenberger M A, Chan D W, Pearson J D, Walsh P C. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281: 1591-1597 /PubMed/ 3. Jhaveri F M, Zippe C D, Klein E A, Kupelian P A. Biochemical failure does not predict overall survival after radical prostatectomy for localized prostate cancer: 10-year results: Urology 1999; 54: 884-890 /PubMed/ 4. Kupelian P A, Buchsbaum J C, Patel C, Eishaikh M, Reddy C A, Zippa C, Klein E A. Impact of biochemical failure on overall survival after radiation therapy for localized prostate cancer in the PSA era. Int J Radial Oncol Biol Phys 2002; 52: 704-711 5. D Amico A V, Cote K, Lofredo M, Renshaw A A, Chen M. Pretreatment predictors of time to cancer specific death after prostate specific antigen failure. J Urol 2003; 169: 1320-1324 /Article/PubMed/ 6. Egawa S. Detection of prostate cancer by prostate-specific antigen. Biomed Phamarcother 2001; 55: 130-134; /PubMed/ 7. Egawa S, Matsumoto K, Iwamura M, Uchida T, Kuwao S, Koshiba K. Impact of life expectancy and tumor doubling time on the clinical significance of prostate cancer in Japan. Jpn. J Clin Oncol 1997; 27: 394-400; /PubMed/ 8. Partin A W, Oesterling J E. The clinical usefulness of prostate specific antigen: update 1994 J Urol 1994; 15: 1358 1368. 9. Egawa S, Matsui Y, Matsum oto K, Suyama K, Arai Y, Kuwao S, Baba S. Impact of biochemical failure on long-term clinical outcome after radical prostatectomy for prostate cancer in Japan. Prostate Cancer and Prostatic Diseases 2004; 7: 152 157 The audit department of North Manchester General Hospital Dr Sarah Cotterill, who is Research Fellow of the Research Design Service for the North West; University of Manchester; Salford Royal NHS Foundation Trust. United Kingdom. WebmedCentral > Audit Page 7 of 26

Illustrations Illustration 1 Statistical analyses of outcome (PSA failure / non failure) based upon pre-operative Serum PSA Contingency table analysis For Table 1 Observed 31 4 35 Expected 27.3 7.7 % of row 88.57% 11.43% % of col 79.49% 36.36% 70% Observed 6 4 10 Expected 7.8 2.2 % of row 60% 40% % of col 15.38% 36.36% 20% Observed 2 3 5 Expected 3.9 1.1 % of row 40% 60% % of col 5.13% 27.27% 10% Total 39 11 50 % of n 78% 22% TOTAL number of cells = 6 WebmedCentral > Audit Page 8 of 26

Warning: 3 out of 6 cells have EXPECTATION < 5 NOMINAL INDEPENDENCE Chi-square = 8.374958 DF = 2 P = 0.0152 G-square = 7.623643 DF = 2 P = 0.0221 Fisher-Freeman-Halton exact P = 0.0137 ANOVA Chi-square for equality of mean column scores = 8.140708 DF = 1 P = 0.0043 LINEAR TREND Sample correlation (r) = 0.407599 Chi-square for linear trend (M²) = 8.140708 DF = 1 P = 0.0043 NOMINAL ASSOCIATION Phi = 0.409267 Pearson's contingency = 0.378772 Cramér's V = 0.409267 WebmedCentral > Audit Page 9 of 26

ORDINAL Goodman-Kruskal gamma = 0.709091 Approximate test of gamma = 0: SE = 0.160025 P < 0.0001 95% CI = 0.395447 to 1.022734 Approximate test of independence: SE = 0.289497 P = 0.0143 95% CI = 0.141688 to 1.276494 Kendall tau-b = 0.39262 Approximate test of tau-b = 0: SE = 0.140822 P = 0.0053 95% CI = 0.116613 to 0.668627 Approximate test of independence: SE = 0.160293 P = 0.0143 95% CI = 0.078452 to 0.706787 WebmedCentral > Audit Page 10 of 26

Illustration 2 Statistical analyses of outcome (PSA failure / non failure) based upon Gleason Score of trans rectal ultrasound scan prostate Biopsy Specimen Contingency table analysis for table 2 Observed 25 7 32 Expected 24.96 7.04 % of row 78.12% 21.88% % of col 64.1% 63.64% 64% Observed 13 2 15 Expected 11.7 3.3 % of row 86.67% 13.33% % of col 33.33% 18.18% 30% Observed 1 2 3 Expected 2.34 0.66 % of row 33.33% 66.67% % of col 2.56% 18.18% 6% Total 39 11 50 % of n 78% 22% TOTAL number of cells = 6 WebmedCentral > Audit Page 11 of 26

Warning: 1 out of 6 cells have EXPECTATION < 1 Warning: 3 out of 6 cells have EXPECTATION < 5 NOMINAL INDEPENDENCE Chi-square = 4.144814 DF = 2 P = 0.1259 G-square = 3.470913 DF = 2 P = 0.1763 Fisher-Freeman-Halton exact P = 0.1707 ANOVA Chi-square for equality of mean column scores = 0.598237 DF = 1 P = 0.4393 LINEAR TREND Sample correlation (r) = 0.110494 Chi-square for linear trend (M²) = 0.598237 DF = 1 P = 0.4393 NOMINAL ASSOCIATION Phi = 0.287917 Pearson's contingency = 0.276678 Cramér's V = 0.287917 WebmedCentral > Audit Page 12 of 26

ORDINAL Goodman-Kruskal gamma = 0.115044 Approximate test of gamma = 0: SE = 0.33517 P = 0.7314 95% CI = -0.541877 to 0.771965 Approximate test of independence: SE = 0.347392 P = 0.7405 95% CI = -0.565832 to 0.79592 Kendall tau-b = 0.050373 Approximate test of tau-b = 0: SE = 0.151239 P = 0.7391 95% CI = -0.246049 to 0.346795 Approximate test of independence: SE = 0.152109 P = 0.7405 95% CI = -0.247754 to 0.348501 These results may indicate that perhaps Gleason score of the trans-rectal ultrasound scan biopsy specimens may not be accurate predictors of PSA biochemical failure. This may be because the biopsy specimens may not be the true representation of the true and accurate Gleason score of the whole prostate considering the fact that down-grading or up-grading may occur after the whole radical prostatectomy specimen has been examined subsequently. In our opinion the surgeon would need to tell each patient prior to his radical prostatectomy that up-grading or down-grading of the Gleason score may occur after radical prostatectomy. Various statistical analyses of the outcome of PSA failure and non failure were also done with regard to the Gleason score of the radical prostatectomy specimens using sure start; the results show p values that are less than the p values of obtained using the Gleason scores of the trans-rectal prostate biopsy specimens; the detailed results are outlined as follows: WebmedCentral > Audit Page 13 of 26

Gleason Score Radical prostatectomy specimens (Whole Prostate Specimens) Contingency table analysis for table 3 Observed 19 4 23 Expected 17.94 5.06 % of row 82.61% 17.39% % of col 48.72% 36.36% 46% Observed 20 5 25 Expected 19.5 5.5 % of row 80% 20% % of col 51.28% 45.45% 50% Observed 0 2 2 Expected 1.56 0.44 % of row 0% 100% % of col 0% 18.18% 4% Total 39 11 50 % of n 78% 22% TOTAL number of cells = 6 WebmedCentral > Audit Page 14 of 26

Warning: 1 out of 6 cells have EXPECTATION < 1 Warning: 2 out of 6 cells have EXPECTATION < 5 NOMINAL INDEPENDENCE Chi-square = 7.43387 DF = 2 P = 0.0243 G-square = 6.416977 DF = 2 P = 0.0404 Fisher-Freeman-Halton exact P = 0.0661 ANOVA Chi-square for equality of mean column scores = 2.422885 DF = 1 P = 0.1196 LINEAR TREND Sample correlation (r) = 0.222366 Chi-square for linear trend (M²) = 2.422885 DF = 1 P = 0.1196 WebmedCentral > Audit Page 15 of 26

NOMINAL ASSOCIATION Phi = 0.385587 Pearson's contingency = 0.359769 Cramér's V = 0.385587 ORDINAL Goodman-Kruskal gamma = 0.367589 Approximate test of gamma = 0: SE = 0.297287 P = 0.2163 95% CI = -0.215083 to 0.950261 Approximate test of independence: SE = 0.325123 P = 0.2582 95% CI = -0.269641 to 1.004819 Kendall tau-b = 0.173338 Approximate test of tau-b = 0: SE = 0.148313 P = 0.2425 95% CI = -0.117351 to 0.464027 Approximate test of independence: SE = 0.153313 P = 0.2582 95% CI = -0.12715 to 0.473825 WebmedCentral > Audit Page 16 of 26

Illustration 3 Statistical analyses of outcome (PSA failure and no failure) based upon tumour staging in to 3 groups (T1-2a; T2b; T2c-T3) Contingency table analysis for table 4 with the tumours divided into 3 stage groups Observed 24 1 25 Expected 19.5 5.5 % of row 96% 4% % of col 61.54% 9.09% 50% Observed 2 0 2 Expected 1.56 0.44 % of row 100% 0% % of col 5.13% 0% 4% Observed 13 10 23 Expected 17.94 5.06 % of row 56.52% 43.48% % of col 33.33% 90.91% 46% Total 39 11 50 % of n 78% 22% TOTAL number of cells = 6 WebmedCentral > Audit Page 17 of 26

Warning: 1 out of 6 cells have EXPECTATION < 1 Warning: 2 out of 6 cells have EXPECTATION < 5 NOMINAL INDEPENDENCE Chi-square = 11.467518 DF = 2 P = 0.0032 G-square = 12.80124 DF = 2 P = 0.0017 Fisher-Freeman-Halton exact P = 0.0022 ANOVA Chi-square for equality of mean column scores = 10.62028 DF = 1 P = 0.0011 LINEAR TREND Sample correlation (r) = 0.465554 Chi-square for linear trend (M²) = 10.62028 DF = 1 P = 0.0011 NOMINAL ASSOCIATION Phi = 0.478905 Pearson's contingency = 0.431929 Cramér's V = 0.478905 WebmedCentral > Audit Page 18 of 26

ORDINAL Goodman-Kruskal gamma = 0.890909 Approximate test of gamma = 0: SE = 0.112743 P < 0.0001 95% CI = 0.669937 to 1.111881 Approximate test of independence: SE = 0.25083 P = 0.0004 95% CI = 0.399291 to 1.382527 Kendall tau-b = 0.456642 Approximate test of tau-b = 0: SE = 0.104479 P < 0.0001 95% CI = 0.251868 to 0.661417 Approximate test of independence: SE = 0.128565 P = 0.0004 95% CI = 0.20466 to 0.708625 Statistical analyses of outcome (PSA failure / non failure) Staging (Stages grouped into 2) (T1-T2b; T2c-T3) Contingency table analysis for table 4 modified with the tumours arranged in to 2 groups Observed 26 1 27 Expected 21.06 5.94 % of row 96.3% 3.7% % of col 66.67% 9.09% 54% Observed 13 10 23 Expected 17.94 5.06 % of row 56.52% 43.48% % of col 33.33% 90.91% 46% Total 39 11 50 % of n 78% 22% TOTAL number of cells = 4 WebmedCentral > Audit Page 19 of 26

NOMINAL INDEPENDENCE Chi-square = 11.450251 DF = 1 P = 0.0007 G-square = 12.644277 DF = 1 P = 0.0004 Fisher-Freeman-Halton exact P = 0.0012 ANOVA Chi-square for equality of mean column scores = 11.221246 DF = 1 P = 0.0008 LINEAR TREND Sample correlation (r) = 0.478545 Chi-square for linear trend (M²) = 11.221246 DF = 1 P = 0.0008 NOMINAL ASSOCIATION Phi = 0.478545 Pearson's contingency = 0.431664 Cramér's V = 0.478545 (signed) ORDINAL Goodman-Kruskal gamma = 0.904762 Approximate test of gamma = 0: SE = 0.099995 P < 0.0001 95% CI = 0.708775 to 1.100748 Approximate test of independence: SE = 0.250086 P = 0.0003 95% CI = 0.414602 to 1.394922 Kendall tau-b = 0.478545 Approximate test of tau-b = 0: SE = 0.106623 P < 0.0001 95% CI = 0.269568 to 0.687521 Approximate test of independence: SE = 0.132275 P = 0.0003 95% CI = 0.21929 to 0.737799 WebmedCentral > Audit Page 20 of 26

Illustration 4 Tables PSA Level PSA < 10 ug/l Table 1: Pre-radical prostatectomy PSA levels as predictor of post prostatectomy Biochemical (PSA) failure and non failure outcome of 50 patients who underwent radical prostatectomy for localized prostate cancer between December 1999 and January 2006 PSA Non failure (number of patients) PSA Failure (number of patients) Totals 31 4 35 11% PSA 6 4 10 40% >10-<20 ug/l PSA > 20 2 3 5 60% ug/l Totals 39 11 50 22% Percentage failure WebmedCentral > Audit Page 21 of 26

Table 2 Gleason Score/Grade of trans-rectal ultrasound scan (TRUSS) specimen in predicting outcome/biochemical failure rate after radical prostatectomy for carcinoma of prostate between December 1999 and January 2006 Gleason Score/Grade PSA Non failure (Number of patients) PSA failure (Number of patients) Died (Number of patients who died as a result of prostate cancer) Totals Percentage failure 6 25 7 32 21.9% 7 13 2 15 13.3% 8-10 0 2 1 3 100% WebmedCentral > Audit Page 22 of 26

Table 3 Gleason score of radical prostatectomy specimens of prostate cancer and prediction of subsequent PSA (Biochemical) failure Gleason score (radical prostatectomy specimen) PSA Non Failure (number of patients) PSA failure (number of patients) Totals Percentage Failure 6 19 4 23 17% 7 20 5 25 20% 8-10 1 1 2 50% WebmedCentral > Audit Page 23 of 26

Table 4 Staging of radical prostatectomy specimen as predictor of outcome (PSA Failure and non failure rate) Clinical Stage (radical prostatectomy specimen) PSA Non failure (Number of Patients) PSA Failure (Number of Patients) Totals T1 2a 24 1 25 4% T2b 2 0 2 0% T2c T3 13 10 23 43% Totals 39 11 50 22% Percentage PSA Failure WebmedCentral > Audit Page 24 of 26

Table 5 Management PSA Failure Patients Treatment PSA Failure Time Outcome- PSA level after treatment Previous radical PSA failure after Died radiotherapy, hormonal treatment radiotherapy and then treated by radical prostatectomy Post-op Radiotherapy+ 6 months 0.681/1.95 hormonal Rx Post-op Radiotherapy 4 months 0.22/<0.050 Post-op Radiotherapy 33 months <0.050/<0.050/<0.050 Post-op Radiotherapy 4 months <0.050 Referred to oncologist 7 years Referred to oncologist awaiting outcome Referred to oncologist 4 years Referred to oncologist awaiting outcome Post-op Radiotherapy 3 years <0.050/<0.050/<0.050 Post-op Radiotherapy 8 months <0.050/<0.050/<0.050 Post-op Radiotherapy 2 months <0.050/<0.050 +hormonal treatment Post-op Radiotherapy 2 years 0.05 WebmedCentral > Audit Page 25 of 26

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