Abstract
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.
Introduction
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 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;
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 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 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 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
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.
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