78 EFFECT OF BASELINE CHARACTERISTICS ON RELATIVE RISK OF PROSTATE CANCER PROGRESSION IN THE REDUCTION BY DUTASTERIDE OF CLINICAL PROGRESSION EVENTS IN EXPECTANT MANAGEMENT (REDEEM) TRIAL

Introduction & Objectives: HIFU is an advancing alternative treatment option for localised prostate cancer (PC). Long-term results are mandatory to judge the oncologic efficacy of HIFU. We present oncologic outcome of a single centre series with a follow-up ranging up to 11.8 years. Materials & Methods: Patients with the following inclusion criteria were analysed retrospectively: cT1/T2 PC, Gleason score ≤7, PSA ≤20 ng/ml, no or short-term (<3 months) neo-adjuvant hormone therapy, minimum follow-up of three years. All patients were treated with different generation Ablatherm (EDAP TMS, France) devices and followed-up every three months including PSA measurement and prostate biopsy in case of rising PSA. Biochemical failure was defined according to the HIFU-specific “Stuttgart criteria” (PSA-nadir + 1.2 ng/ml). Disease-free survival rates (DFSR) were calculated using life table methods. The log rank test was used to compare the curves based on Kaplan–Meier models. Results: 310 patients were available for analysis. Median age was 67 (45-83) years, mean PSA was 6.5±1.9 ng/ml. 154 (49.7%) and 156 (50.3%) of patients were classified low and intermediate risk, respectively. Mean follow-up was 6.5±1.9 (range 3-11.8) years. The median PSA-nadir was 0.07 (0-6.2) ng/ml and was reached after a median time of 15.8 (2.1 – 52) weeks. A PSA-nadir <0.2 ng/ml was achieved by 72% of patients. Biochemical-free survival during follow-up was 77.7%, with 81.1% and 73.7% for the low and intermediate risk group, respectively. Actuarial DFSR at 7 years were 71% and 58% for the low and intermediate risk group, respectively. Conclusions: This study underlines the oncologic efficacy of HIFU treatment in localised PC. This is the largest patient series with long-term follow-up presented in current literature.

76

Oncological outcomes of high-intensity focused ultrasound for localized prostate cancer in 880 consecutive patients

78

Crouzet S.1, Murat F.J.2, Rouviere O.3, Poissonnier L.1, Martin X.1, Colombel M.1, Chapelon J.Y.4, Gelet A.1 1 Edouard Herriot Hospital, Dept. of Urology, Lyon, France, 2Val D'Ouest Hospital, Dept. of Urology, Ecully, France, 3Edouard Herriot Hospital, Dept. of Radiology, Lyon, France, 4INSERM, Dept. of Therapeutic Ultrasound Research Laboratory, Lyon, France Introduction & Objectives: To report the outcome of patients who have undergone HIFU as primary care option for localized prostate cancer (PCa) and to determine the factors influencing the outcomes Materials & Methods: From 1997 all consecutive patients with localized PCa (T1-2, NX, M0) treated with curative intent (whole gland ablation) and with at least 1 year follow-up were included in this study. Follow-up included serial PSA measurements and systematic control biopsy at 6 month with additional biopsies in case of rising PSA. Patients with previous irradiation were excluded from the study. In case of recurrent PCa after the first HIFU treatment, patients were systematically offered a second session. A salvage therapy (External beam Radiation or hormonal deprivation) was introduced in case of any positive biopsy following the 2nd HIFU session. Kaplan- Meier analysis was performed to determine biochemical survival with failure defined according to the 2006 Phoenix definition (nadir +2) Results: A total of 880 patients were included in the study. Mean age was 70 years ±6.3 years, mean PSA before treatment was 8.4 ±5.1ng/ml, 58% of the Gleason were <6, 34% were =7 and 8% ≥8. The clinical stage were T1 52% and T2 48%; Stratification according to D’Amico’s risk group was low, intermediate and high in 36%, 48% and 16% respectively. Median follow-up was 41 months (12 - 132). Mean number of session/patient was 1.41. Mean PSA nadir was 0.45 ± 1ng/ml (median 0.1) with 69% reaching nadir ≤0.3ng/ml. 67 % of the control biopsies were negatives. The overall and cancer specific survival rate at 7 years were 90% and 98%, respectively. The metastasis free survival rate at 7 years was 96%. The 5 and 7 years biochemical survival rates were 75%-62%, 59%-50% and 45-39% for low, intermediate and high risk patients, respectively (p=0.0001). PSA nadir was a major predictive factor HIFU success with 5 and 7 years biochemical survival rates significantly influenced by the PSA nadir (≤0.3ng/ml: 75-67%,0.31-1ng/ml: 42-31%, >1ng/ml: 18-8%; p<.0001). Patients with biopsy proven local relapse underwent salvage therapy, either external beam therapy or androgen deprivation in 156 and 83 patients, respectively Conclusions: Local control and disease free survival rates achieved with HIFU were similar to those expected with conformal external beam radiation therapy. HIFU can be repeated when necessary and is not a therapeutic impasse: it can also be associated to a salvage radiation therapy which will lead to excellent prostate cancer control results

77

Long term oncologic outcomes of patients treated with high intensity focused ultrasound for localized prostate cancer

Sanchez-Salas R.E. , Prapotnich D. , Secin F.P. , Favaretto R. , Flamand V. , Rozet F.1, Galiano M.1, Barret E.1, Cathelineau X.1 1 Institute Montsouris, Dept. of Urology, Paris, France, 2CEMIC, Dept. of Urology, Buenos Aires, Argentina 1

1

2

1

Ablatherm in patients with localized prostate cancer treated in a pioneering HIFU institution who had more than five years of follow-up. Materials & Methods: From January 1996 to October 2010, 528 patients with localized PCA have been treated in our institution. Out of these, 260 have achieved more than five years follow-up and were considered in this study. Data on Prostatespecific antigen (PSA), clinical stage, cancer control, recurrence and complications has been prospectively collected and retrospectively analyzed in order to define long term oncologic efficacy, recurrence defined as PSA nadir + 2 (Phoenix definition) or positive biopsies or secondary treatment patterns. Disease-free survival (DFS) was estimated with Kaplan-Meier curves. Results: We identified 255 patients with more than 5 years of reliable follow-up data. The mean follow-up was 7.2 years (range 5, 12.3 years). The median age at time of treatment was 73 years (range 51-84), median PSA 7,7 ng/ml (range 1.1-44), median prostate volume 37g (range 15-70) and median Gleason score 6 (range 6-9). Stratification according to D’Amico’s risk group was low, intermediate, and high in 117(46%), 128 (50%) and 10(4%) of patients, respectively. The median PSA nadir was 0,8 ng/ml (0-45) with a median time to nadir of 11.4 weeks (0.126.1). Control biopsies were available in 143 (56%) patients within 1 year of HIFU therapy and 79(55%) were reported as negative at 12 months. Recurrence free survival rate at 5 yr was 73%. Secondary therapy free survival rates were 84%, 72%, and 45% (p<0.001) for low-, intermediate-, and high-risk patients, respectively. 43 (17%) patients received re -treatment with HIFU. Ninety percent of patients presented with grade 1 complications (dysuria). Conclusions: Adequate local control and recurrence free survival achieved with HIFU at a long term follow-up are circumscribed for low risk patients. High risk patients should not be considered for HIFU treatment.

1

Introduction & Objectives: To report long term oncologic outcome of HIFU-

Effect of baseline characteristics on relative risk of prostate cancer progression in the Reduction by Dutasteride of clinical progression events in expectant management (REDEEM) trial

Fleshner N.E.1, Lucia M.S.2, Egerdie B.3, Black L.4, Melich K.4, Nandy I.4, Rittmaster R.4 1 Princess Margaret Hospital, Division of Urology, Toronto, Canada, 2University of Colorado School of Medicine, Dept. of Pathology, Aurora, United States of America, 3Urology Associates, Urologic Medical Research, Kitchener, Canada, 4 GlaxoSmithKline, Research and Development, Research Triangle Park, United States of America Introduction & Objectives: The REDEEM trial evaluated the effect of the dual 5α-reductase inhibitor dutasteride in prostate cancer (PCa) progression. Overall, dutasteride significantly delayed progression of PCa compared with placebo. Here we explore the key risk factors in PCa progression. Materials & Methods: REDEEM was a double-blind, placebo-controlled study to assess the efficacy and safety of 0.5 mg/day dutasteride for 3 years in extending the time to disease progression in men 48–82 years of age diagnosed with lowrisk, low-grade PCa and who were otherwise under active surveillance. 12-core prostate biopsies were scheduled at 1.5 and 3 years to evaluate pathological progression; for-cause biopsies were allowed any time during the study if deemed necessary by the investigator. Pathological progression (Gleason score >6, ≥4 cores positive, or ≥50% of any core involved) or initiation of any treatment for PCa, whichever was earlier, was defined as disease progression. A Cox proportional hazard regression, stratified by country, with alpha level 0.10 for retention was used to explore which of the baseline characteristics influence the time to disease progression over 3 years. Results: The relative risk of disease progression and pathological progression increased with higher age, positive family history, higher baseline PSA, and lower baseline prostate volume. Race, baseline PSA velocity and baseline DHT/T levels were not significant predictors of progression. Lower baseline IPSS and lower number of cores evaluated in the baseline biopsy increased risk of disease progression but did not affect pathological progression. Factors affecting time to PCa progression are shown below (table). The relative risk of progression with dutasteride versus placebo decreased from 0.61 to 0.58 when adjusted for significant baseline variables. Table Factors affecting time to progression over three years Disease progression

Pathological progression

Variable

Relative Risk Estimate (95% CI)

p-value

Relative Risk Estimate (95% CI)

p-value

Treatment

0.58 (0.39, 0.86)

0.006

0.70 (0.45, 1.08)

0.11

Family history of PCa

1.75 (1.11, 2.76)

0.016

1.67 (0.99, 2.83)

0.057

Baseline age, years

1.04 (1.01, 1.07)

0.020

1.05 (1.01, 1.08)

0.008

Baseline prostate volume, cc

0.99 (0.97, 1.00)

0.030

0.97 (0.96, 0.99)

<0.001

Eur Urol Suppl 2011;10(2):51

Baseline PSA, ng/mL

1.15 (1.06, 1.24)

<0.001

1.16 (1.06, 1.27)

0.002

Baseline IPSS

0.97 (0.93, 1.01)

0.090

-

-

No. of cores evaluated on baseline biopsy

0.89 (0.77, 1.02)

0.081

-

-

Conclusions: In men with low-risk, low-grade PCa, family history of PCa, age, prostate volume and PSA at baseline, in addition to treatment with dutasteride, are significant determinants of risk of progression.

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Long-term outcome of randomized trial between cryoablation and external beam therapy for locally advanced prostate cancer (t2c−t3b)

Al-Zahrani A.A.1, Autran A.M.1, Williams A.1, Bauman G.2, Chin J.L.1 1 London Health Sciences Centre, University of Western Ontario, Dept. of Surgery, Division of Urology, London Ontario, Canada, 2London Health Sciences Centre, University of Western Ontario, Dept. of Oncology, Division of Radiation, London Ontario, Canada Introduction & Objectives: Our primary objective is to assess and compare the survival outcomes between cryoablation (CRYO) and External Beam Radiation Therapy (EBRT) in locally advanced prostate cancer (T2c−T3b). Materials & Methods: Patients with cT2c−cT3b prostate cancer (CaP)(PSA < 25ng/ml, negative metastatic evaluation on CT and bone scan), initially recruited for the trial from 1999 to 2002, were randomized to either primary CRYO (Cryocare System, Endocare Inc., Irvine, CA, USA) or EBRT (66 Gy in 33 fractions, administered at 2 Gy per day, 5 days a week for 6.5 weeks, directed at the prostate, seminal vesicles, and peri-prostatic region). All patients received neoadjuvant hormonal therapy (HT) for 3 months prior and continued for 3 months after the procedures. Patients underwent regular transrectal ultrasound and biopsy till 24 months of follow-up (at 3, 6, 12, 18, 24 months for CRYO and at 18, 24 months for EBRT) and as clinically indicated thereafter. Biochemical failure was based on the Phoenix criteria (PSA nadir + 2ng/dl). Biochemical disease-free survival (bDFS), disease-specific survival (DSS) and overall survival (OS) were analysed with Kaplan-Meier curve.

Results: Median follow-up was 105.2 (± 35.8) months. Accrual was limited due to newer data favoring longer neoadjuvant HT and higher EBRT dose for patients for locally advance CaP. Sixty two patients completed the trial. Preoperative demographic and clinicopathological characteristics of both groups were comparable. Prostate volume before therapy was smaller in the CRYO group (31.3 ml vs. 40.9 ml) (p≤0.01). There was greater reduction in prostate volume in the CRYO group after intervention (−54% vs. 34%) (p≤0.01). DSS and OS were comparable between both groups. The 8−year bDFS rate was significant lower in the CRYO group (17.4% vs. 59.1%) (p=0.01), however median time to bDFS was not significantly different (Figure). Figure: Kaplan Meier curve for biochemical disease-free survival (bDFS) of external beam radiotherapy (EBRT) group versus cryoablation (CRYO) group (p<0.01) Conclusions: This randomized trial showed that CRYO was inferior in attaining bDFS close to 9 years in patients with locally advanced CaP (cT2c-T3). A recent randomized trial for more localized CaP showed favorable outcome with CRYO cancer. CRYO may be more suited for less bulky CaP or longer neoadjuvant HT is required for optimal bDFS.

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Low-intermediate risk prostate cancer treated with CyberKnife-delivered hypofractionated radiotherapy

Scremin, E.1, Tambone, C.1, Bolzicco, G.2, Favretto, M.S.2, D’Amato, G.2, Ferrarese, P.1, Abatangelo, G.1, Nigro, F.1, Tasca, A.1 1 San Bortolo Hospital, Dept. of Urology, Vicenza, Italy, 2San Bortolo Hospital, Dept. of Radiation Oncology, Vicenza, Italy

Eur Urol Suppl 2011;10(2):52

Introduction & Objectives: The modern Radiotherapy offers technological advances and recent studies suggest that prostate cancer can be treated with few and large doses of radiation. To evaluate safety and feasibility of hypofractionationed body radiation therapy delivered by CyberKnife®, the results of 55 patients with low and intermediate risk prostate cancer are reported. Materials & Methods: From June 2006 to June 2010, 55 patients (Pts) with localized biopsy-proven prostate adenocarcinoma were treated. The median age was 75 (range 57 – 81 years). Gleason score was from 2+2 to 3+2 in 4 patients, 3+3 in 44 patients and 3+4 in 7 patients. Twenty-six Pts were low and 29 intermediate risk. As for clinical stage, 23 patients were T1c, 17 were T2a-b and 15 were T2c. The mean PSA value at diagnosis was 8.9 ng/mL. CyberKnife® Robotic Radiosurgery System, a 6-MV linear accelerator installed on a computercontrolled robotic arm, was used. Four gold fiducials were implanted in the prostate with transperineal ultrasound guidance, with a mean prostate volume of 32.5 cc. Treatment was planned with two CT, acquired with 1mm slice thickness, the second one with bladder contrast. The two studies were fused to better define bladder, urethra and the anatomical border of prostate. Minimum target coverage was 95%, with a prescription dose of 35 Gy in 5 consecutive fractions at the isodose of 80%. Results: At a median follow up of 21 months (range 3–47), there were no biochemical failure and PSA mean value progressively declined from of 4.87 ng/ mL prior to RT to 1.14, 0.68, 0.51 at 6, 12, 18 months respectively. Acute and late side effects were assessed using RTOG criteria: acute grade II urinary and rectal toxicity occurred in 12.7 % and 21.8 % of Pts respectively. Late grade II urinary and rectal toxicity was equally 3.6 % in the 2 groups; there was only 1 Patient (1.8 %) grade III late urinary toxicity. Conclusions: CyberKnife-delivered hypofractionated radiotherapy seems to be an effective and safe treatment for localized prostate cancer.

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Factors increasing late urinary toxicity in prostate cancer radiotherapy

Mathieu R.1, Delobel J.B.2, Chira C.2, Messai T.3, Bossi A.3, Le Prise E.2, Vincendeau S.1, De Crevoisier R.2 1 CHU Pontchaillou, Dept. of Urology, Rennes, France, 2Centre Eugene Marquis, Dept. of Radiation, Rennes, France, 3Institute Gustave-Roussy, Dept. of Radiation, Villejuif, France Introduction & Objectives: To identify patient (pts) co-morbidity or treatment related factors increasing late urinary toxicity in a large series of patients having received prostate cancer radiotherapy (RT). Materials & Methods: A total of 608 pts having received RT in 2 institutions for localized prostate adenocarcinoma has been analyzed. Mean age of the pts was 68 years (45-83), among them: 6% presented with diabetes and 19% had anticoagulant therapy. The tumors were (D’Amico classification): low risk (17%), intermediate (52%) and high risk (31%). The total doses of RT were: 65 Gy (2.5 Gy/fraction) in 23% of pts, 70 Gy in 44% (at 2 Gy/fr. in 44% of them, or 2.5 Gy/fr. in 56%) or 80 Gy at 2 Gy/fr. in 33% of pts. Intensity modulated RT and image guided RT were used in: 53% and 20% of pts receiving 80 Gy, respectively. Late toxicity was assessed according to RTOG classification. Results: Median follow-up was 56 months (6-206). In multivariate analysis, urinary toxicity (> grade 2) was significantly increased by: high dose of RT (RR=1.8, p=0.008)(figure1), anticoagulant treatment (RR=1.7, p=0.05)(figure 2) and diabetes (RR=2.1, p=0.04). Increasing the dose per fraction from 2 Gy to 2.5 Gy (while irradiating to the same total dose of 70 Gy in 7 weeks) didn’t increase the risk of urinary toxicity (p=0.99). Rectal bleeding was also significantly increased by the total dose of radiotherapy (p<0.001) and anticoagulant treatment (RR=1.9, p=0.001). IGRT and IMRT didn’t decreased urinary toxicity significantly.

Conclusions: Diabetes, anticoagulant therapy and high dose of RT increased significantly the risk of late urinary toxicity in prostate cancer RT. The clinical benefit of complex radiation techniques to decrease such toxicity has not been found.