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732A health economic analysis of feedback microwave thermotherapy versus drug treatment in patients with benign prostatic hyperplasia
729
730
RETROSPECTIVE QUANTITATIVE ANALYSIS OF GSTPI P R O M O T O R HYPERMETHYLATION IN SERA OF PATIENTS W I T H CANCER AND BENIGN HYPERPLASIA OF THE PROSTATE
PROSTATE CANCER (PCA) PATIENTS DISPLAY S I G N I F I C A N T H I G H E R PLASMA LEVELS OF CELL- FREE DNA
Eilers T. 1, Peters I. 1, Lichtinghagen R. 2, Machtens SJ, Jonas U?, Serth J.~
Chun F: 1, Mfiller I.2, Urban K. 2, Gottberg M. 2, Lange I5, Friedrich M. 1, Erbersdobler A. 3, Pantel K. 2, Huland H. 1, Schwarzcnbach H. 2
~Medizinische Hoehschule Hannover, Urology, Hannover, Germany, 2Medizinische Hochschule Hannover, Clinical Chemistry, Harmover, Germany INTRODUCTION & OBJECTIVES: Epigenetic alterations in the promotor region of glutathione S transferase Pl (GSTP1) gene have been suggested to serve as a diagnostic target for the detection of prostatic carcinomas (CAP). We investigated whether quantitative GSTP1 hypermethytation analysis of free DNA in archival sertan is feasible and possibly improves the specificity of CaP diagnosis. MATERIAL & METHODS: Free serum DNA was isolated using archival serum samples stored at -80°C. After bisulfite conversion, both the converted normal and methylated GSTP1 sequences were specifically quantitated by real-time fluorescence PCR using a modified HeavyMethyl assay. Plasmids were constructed and applied as internal standards to allow the calibration of quantitative.real time PCR, the monitoring of the overall efficiency of the DNA bisulfite conversion process and the control of sensitivity of each PCR run. RESULTS: No statistical con'elation was found between age of serum samples and amount of isolated free serum DNA. Unmethylated GSTP1 promotor sequences were detected in 26 of 42 (62%) and 10 of 18 (56%) serum samples obtained from patients diagnosed with CaP by fine needle biopsy (Gleason sum >4) and benign prostatic hyperplasia (BPH), respectively. Mean values of 1.7x105 and 1.5x105 ofunmethylated GSTP1 promotor copies per ml serum were measured in sera of CaP and BPH patients, respectively. Methylated GSTP 1 promotor sequences were detected in 11 of 42 sera of the CaP group (mean copy number 1.5 x 104/ml), indicating a diagnostic sensitivity of 26%. Copy numbers of methylated sequences were not increased in 17/18 patients with prostatitis or benign prostatic hyperplasia (BPH) indicating a specificity of 94%. Hypcrmethylated sequences represented on average 16% (range 2.5-48%, median 11%) of total free serum DNA. CONCLUSIONS: Our data demonstrate that archival serum samples can be used for retrospective hypemaethylation analyses. However, considering that both the overall amount of free serum DNA and the proportion of hypermethylated sequences are low, it is expected that the diagnostic sensitivity and specificity of GSTP1 hypermethylation analysis from serum can be improved by a higher analytical sensitivity of our quantitative assay. Hence, increasing serum aliquots used for hypermethylation analysis and improving analytical sensitivity could contribute~to a higher specificity of detection of CaP in serum.
P43
Friday;18 March:;15:45!i7 !5
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1University Hospital Hamburg-Eppendorf, Dept. of Urology, Hamburg, Germany, 2University Hospital Hamburg-Eppendorf, Institute of Tumour Biology, Hamburg, Germany, 3University Hospital Hamburg-Eppendorf, Institute of Pathology, Hamburg, Germany INTRODUCTION & OBJECTIVES: Blood of patients with various cancer entities contain significant amounts of free, circulating DNA. The aim of this study was to investigate if plasma levels are associated with tumour stage/grading and can be used as.diagnostic marker for PCa. MATERIAL & M E T H O D S : We included 114 patients in this prospective study. All suspected patients underwent DRE, TRUS and ultrasound-guided transrectal 10-core biopsy. Of all patients 20 ml of peripheral plasma was drawn prior to any manipulation of the prostate. Genomic DNA was extracted from plasma (QIAmp DNA Mini Kit) and quantified spectrophotometrically. RESULTS: According to the biopsy diagnosis subgroups were built, consisting of 96 PCa and 19 BPH patients. Median plasma level of cell free DNA in BPH patients was 267ng/ml (77-2908ng/ml) versus 657 ng/ml (40-4823 ng/ml) in PCa patients. PCa patients displayed significantly higher levels of cell free plasma DNA than BPH patients (p=0.024). All other correlation to clinicopathologic parameters (tPSA ranges, fPSA, pT stage, Gleason grade, organ confined vs. nonorgan confined PCa) were not statistically significant. CONCLUSIONS: PCa patients display significantly higher levels of cell free DNA. This difference might explain a biological origin of carcinogenesis of cell free DNA in plasma. However, no other clinical' or pathological parameter correlated with elevated cell free DNA plasma levels.
732
731
TRANSURETHRAL.MICROWAVE THERAPY FOR BENIGN PROSTATE HYPERPLASIA - A TREATMENT OPTION FOR H I G H RISK PATIENTS W I T H INDWELLING CATHETER Pointner J. Obwexer S., Wiunig C., Reissigl A.
A HEALTH E C O N O M I C ANALYSIS OF FEEDBACK MICROWAVE THERMOTHERAPY VERSUS DRUG TREATMENT IN PATIENTS W I T H BENIGN PROSTATIC HYPERPLASIA Ragnarson Tennvall G. ~, Hjelmgren J.~, Malmberg L.2
LKH-Bregenz, Urology, Bregenz, Austria
1The Swedish Institute for Health Economics, IHE, Lund, Sweden, 2University Hospital Lurid, Department of Urology; Lund, Sweden
I N T R O D U C T I O N & O B J E C T I V E S : Transurethral microwave therapy (TUMT) is being used with increasing frequency as a minimal invasive therapy for benign prostate hyperplasia. We performed a retrospective analysis of 44 patients with long-time indwelling catheter, because of persistent urinary retention by enlarged prostate, treated with TUMT. These high risk patients with multiple co morbidity were not suitable for surgery.
INTRODUCTION & OBJECTIVES: Health-economic evaluations and long-term followup of treatment alternatives for benign prostatic hyperplasia(BPH) are relatively uncommon. A health-economic analysis incorporatinga long-termperspective could be a valuable t0ol for decision makers when interventions are introduced differently over time, when the effectiveness differs, and when resource utilization and costs of interventions are different. The objective was to evaluate the long-termcost-effectivenessof microwave thermotherapy, specifically the ProstaLund Feedback Treatment (PLFT); versus alpha-blockade in patients with BPH and lower urinary tract symptoms(LUTS):
MATERIAL & M E T H O D S : A total of 44 patients were treated using Prostalund Feedback Treatment (PLFT), all of them had an indwelling catheter for a long period. The mean age was 78.2 (range: 62 - 90). The mean prostate size prior to TUMT was 66 ml (range: 30 - 176). Preoperative evaluation in each patient was performed, including transrectal ultrasound of the prostate, urethrocystoseopy and sonography of the upper and lower urinary tract. The.treatment was performed in local anaesthesia and based on PLFT guidelines. Responder were defined as patients who successfully were relieved from the indwelling catheter with residual urine < 100 ml.
MATERIAL & METHODS: Data from published literature, treatment programs, and official price lists were used to develop a disease progressionmodel for evaluation of the costeffectiveness of two interventions, PLFT and alpha-blockade. Disease severitywas expressed with the International Prostate Symptom Score (IPSS). Three time dependent features of disease progression were applied in the model: (1) a phase where initial symptoms are reduced, (2) a stationary post-treatment phase and (3) a phase where the probability of a re-intereention will increase. All three phases could be adjusted in the model to capture differences in treatment effects between different treatment options. Costs and quality adjusted life years (QALY) were calculated for a period of three years in the base-case analysis. In the base-case analysis an IPSS level of 19 was applied. Sensitivity analyses were performed where scenarios regarding baseline disease severity, treatment effects, time perspective one to five years, discount rate, age at initiation of treatment, QALYweights, and the probability of re-treatment were altered.
RESULTS: The average treatment duration was 38.4 rain., the average maximal intraprostatic temperature was 55. I°C. The calculated destructed mass averaged 28.9 %. After treatment an 18F transurethral-catheter was left for 5.2 weeks (range: 3 - 12). Post treatment complication included slight haematuria (47.7%) and irritative symptoms and urinary infection (20.5%). At 3-month follow-up, 35 patients (79.5%) showed a successful spontaneous micturition with a mean residual urine of 31.2 ml (range: 0 - 100): In 5 of 6 patients a successful Re-TUMT was performed. The overall responder-rate is 90.9%. CONCLUSIONS: TUMT with PLFT is an effective treatment with low morbidity in high risk patients with indwelling catheter, who are not suitable for surgery. However, the duration to remove the catheter was relatively long, but without TUMT they are forced to have indwelling catheters a lifelong.
RESULTS: The total three-year cost of PLFT (including re-treatment) and alpha-blockade was calculated at 492 059 and gl 411, respectively (costs in Euro, 2003 prices). According to the model PLFT would result in 0.07 more QALYscomparedto alpha-blockade.resultingin a cost-effectiveness ratio of C9 500. Due to lower future expected costs of PLFT compared to alpha-blockade the results indicate that PLFT would be cost-savingwhen the time perspective is extended to five years. One importantfinding from the model simulationis that PLFT seems to be favourable even for patients with lower IPSS than treated in clinical practice in Sweden today. This result could be further validated when additional results from controlled clinical trials will be available. CONCLUSIONS: PLFT is cost-effective compared to alpha-blockade in the short run. The cost-effectivenessimprovesin a longer time perspective and PLFT would be cost-saving if the time perspective is 5 years or longer. The conclusionsremained stable in the sensitivity analyses.
European Urology Supplements 4 (2005) No. 3, pp. 185
730
RETROSPECTIVE QUANTITATIVE ANALYSIS OF GSTPI P R O M O T O R HYPERMETHYLATION IN SERA OF PATIENTS W I T H CANCER AND BENIGN HYPERPLASIA OF THE PROSTATE
PROSTATE CANCER (PCA) PATIENTS DISPLAY S I G N I F I C A N T H I G H E R PLASMA LEVELS OF CELL- FREE DNA
Eilers T. 1, Peters I. 1, Lichtinghagen R. 2, Machtens SJ, Jonas U?, Serth J.~
Chun F: 1, Mfiller I.2, Urban K. 2, Gottberg M. 2, Lange I5, Friedrich M. 1, Erbersdobler A. 3, Pantel K. 2, Huland H. 1, Schwarzcnbach H. 2
~Medizinische Hoehschule Hannover, Urology, Hannover, Germany, 2Medizinische Hochschule Hannover, Clinical Chemistry, Harmover, Germany INTRODUCTION & OBJECTIVES: Epigenetic alterations in the promotor region of glutathione S transferase Pl (GSTP1) gene have been suggested to serve as a diagnostic target for the detection of prostatic carcinomas (CAP). We investigated whether quantitative GSTP1 hypermethytation analysis of free DNA in archival sertan is feasible and possibly improves the specificity of CaP diagnosis. MATERIAL & METHODS: Free serum DNA was isolated using archival serum samples stored at -80°C. After bisulfite conversion, both the converted normal and methylated GSTP1 sequences were specifically quantitated by real-time fluorescence PCR using a modified HeavyMethyl assay. Plasmids were constructed and applied as internal standards to allow the calibration of quantitative.real time PCR, the monitoring of the overall efficiency of the DNA bisulfite conversion process and the control of sensitivity of each PCR run. RESULTS: No statistical con'elation was found between age of serum samples and amount of isolated free serum DNA. Unmethylated GSTP1 promotor sequences were detected in 26 of 42 (62%) and 10 of 18 (56%) serum samples obtained from patients diagnosed with CaP by fine needle biopsy (Gleason sum >4) and benign prostatic hyperplasia (BPH), respectively. Mean values of 1.7x105 and 1.5x105 ofunmethylated GSTP1 promotor copies per ml serum were measured in sera of CaP and BPH patients, respectively. Methylated GSTP 1 promotor sequences were detected in 11 of 42 sera of the CaP group (mean copy number 1.5 x 104/ml), indicating a diagnostic sensitivity of 26%. Copy numbers of methylated sequences were not increased in 17/18 patients with prostatitis or benign prostatic hyperplasia (BPH) indicating a specificity of 94%. Hypcrmethylated sequences represented on average 16% (range 2.5-48%, median 11%) of total free serum DNA. CONCLUSIONS: Our data demonstrate that archival serum samples can be used for retrospective hypemaethylation analyses. However, considering that both the overall amount of free serum DNA and the proportion of hypermethylated sequences are low, it is expected that the diagnostic sensitivity and specificity of GSTP1 hypermethylation analysis from serum can be improved by a higher analytical sensitivity of our quantitative assay. Hence, increasing serum aliquots used for hypermethylation analysis and improving analytical sensitivity could contribute~to a higher specificity of detection of CaP in serum.
P43
Friday;18 March:;15:45!i7 !5
::
1University Hospital Hamburg-Eppendorf, Dept. of Urology, Hamburg, Germany, 2University Hospital Hamburg-Eppendorf, Institute of Tumour Biology, Hamburg, Germany, 3University Hospital Hamburg-Eppendorf, Institute of Pathology, Hamburg, Germany INTRODUCTION & OBJECTIVES: Blood of patients with various cancer entities contain significant amounts of free, circulating DNA. The aim of this study was to investigate if plasma levels are associated with tumour stage/grading and can be used as.diagnostic marker for PCa. MATERIAL & M E T H O D S : We included 114 patients in this prospective study. All suspected patients underwent DRE, TRUS and ultrasound-guided transrectal 10-core biopsy. Of all patients 20 ml of peripheral plasma was drawn prior to any manipulation of the prostate. Genomic DNA was extracted from plasma (QIAmp DNA Mini Kit) and quantified spectrophotometrically. RESULTS: According to the biopsy diagnosis subgroups were built, consisting of 96 PCa and 19 BPH patients. Median plasma level of cell free DNA in BPH patients was 267ng/ml (77-2908ng/ml) versus 657 ng/ml (40-4823 ng/ml) in PCa patients. PCa patients displayed significantly higher levels of cell free plasma DNA than BPH patients (p=0.024). All other correlation to clinicopathologic parameters (tPSA ranges, fPSA, pT stage, Gleason grade, organ confined vs. nonorgan confined PCa) were not statistically significant. CONCLUSIONS: PCa patients display significantly higher levels of cell free DNA. This difference might explain a biological origin of carcinogenesis of cell free DNA in plasma. However, no other clinical' or pathological parameter correlated with elevated cell free DNA plasma levels.
732
731
TRANSURETHRAL.MICROWAVE THERAPY FOR BENIGN PROSTATE HYPERPLASIA - A TREATMENT OPTION FOR H I G H RISK PATIENTS W I T H INDWELLING CATHETER Pointner J. Obwexer S., Wiunig C., Reissigl A.
A HEALTH E C O N O M I C ANALYSIS OF FEEDBACK MICROWAVE THERMOTHERAPY VERSUS DRUG TREATMENT IN PATIENTS W I T H BENIGN PROSTATIC HYPERPLASIA Ragnarson Tennvall G. ~, Hjelmgren J.~, Malmberg L.2
LKH-Bregenz, Urology, Bregenz, Austria
1The Swedish Institute for Health Economics, IHE, Lund, Sweden, 2University Hospital Lurid, Department of Urology; Lund, Sweden
I N T R O D U C T I O N & O B J E C T I V E S : Transurethral microwave therapy (TUMT) is being used with increasing frequency as a minimal invasive therapy for benign prostate hyperplasia. We performed a retrospective analysis of 44 patients with long-time indwelling catheter, because of persistent urinary retention by enlarged prostate, treated with TUMT. These high risk patients with multiple co morbidity were not suitable for surgery.
INTRODUCTION & OBJECTIVES: Health-economic evaluations and long-term followup of treatment alternatives for benign prostatic hyperplasia(BPH) are relatively uncommon. A health-economic analysis incorporatinga long-termperspective could be a valuable t0ol for decision makers when interventions are introduced differently over time, when the effectiveness differs, and when resource utilization and costs of interventions are different. The objective was to evaluate the long-termcost-effectivenessof microwave thermotherapy, specifically the ProstaLund Feedback Treatment (PLFT); versus alpha-blockade in patients with BPH and lower urinary tract symptoms(LUTS):
MATERIAL & M E T H O D S : A total of 44 patients were treated using Prostalund Feedback Treatment (PLFT), all of them had an indwelling catheter for a long period. The mean age was 78.2 (range: 62 - 90). The mean prostate size prior to TUMT was 66 ml (range: 30 - 176). Preoperative evaluation in each patient was performed, including transrectal ultrasound of the prostate, urethrocystoseopy and sonography of the upper and lower urinary tract. The.treatment was performed in local anaesthesia and based on PLFT guidelines. Responder were defined as patients who successfully were relieved from the indwelling catheter with residual urine < 100 ml.
MATERIAL & METHODS: Data from published literature, treatment programs, and official price lists were used to develop a disease progressionmodel for evaluation of the costeffectiveness of two interventions, PLFT and alpha-blockade. Disease severitywas expressed with the International Prostate Symptom Score (IPSS). Three time dependent features of disease progression were applied in the model: (1) a phase where initial symptoms are reduced, (2) a stationary post-treatment phase and (3) a phase where the probability of a re-intereention will increase. All three phases could be adjusted in the model to capture differences in treatment effects between different treatment options. Costs and quality adjusted life years (QALY) were calculated for a period of three years in the base-case analysis. In the base-case analysis an IPSS level of 19 was applied. Sensitivity analyses were performed where scenarios regarding baseline disease severity, treatment effects, time perspective one to five years, discount rate, age at initiation of treatment, QALYweights, and the probability of re-treatment were altered.
RESULTS: The average treatment duration was 38.4 rain., the average maximal intraprostatic temperature was 55. I°C. The calculated destructed mass averaged 28.9 %. After treatment an 18F transurethral-catheter was left for 5.2 weeks (range: 3 - 12). Post treatment complication included slight haematuria (47.7%) and irritative symptoms and urinary infection (20.5%). At 3-month follow-up, 35 patients (79.5%) showed a successful spontaneous micturition with a mean residual urine of 31.2 ml (range: 0 - 100): In 5 of 6 patients a successful Re-TUMT was performed. The overall responder-rate is 90.9%. CONCLUSIONS: TUMT with PLFT is an effective treatment with low morbidity in high risk patients with indwelling catheter, who are not suitable for surgery. However, the duration to remove the catheter was relatively long, but without TUMT they are forced to have indwelling catheters a lifelong.
RESULTS: The total three-year cost of PLFT (including re-treatment) and alpha-blockade was calculated at 492 059 and gl 411, respectively (costs in Euro, 2003 prices). According to the model PLFT would result in 0.07 more QALYscomparedto alpha-blockade.resultingin a cost-effectiveness ratio of C9 500. Due to lower future expected costs of PLFT compared to alpha-blockade the results indicate that PLFT would be cost-savingwhen the time perspective is extended to five years. One importantfinding from the model simulationis that PLFT seems to be favourable even for patients with lower IPSS than treated in clinical practice in Sweden today. This result could be further validated when additional results from controlled clinical trials will be available. CONCLUSIONS: PLFT is cost-effective compared to alpha-blockade in the short run. The cost-effectivenessimprovesin a longer time perspective and PLFT would be cost-saving if the time perspective is 5 years or longer. The conclusionsremained stable in the sensitivity analyses.
European Urology Supplements 4 (2005) No. 3, pp. 185