- Email: [email protected]
1728 EARLY DETECTION OF PROSTATE CANCER (TYROL PROSTATE CANCER DEMONSTRATION PROJECT 1988-2008): 20 YEARS EXPERIENCE
Vol. 183, No. 4, Supplement, Tuesday, June 1, 2010
THE JOURNAL OF UROLOGY姞
tomatic men is usually recommended in the age group 50-70 years. Although prostate cancer is rare in men aged ⬍50 years, early detection and curative therapy are more important in this group than in older men with limited life expectancy. METHODS: We analysed the data of 1571 men diagnosed with adenocarcinoma of the prostate in the period January 1997 to December 2008 and treated at our institution, a tertiary level public sector (state) hospital serving a largely indigent population with no medical insurance. Most men presented because of symptoms, because PSA testing is not available at primary level clinics or secondary hospitals in our referral area. Statistical analysis was performed using Student¡⫺ t-test for parametric data, Mann-Whitney test for non-parametric data and Fisher¡⫺s exact test for contingency table analysis. A two-tailed p-value ⬍0.05 was accepted as statistically significant (SS). RESULTS: The majority of patients presented with T3-4 tumors and very high mean and median PSA values (Table). Compared with the groups aged 51-60 (17.4%) and 61-70 years (46.1%) the group ⬍50 years old had higher PSA at diagnosis, greater proportion of T3-4 tumors and lower survival after diagnosis (SS). CONCLUSIONS: In our referral population, where PSA testing is not readily available, men aged ⬍50 years presenting with symptoms due to adenocarcinoma of the prostate had significantly more advanced disease and a poorer prognosis than men aged ⬎50 years. To diagnose prostate cancer at a potentially curable stage in men ⬍50-55 years it may be advisable to obtain an initial PSA test at age 40-45, select men with a baseline PSA ⬎1.0-1.5 ng/ml for annual or biennial PSA testing, then select those with PSA velocity ⬎0.75-1.0 ng/ml/year for prostate biopsy before the PSA reaches ⬎10 ng/ml, i.e. when the disease is still potentially curable in young men with a life expectancy ⬎20-25 years. Age group Patients (n) Pts (% of total)
<50 47 3.0%
51-60 273 17.4%
61-70 724 46.1%
71-80 446 28.4%
81-90 81 5.2%
METHODS: A sample of 50 volunteers between 50 and 80 years (25 healthy men as control group and 25 with CaP) was selected for the study. Also, the CaP group was subclassified according to the Gleason score (indicator of aggressiveness). Rectal examination, transrectal ultrasound and prostatic biopsy (12-14 cores) were performed; blood sample was obtained to determine PSA, leptin and adiponectin; and a nutritional interview including anthropometric measurements and food frequency questionnaire was carried out. Statistical analysis was performed by Student test, ANOVA and Bonferroni (p ⬍0.05). RESULTS: The mean age of the volunteers was 62.71 ⫾ 0.97 years old. Body mass index (BMI) and percentage of body fat mass were not statistically different between the cancer and control groups. However, both antropometric variables were higher in subjects with more aggressive tumors (p ⬍0.05) (Table 1). Cancer patients had lower leptin levels than healthy subjects (Table 1). Simultaneously, leptin levels increased with the Gleason Score (2.96 ⫾ 0.76 ng/ml; 4.57 ⫾ 1.00 ng/ml and 12.09 ⫾ 3.00 ng/ml, p ⬍0.001). Adiponectin levels showed no statistical differences regarding the presence and aggressiveness of the tumor (p ⬎ 0.05). Finally, consumption and nutrient intake did not differ according to the groups studied. CONCLUSIONS: Body composition and adipokines are related with the aggressiveness of CaP rather than its prevalence. Leptin may influence the progression, invasion and metastasis of prostate tumors, whereas adiponectin may not affect the carcinogenesis. Table 1. Characteristics of the sample.
Median Range
621.08
513.65
386.83
433.00
446.14
74.05
15.00
16.40
32.10
71.00
Control 25
n
Cancer 25
P
Low 9
Gleason Score Intermediate 12
High 4
P
BMI (kg/m2)
34,25 ⫾ 1,2 30,75 ⫾ 0,7 0,073 28,62 ⫾ 1,2
31,47 ⫾ 0,8
33,4 ⫾ 1,6 0,041
Fat mass %
27,96 ⫾ 1,9 25,33 ⫾ 1,0 0,124 22,04 ⫾ 1,3
27,06 ⫾ 1,1
30,8 ⫾ 0,4 0,003
2,96 ⫾ 0,7
4,57 ⫾ 1,0
12,09 ⫾ 3,0 0,001
22,05 ⫾ 3,5
20,48 ⫾ 2,9
23,20 ⫾ 3,2 0,902
Leptin (ng/ml) 12,29 ⫾ 5,1 Adiponectin (ng/ml)
PSA at diagnosis (ng/ml) Mean
e667
5,32 ⫾ 0,9 0,001
14,41 ⫾ 1,9 21,48 ⫾ 1,9 0,95
Source of Funding: Fundacio´n Allende, Co´rdoba, Argentina. Universidad Juan Agustı´n Maza, Mendoza, Argentina.
2.6-7,000 0.5-22,600 0.2-19,120 0.2-37,160 6.0-4,349
1728
Clinical T-stage at diagnosis T1
30.2%
34.4%
32.0%
20.4%
11.7%
T2
14.0%
23.6%
25.6%
21.6%
14.3%
T3
9.3%
14.7%
18.5%
20.4%
33.8%
T4
46.5%
27.4%
23.9%
37.6%
40.3%
24.32
30.61
34.65
29.42
23.80
13.00
20.20
24.29
19.11
18.20
Survival followup after diagnosis (months) Mean Median
Source of Funding: None
1727 RELATIONSHIP BETWEEN OBESITY AND ADIPOKINES WITH PROSTATE CANCER PREVALENCE AND AGGRESSIVENESS Jose´ Lo´pez Laur*, Rafael Perez Elizalde, Alberto Co´rica, Ana Uvilla Recupero, Nicola´s Di Milta Mo´naco, Eugenia Maselli, Cristina Vanrell, Mendoza, Argentina; Diego N. Messina, San Martı´n, Argentina; Gabriela Recalde, Constanza Lo´pez Fontana, Mendoza, Argentina INTRODUCTION AND OBJECTIVES: Recent studies indicate that adipose tissue and adipokines might promote or prevent the development of prostate cancer (CaP). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of the present study was to identify and correlate body composition, leptin and adiponectin levels with the prevalence and aggressiveness of CaP, in Mendoza, Argentina.
EARLY DETECTION OF PROSTATE CANCER (TYROL PROSTATE CANCER DEMONSTRATION PROJECT 1988-2008): 20 YEARS EXPERIENCE Georg Bartsch*, Wolfgang Horninger, Helmut Klocker, Wilhelm Oberaigner, Georg Scha¨fer, Ferdinand Frauscher, Innsbruck, Austria; Chris Robertson, Mathieu Boniol, Peter Boyle, Lyon, France INTRODUCTION AND OBJECTIVES: To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate –specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993. METHODS: In 1988, the concept of early detection and curative radical therapy for prostate cancer was introduced in the Tyrol. In 2005 a cumulative testing rate of 86.6% was achieved. Overall 8054 transrectal ultrasound-guided biopsies were performed; before 1998 ten biopsies were obtained with the B-mode, subsequently five additional biopsies were performed using contrast-enhanced color Doppler ultrasound. In men with organ-confined lesions surgical removal of the prostate was recommended; 86.3% of patients with T1 or T2 disease were treated with low-morbidity radical prostatectomy, 8.7% with brachytherapy, and 8.7% with radiotherapy. Between 1988 and 2008 2153 radical prostatectomies were performed mostly by two surgeons (G.B., W.H.). Patients presenting with T3 lesions underwent external beam radiotherapy. RESULTS: Radical prostatectomy has been associated with low morbidity; 30-day mortality was zero and none of the patients suffered a ureteral injury. The rectal injury rate dropped to 0.1% from 0.6% before the year 2000. Only 0.7% of the patients had postoperative bleeding requiring intervention. One year after surgery, 95.1% of men
e668
THE JOURNAL OF UROLOGY姞
were continent (no pads) and potency could be preserved in 78.9% of men below 65 years of age. The morbidity associated with transrectal ultrasound-guided biopsy was low; major complications were seen in a small percentage of patients only (0.8% of patients with fevers higher than 100.4°F required hospitalization). Since 1996 a significant reduction in mortality from prostate cancer has been observed in the Tyrol. In the years 2003-2008 prostate cancer mortality rates decreased by 48%, 55%, 52%, 49%, 41%, and 64% (2008) respectively. CONCLUSIONS: These findings confirm the hypothesis that freely available PSA testing, which has met with wide acceptance in the population, is associated with a reduction in prostate cancer mortality in an area where effective treatment is freely available to all men. It is likely that much of this decline in mortality rates is due to earlier detection and successful treatment of prostate cancer. However, and important corollary implication of our study is that screening is only the first step in the optimal management of prostate cancer. Source of Funding: None
1729 THE EFFECT OF NON-COMPLIANCE AND PSA TESTING BEFORE STUDY IN THE INTERVENTION ARM OF THE EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER SECTION ROTTERDAM Pim Van Leeuwen*, Roderick van den Bergh, Tineke Wolters, Fritz Schro¨der, Monique Roobol, Rotterdam, Netherlands INTRODUCTION AND OBJECTIVES: Prostate cancer (PC) screening has the potential to reduce the distant metastasis and PC specific mortality. Non-compliers in the intervention arm of the ERSPC Gothenburg were found to be at an increased risk for death from PC with respect to compliers, and men who were screened before study participation in the PLCO trial were found to be at a reduced risk of death from PC. These two screening related effects are analysed using data of the Rotterdam section of the ERSPC. METHODS: A total of 21,175 men signed informed consent before study participation. Men who had a PSA test during the 4-years before study entry were identified using a questionnaire, i.e. contaminators. The PC mortality and metastasis were attributed to whether the men were compliers in the screening program (attending at first screening) or non-compliers. The PC deaths and distant metastasis were assessed among contaminators and non-contaminators in the intervention arm. RESULTS: Up to the end of 2006, 2,153 (10.2%) men were diagnosed with PC, 121 (0.6%) men developed bone metastases and 79 (0.4%) died of PC. Median follow up was 9.2 years. In total 19,950 (94.2%) men who were compliers and 2,403 (11.3%) men reported having had a PSA test within 4-years before study entry, i.e. contaminators. Both the rates of distant metastasis (0.6% vs 0.6%; P⫽0.905) and PC-specific mortality (0.4% vs 0.4%; P⫽0.756) were found not to be different among non-compliers compared with compliers. Furthermore, among the 19,950 compliers, the distant metastasis (0.6% vs 0.5%; P⫽0.226) and PC-specific mortality (0.4% vs 0.4 %; P⫽0.994) were found not to be different among the contaminators and noncontaminators. Among the contaminators PC was diagnosed in 312 (13.3%) men, PC was diagnosed in 1793 (10.2%) non-contaminators, P⫽0.001. CONCLUSIONS: The intuitively assumed and proven protective effect of PSA testing before study entry and the increasing risk at PC death among non-compliers in the intervention arm of a screening trial could not be established. The unobserved effect among noncompliers might due to the relative high attendance rate in the ERSPCRotterdam, and the difference in the randomization between the ERSPC-Gothenburg (randomization before written informed consent) and the ERSPC-Rotterdam (randomization after written informed consent). The insignificant effect of contamination had minor influence in the
Vol. 183, No. 4, Supplement, Tuesday, June 1, 2010
ERSPC-Rotterdam which might be due the low biopsy rates in men with moderate elevated PSA in the period 1989-1999 in the Netherlands compared to the US. Source of Funding: Dutch Cancer Society (KWF 94-869, 98-1657, 2002-277, 2006-3518), The Bonnema foundation, The Netherlands Organization for Health Research and Development (002822820, 22000106, 50-50110-98-311), 6th Framework Program of the EU: P-Mark: LSHC-CT-2004503011, Beckman Coulter Hybritech Inc and of Europe against Cancer (SOC 95 35109, SOC 96 201869 05F02, SOC 97 201329, SOC 98 32241).
1730 WHAT IS THE TRUE NUMBER-NEEDED-TO-SCREEN AND TREAT TO SAVE A LIFE WITH PSA SCREENING? Stacy Loeb*, Baltimore, MD; Edward F. Vonesh, Chicago, IL; E. Jeffrey Metter, H. Ballentine Carter, Baltimore, MD; Peter H. Gann, William J. Catalona, Chicago, IL INTRODUCTION AND OBJECTIVES: The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction (hazard ratio, HR of 0.80) with PSA screening (NEJM 2009; 360: 1320), which increased to 31% when corrected for noncompliance in the screening arm and contamination in the control arm (Eur Urol 2009; 56:584). Based on the intent-to-treat analysis, they estimated a number-needed-to-screen (NNS) of 1410 and numberneeded-to-treat (NNT) of 48 to prevent 1 prostate cancer death at a median follow-up time of 9 years (just when the cumulative hazard functions began to diverge). Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, there are numerous pitfalls in their calculation and interpretation. The objective of our study was to re-examine the effect of varying follow-up times on the NNS and NNT using simulated data extrapolated from the ERSPC report. METHODS: Based on previously reported data from the ERSPC, we modeled the cumulative hazard function using a piecewise exponential model. We assumed a constant hazard of 0.0002 for both the screening and control groups for years 1-7 of the trial; whereas, we assumed different constant rates of 0.00062 and 0.00102 for the screening and control groups for years 8 to 12, respectively. Based on this non-proportional hazards assumption, we computed patient survival and cumulative hazard ratios (CHR) over time as a function of the cumulative hazard function. Annualized cancer detection and drop-out rates were also approximated based upon the observed number of individuals at risk in published ERSPC data. RESULTS: Figure 1 compares the simulated cumulative hazard functions to published data from the ERSPC. According to our model, the NNS and NNT at 9 years were 1254 and 43, respectively. This corresponds to a CHR of 0.77 similar to the crude HR of 0.80 from the ERSPC report. Subsequently, the NNS decreased from 837 at year 10 to 503 at year 12, and the NNT decreased from 29 to 18. CONCLUSIONS: Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls among the urological community, the media, and the general public. With additional follow-up in the ERSPC, if the mortality difference continues to grow, this will lead to a decrease in the NNT.
THE JOURNAL OF UROLOGY姞
tomatic men is usually recommended in the age group 50-70 years. Although prostate cancer is rare in men aged ⬍50 years, early detection and curative therapy are more important in this group than in older men with limited life expectancy. METHODS: We analysed the data of 1571 men diagnosed with adenocarcinoma of the prostate in the period January 1997 to December 2008 and treated at our institution, a tertiary level public sector (state) hospital serving a largely indigent population with no medical insurance. Most men presented because of symptoms, because PSA testing is not available at primary level clinics or secondary hospitals in our referral area. Statistical analysis was performed using Student¡⫺ t-test for parametric data, Mann-Whitney test for non-parametric data and Fisher¡⫺s exact test for contingency table analysis. A two-tailed p-value ⬍0.05 was accepted as statistically significant (SS). RESULTS: The majority of patients presented with T3-4 tumors and very high mean and median PSA values (Table). Compared with the groups aged 51-60 (17.4%) and 61-70 years (46.1%) the group ⬍50 years old had higher PSA at diagnosis, greater proportion of T3-4 tumors and lower survival after diagnosis (SS). CONCLUSIONS: In our referral population, where PSA testing is not readily available, men aged ⬍50 years presenting with symptoms due to adenocarcinoma of the prostate had significantly more advanced disease and a poorer prognosis than men aged ⬎50 years. To diagnose prostate cancer at a potentially curable stage in men ⬍50-55 years it may be advisable to obtain an initial PSA test at age 40-45, select men with a baseline PSA ⬎1.0-1.5 ng/ml for annual or biennial PSA testing, then select those with PSA velocity ⬎0.75-1.0 ng/ml/year for prostate biopsy before the PSA reaches ⬎10 ng/ml, i.e. when the disease is still potentially curable in young men with a life expectancy ⬎20-25 years. Age group Patients (n) Pts (% of total)
<50 47 3.0%
51-60 273 17.4%
61-70 724 46.1%
71-80 446 28.4%
81-90 81 5.2%
METHODS: A sample of 50 volunteers between 50 and 80 years (25 healthy men as control group and 25 with CaP) was selected for the study. Also, the CaP group was subclassified according to the Gleason score (indicator of aggressiveness). Rectal examination, transrectal ultrasound and prostatic biopsy (12-14 cores) were performed; blood sample was obtained to determine PSA, leptin and adiponectin; and a nutritional interview including anthropometric measurements and food frequency questionnaire was carried out. Statistical analysis was performed by Student test, ANOVA and Bonferroni (p ⬍0.05). RESULTS: The mean age of the volunteers was 62.71 ⫾ 0.97 years old. Body mass index (BMI) and percentage of body fat mass were not statistically different between the cancer and control groups. However, both antropometric variables were higher in subjects with more aggressive tumors (p ⬍0.05) (Table 1). Cancer patients had lower leptin levels than healthy subjects (Table 1). Simultaneously, leptin levels increased with the Gleason Score (2.96 ⫾ 0.76 ng/ml; 4.57 ⫾ 1.00 ng/ml and 12.09 ⫾ 3.00 ng/ml, p ⬍0.001). Adiponectin levels showed no statistical differences regarding the presence and aggressiveness of the tumor (p ⬎ 0.05). Finally, consumption and nutrient intake did not differ according to the groups studied. CONCLUSIONS: Body composition and adipokines are related with the aggressiveness of CaP rather than its prevalence. Leptin may influence the progression, invasion and metastasis of prostate tumors, whereas adiponectin may not affect the carcinogenesis. Table 1. Characteristics of the sample.
Median Range
621.08
513.65
386.83
433.00
446.14
74.05
15.00
16.40
32.10
71.00
Control 25
n
Cancer 25
P
Low 9
Gleason Score Intermediate 12
High 4
P
BMI (kg/m2)
34,25 ⫾ 1,2 30,75 ⫾ 0,7 0,073 28,62 ⫾ 1,2
31,47 ⫾ 0,8
33,4 ⫾ 1,6 0,041
Fat mass %
27,96 ⫾ 1,9 25,33 ⫾ 1,0 0,124 22,04 ⫾ 1,3
27,06 ⫾ 1,1
30,8 ⫾ 0,4 0,003
2,96 ⫾ 0,7
4,57 ⫾ 1,0
12,09 ⫾ 3,0 0,001
22,05 ⫾ 3,5
20,48 ⫾ 2,9
23,20 ⫾ 3,2 0,902
Leptin (ng/ml) 12,29 ⫾ 5,1 Adiponectin (ng/ml)
PSA at diagnosis (ng/ml) Mean
e667
5,32 ⫾ 0,9 0,001
14,41 ⫾ 1,9 21,48 ⫾ 1,9 0,95
Source of Funding: Fundacio´n Allende, Co´rdoba, Argentina. Universidad Juan Agustı´n Maza, Mendoza, Argentina.
2.6-7,000 0.5-22,600 0.2-19,120 0.2-37,160 6.0-4,349
1728
Clinical T-stage at diagnosis T1
30.2%
34.4%
32.0%
20.4%
11.7%
T2
14.0%
23.6%
25.6%
21.6%
14.3%
T3
9.3%
14.7%
18.5%
20.4%
33.8%
T4
46.5%
27.4%
23.9%
37.6%
40.3%
24.32
30.61
34.65
29.42
23.80
13.00
20.20
24.29
19.11
18.20
Survival followup after diagnosis (months) Mean Median
Source of Funding: None
1727 RELATIONSHIP BETWEEN OBESITY AND ADIPOKINES WITH PROSTATE CANCER PREVALENCE AND AGGRESSIVENESS Jose´ Lo´pez Laur*, Rafael Perez Elizalde, Alberto Co´rica, Ana Uvilla Recupero, Nicola´s Di Milta Mo´naco, Eugenia Maselli, Cristina Vanrell, Mendoza, Argentina; Diego N. Messina, San Martı´n, Argentina; Gabriela Recalde, Constanza Lo´pez Fontana, Mendoza, Argentina INTRODUCTION AND OBJECTIVES: Recent studies indicate that adipose tissue and adipokines might promote or prevent the development of prostate cancer (CaP). Leptin would have a stimulating effect on prostate cancer cells by inducing promotion and progression, whereas adiponectin would have a protective effect. The aim of the present study was to identify and correlate body composition, leptin and adiponectin levels with the prevalence and aggressiveness of CaP, in Mendoza, Argentina.
EARLY DETECTION OF PROSTATE CANCER (TYROL PROSTATE CANCER DEMONSTRATION PROJECT 1988-2008): 20 YEARS EXPERIENCE Georg Bartsch*, Wolfgang Horninger, Helmut Klocker, Wilhelm Oberaigner, Georg Scha¨fer, Ferdinand Frauscher, Innsbruck, Austria; Chris Robertson, Mathieu Boniol, Peter Boyle, Lyon, France INTRODUCTION AND OBJECTIVES: To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate –specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993. METHODS: In 1988, the concept of early detection and curative radical therapy for prostate cancer was introduced in the Tyrol. In 2005 a cumulative testing rate of 86.6% was achieved. Overall 8054 transrectal ultrasound-guided biopsies were performed; before 1998 ten biopsies were obtained with the B-mode, subsequently five additional biopsies were performed using contrast-enhanced color Doppler ultrasound. In men with organ-confined lesions surgical removal of the prostate was recommended; 86.3% of patients with T1 or T2 disease were treated with low-morbidity radical prostatectomy, 8.7% with brachytherapy, and 8.7% with radiotherapy. Between 1988 and 2008 2153 radical prostatectomies were performed mostly by two surgeons (G.B., W.H.). Patients presenting with T3 lesions underwent external beam radiotherapy. RESULTS: Radical prostatectomy has been associated with low morbidity; 30-day mortality was zero and none of the patients suffered a ureteral injury. The rectal injury rate dropped to 0.1% from 0.6% before the year 2000. Only 0.7% of the patients had postoperative bleeding requiring intervention. One year after surgery, 95.1% of men
e668
THE JOURNAL OF UROLOGY姞
were continent (no pads) and potency could be preserved in 78.9% of men below 65 years of age. The morbidity associated with transrectal ultrasound-guided biopsy was low; major complications were seen in a small percentage of patients only (0.8% of patients with fevers higher than 100.4°F required hospitalization). Since 1996 a significant reduction in mortality from prostate cancer has been observed in the Tyrol. In the years 2003-2008 prostate cancer mortality rates decreased by 48%, 55%, 52%, 49%, 41%, and 64% (2008) respectively. CONCLUSIONS: These findings confirm the hypothesis that freely available PSA testing, which has met with wide acceptance in the population, is associated with a reduction in prostate cancer mortality in an area where effective treatment is freely available to all men. It is likely that much of this decline in mortality rates is due to earlier detection and successful treatment of prostate cancer. However, and important corollary implication of our study is that screening is only the first step in the optimal management of prostate cancer. Source of Funding: None
1729 THE EFFECT OF NON-COMPLIANCE AND PSA TESTING BEFORE STUDY IN THE INTERVENTION ARM OF THE EUROPEAN RANDOMIZED STUDY OF SCREENING FOR PROSTATE CANCER SECTION ROTTERDAM Pim Van Leeuwen*, Roderick van den Bergh, Tineke Wolters, Fritz Schro¨der, Monique Roobol, Rotterdam, Netherlands INTRODUCTION AND OBJECTIVES: Prostate cancer (PC) screening has the potential to reduce the distant metastasis and PC specific mortality. Non-compliers in the intervention arm of the ERSPC Gothenburg were found to be at an increased risk for death from PC with respect to compliers, and men who were screened before study participation in the PLCO trial were found to be at a reduced risk of death from PC. These two screening related effects are analysed using data of the Rotterdam section of the ERSPC. METHODS: A total of 21,175 men signed informed consent before study participation. Men who had a PSA test during the 4-years before study entry were identified using a questionnaire, i.e. contaminators. The PC mortality and metastasis were attributed to whether the men were compliers in the screening program (attending at first screening) or non-compliers. The PC deaths and distant metastasis were assessed among contaminators and non-contaminators in the intervention arm. RESULTS: Up to the end of 2006, 2,153 (10.2%) men were diagnosed with PC, 121 (0.6%) men developed bone metastases and 79 (0.4%) died of PC. Median follow up was 9.2 years. In total 19,950 (94.2%) men who were compliers and 2,403 (11.3%) men reported having had a PSA test within 4-years before study entry, i.e. contaminators. Both the rates of distant metastasis (0.6% vs 0.6%; P⫽0.905) and PC-specific mortality (0.4% vs 0.4%; P⫽0.756) were found not to be different among non-compliers compared with compliers. Furthermore, among the 19,950 compliers, the distant metastasis (0.6% vs 0.5%; P⫽0.226) and PC-specific mortality (0.4% vs 0.4 %; P⫽0.994) were found not to be different among the contaminators and noncontaminators. Among the contaminators PC was diagnosed in 312 (13.3%) men, PC was diagnosed in 1793 (10.2%) non-contaminators, P⫽0.001. CONCLUSIONS: The intuitively assumed and proven protective effect of PSA testing before study entry and the increasing risk at PC death among non-compliers in the intervention arm of a screening trial could not be established. The unobserved effect among noncompliers might due to the relative high attendance rate in the ERSPCRotterdam, and the difference in the randomization between the ERSPC-Gothenburg (randomization before written informed consent) and the ERSPC-Rotterdam (randomization after written informed consent). The insignificant effect of contamination had minor influence in the
Vol. 183, No. 4, Supplement, Tuesday, June 1, 2010
ERSPC-Rotterdam which might be due the low biopsy rates in men with moderate elevated PSA in the period 1989-1999 in the Netherlands compared to the US. Source of Funding: Dutch Cancer Society (KWF 94-869, 98-1657, 2002-277, 2006-3518), The Bonnema foundation, The Netherlands Organization for Health Research and Development (002822820, 22000106, 50-50110-98-311), 6th Framework Program of the EU: P-Mark: LSHC-CT-2004503011, Beckman Coulter Hybritech Inc and of Europe against Cancer (SOC 95 35109, SOC 96 201869 05F02, SOC 97 201329, SOC 98 32241).
1730 WHAT IS THE TRUE NUMBER-NEEDED-TO-SCREEN AND TREAT TO SAVE A LIFE WITH PSA SCREENING? Stacy Loeb*, Baltimore, MD; Edward F. Vonesh, Chicago, IL; E. Jeffrey Metter, H. Ballentine Carter, Baltimore, MD; Peter H. Gann, William J. Catalona, Chicago, IL INTRODUCTION AND OBJECTIVES: The European Randomized Study of Screening for Prostate Cancer (ERSPC) reported a 20% mortality reduction (hazard ratio, HR of 0.80) with PSA screening (NEJM 2009; 360: 1320), which increased to 31% when corrected for noncompliance in the screening arm and contamination in the control arm (Eur Urol 2009; 56:584). Based on the intent-to-treat analysis, they estimated a number-needed-to-screen (NNS) of 1410 and numberneeded-to-treat (NNT) of 48 to prevent 1 prostate cancer death at a median follow-up time of 9 years (just when the cumulative hazard functions began to diverge). Although NNS and NNT are useful statistics to assess the benefits and harms of an intervention, there are numerous pitfalls in their calculation and interpretation. The objective of our study was to re-examine the effect of varying follow-up times on the NNS and NNT using simulated data extrapolated from the ERSPC report. METHODS: Based on previously reported data from the ERSPC, we modeled the cumulative hazard function using a piecewise exponential model. We assumed a constant hazard of 0.0002 for both the screening and control groups for years 1-7 of the trial; whereas, we assumed different constant rates of 0.00062 and 0.00102 for the screening and control groups for years 8 to 12, respectively. Based on this non-proportional hazards assumption, we computed patient survival and cumulative hazard ratios (CHR) over time as a function of the cumulative hazard function. Annualized cancer detection and drop-out rates were also approximated based upon the observed number of individuals at risk in published ERSPC data. RESULTS: Figure 1 compares the simulated cumulative hazard functions to published data from the ERSPC. According to our model, the NNS and NNT at 9 years were 1254 and 43, respectively. This corresponds to a CHR of 0.77 similar to the crude HR of 0.80 from the ERSPC report. Subsequently, the NNS decreased from 837 at year 10 to 503 at year 12, and the NNT decreased from 29 to 18. CONCLUSIONS: Despite the seemingly simplistic nature of estimating NNT, there is widespread misunderstanding of its pitfalls among the urological community, the media, and the general public. With additional follow-up in the ERSPC, if the mortality difference continues to grow, this will lead to a decrease in the NNT.