proceedings global congress on prostate cancer 2013

From diagnosis to managing advanced diseaseProceedings of the second Global Congress on Prostate Cancer12-14 June 2013 – Marseille, France

Guest editors

Alberto Bossi, Gustave Roussy Institute, Villejuif, FranceKarim Fizazi, Gustave Roussy Institute, Villejuif, FranceNicolas Mottet, University Hospital, Saint Etienne, FranceArnauld Villers, Regional University Hospital Centre of Lille, France

September 2013 — Special Issue: Proceedings of the second Global Congress on Prostate Cancer ISSN: 2034-8393

From diagnosis to managing advanced diseaseProceedings of the second Global Congress on Prostate Cancer12-14 June 2013 – Marseille, France

TABLE OF CONTENTS

Highlights � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 3 Abstracts � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 27Advertorial Dendreon � � � � � � � � � � � � � � � � � � � � � � 85

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HIGHLIGHTS OF THE GLOBAL CONGRESS ON PROSTATE CANCER, 2ND EDITION PERSONALISED MEDICINE IN PROSTATE CANCER: WHERE SCIENCE MEETS PRACTICE12-14 June 2013 – Marseille, France

AbstractFrom 12-14 June 2013, a multidisciplinary faculty of almost 50 urologists, medical oncologists, radiation oncologists and radiologists gathered in Marseille, France for the second edition of the Global Congress on Prostate Cancer (PROSCA) to exchange on state-of-the-art diagnosis and treatment of patients with prostate cancer (PCa). The main focus was on challenges and dilemmas encountered during clinical decision making, but also future developments and the potential of personalised medicine in PCa was discussed.

Topics covered were:

• The multidisciplinary team approach in clinical practice• The use of modern imaging in PCa detection, staging, treatment planning and follow-up• Quality of care in PCa • The future of local treatment in localised PCa • The management of seniors with PCa• The management of high-risk and newly diagnosed metastatic PCa• The concept of personalised medicine

This issue of the Mirrors of Medicine journal provides the highlights of the PROSCA congress as well as the abstracts that were presented at this occasion.

Guest editors

Alberto Bossi, Gustave Roussy Institute, Villejuif, FranceKarim Fizazi, Gustave Roussy Institute, Villejuif, FranceNicolas Mottet, University Hospital, Saint Etienne, FranceArnauld Villers, Regional University Hospital Centre of Lille, France

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A true multidisciplinary approach in clinical practice: threat or opportunity?Prostate cancer (PCa) can be complex and given the range and number of healthcare professionals involved, poor coordination and miscommunication can occur. To tackle these potential issues, a multidisciplinary approach can be envisaged. A multidisciplinary team (MDT) has been defined as a group of people of different healthcare disciplines, which meet together at a given time to discuss a given patient and who are each able to contribute independently to the diagnostic and treatment decisions about the patient [1]. The core members of a MDT in PCa management could be a urologist, a radiation oncologist, a medical oncologist, a pathologist and a nurse specialist. MDTs need a leader to encourage full participation of team members. Every team member should be encouraged to have an active participation and their individual roles should be meaningful and rewarding. The objectives of an MDT are to improve coordination, communication and decision making between healthcare professionals and patients to obtain more positive outcomes. By providing a team approach to care and by ensuring that patients get the right treatment at the right time, cancer outcomes may be improved. A joined decision is more effective than a sum of individual opinions and it might prevent multiple consultations and unnecessary investigations (Figure 1). Moreover, it will show a better adherence to clinical practice guidelines and increase enrolment into clinical trials. Not to mention the enhanced coordination between hospital services and an ideal learning opportunity to learn from other professionals. A MDT might also decrease the occurrence of self-referral, financially biased [2].

Given the observation that specialists prefer the modality they deliver themselves, it is essential to ensure that men have access to balanced information before choosing a particular therapy for PCa. Patients have multiple sources of information (literature, friends/family, books, media, support groups, internet), but the source they rely on the most is their treating physician [3]. Being managed by individual practitioners or by a MDT appears to significantly influence the management of PCa: in men with low-risk PCa managed by a MDT vs. an individual practitioner, more active surveillance (43% vs. 22%) was chosen and the proportion of patients treated by radical prostatectomy (RP) or radiation therapy (RT) decreased by about 30% (P < 0.001) [4]. In another study, the diagnosis and/or treatment plan was changed for 65% of patients when a MDT re-evaluated the recommendation by a single physician [5]. A study amongst 335 patients with lung cancer has shown that overall the MDT adhered to treatment guidelines in 71% of cases

and that discordance was mainly noted in older patients (> 70 years), patients with comorbidities or patients with borderline performance status [6].

During the congress the performance of a MDT in daily clinical practice was illustrated by an example from an institute in France. In this institute the MDT meets on a regular basis (every other month) and deals with all genitourinary (GU) cancers. The MDT consists of at least 3 types of specialists, e.g. a urologist, a radiotherapist, a medical oncologist, a GU radiologist, a pathologist, a palliative care expert. Meetings are face-to-face or by means of teleconferences in a standardised format, e.g. presence of a coordinator and secretary, use of standardised documents and forms to be completed, letter for general practitioner, etc. All patient files are presented but only very specific cases are being discussed. This means that all new patients but mainly those with a relapse, significant side effects, and those included in clinical trials are being evaluated. The decisions taken are documented in the patient file and should be in line with the approved national guidelines, if not, they must be justified. These decisions will thereafter be discussed with the patients by the referring physician.

The management of PCa patients in a multidisciplinary clinic in the UK was also discussed during the meeting. Multidisciplinary clinics are similar to a MDT within a hospital. The advantages seen in clinical practice are clearly demonstrated: a short time from diagnosis to intervention, a large proportion of patients see more than one healthcare professional, active surveillance is offered to a large proportion of new patients and complications of surgery and RT are registered. The patient satisfaction concerning multidisciplinary clinics is high because of efficient clinical care, possibility to schedule different diagnostic tests on the same day, and good availability of support staff and research.

It is clear that a multidisciplinary approach has important advantages for both the patient and the physicians and should be increasingly applied in clinical practice.Figure 1

Patient

Medical oncologist

Radiation oncologist

Urologist

Treatment advice 1

Treatment advice 2

Treatment advice 3

MDT: •  Urologist •  Radiation oncologist •  Medical oncologist •  Psychologist •  Other

Treatment advice 1

+/-

+/-

+/-

Other?

Treatment advice 4 +/-

Figure 1. The multidisciplinary team (MDT) may improve the quality of care

provided to patients by facilitating coordination, communication and decision

making between different healthcare professionals

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Summary box• A MDT has been defined as a group of people

of different healthcare disciplines, which meet together at a given time to discuss a given patient and who are each able to contribute independently to the diagnostic and treatment decisions about the patient

• The objectives of the MDT are to improve coordination, communication and decision making between healthcare professionals and patients to provide a higher quality of patient care and potentially improve cancer outcomes

• Studies have shown that being managed by a MDT vs. individual practitioners significantly impacts on the diagnosis and management of PCa, with more active surveillance being chosen compared with active therapy

• A multidisciplinary approach has important advantages for both the patient and the physician and should be increasingly applied in clinical practice

Modern imaging in prostate cancer: the light at the end of the tunnel?In clinical practice, advances in modern imaging show promise for improved detection and characterisation of PCa at the different stages of its management including diagnosis, staging, treatment planning and follow-up. A set of clinical European guidelines for multiparametric (mp) magnetic resonance imaging (MRI) has been issued by the European Society of Urogenital Radiology (ESUR) based on literature evidence and consensus expert opinion [7]. However, evidence from large, prospective, long-term trials is still pending.

The role of imaging in prostate cancer detection

The current tools in the diagnosis of PCa are the prostate-specific antigen (PSA) level and the digital rectal examination (DRE) based on which a biopsy may be recommended. However, the specificity of PSA and DRE are relatively low, and a biopsy may miss cancer because the prostate and suspicious areas are largely invisible. Two types of imaging, morphologic and functional, may help in the detection of PCa. Morphologic imaging data are obtained using a single technique: T2-weighted MRI. Functional imaging consists of 3 different techniques: diffusion-weighted MRI (DW-MRI), dynamic contrast-enhanced MRI (DCE-MRI) and magnetic resonance spectroscopy imaging (MRSI). Each technique has specific characteristics and performances.

T2-weighted MRI provides an image of the prostate’s zonal anatomy, seminal vesicles and prostatic capsule. It is mostly used for PCa staging but also has some utility for lesion detection and localisation. For peripheral zone cancer, lesions appear on as diffuse low-signal intensity, focal or infiltrating masses. For central gland cancer, lesions can be identified as areas where uniform signal intensity decreases. The signal intensity has also been correlated to the cancer aggressiveness [8]. In a pooled analysis of 15 studies, the sensitivity of T2-weighted MRI for detection of PCa was 86% and the specificity 55% (Table 1) [9].

DW-MRI evaluates the microscopic mobility of water molecules in tissue. Impeded water movements within cellular dense tissues, such as tumours, appear as high-signal regions on DW-MRI images and as darker signals on apparent diffusion coefficient (ADC) maps. In glandular spaces (healthy prostate luminal spaces) or large extracellular spaces, water motion is less impeded, leading to larger signal attenuation (low signal on DW-MRI) and to higher ADC values. In addition to its value in the detection of cancer, a correlation has been shown between DW-MRI and Gleason grading [10]. In a review of MRI, the

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sensitivity and specificity of DW-MRI for diagnosis of PCa has been reported to vary across studies from 57%-93% and 57%-100%, respectively (Table 1) [11].

DCE-MRI dynamically measures a bolus pass of an intravenously administrated contrast agent through the prostate [9]. For its nutrient and oxygen supply, a tumour forms new vessels made through the process of neoangiogenesis. In tumour tissue these vessels are often leaky or incomplete, which makes it easier for a contrast agent to extravagate into the extravascular extracellular space. In this extracellular space, the gadolinium-based contrast agent increases the signal intensity of T1-weighted images. In this way, tissues with increased perfusion and vessel leakage stand out with respect to normally perfused tissue, which enhances less. DCE-MRI measures the time course of the contrast agent passing through the prostate and the time curves can be described semiquantitatively or modelled into pharmacokinetic parameters, which gives either descriptive measures of the enhancement curve (start of enhancement, wash-in gradient, maximum enhancement, time to peak, washout gradient, area under the gadolinium curve, etc.) or model parameters (forward leakage rate, washout rate constant and leakage space) usual after the fitting to a pharmacokinetic model. In a pooled analysis of 3 studies, the sensitivity of DCE-MRI for detection of PCa was 79% and the specificity 52% (Table 1) [9].

MRSI allows evaluation of the metabolic activity. Within the prostate gland, the most commonly found metabolites are choline, creatine, polyamines and citrates but quantities vary whether lesions are benign (less choline, more citrate, more polyamine) or malignant (more choline, less citrate, less polyamine). The ratio choline/citrate seems to be linked to the aggressiveness of the tumour with higher ratios associated with higher-grade tumours [12]. In a pooled analysis of 10 studies, the sensitivity of MRSI for detection of PCa was 92% and the specificity 76% (Table 1) [9].

Table 1. Pooled estimates of the sensitivity and specificity of different magnetic

resonance imaging (MRI) techniques for the detection of prostate cancer [9,11]

% (95% CI) Sensitivity Specificity

T2-weighted MRI 86 (74-93) 55 (44-66)

DW-MRI* 57-93 57-100

DCE-MRI 79 (69-87) 52 (14-88)

MRSI 92 (86-95) 76 (61-87)

* Range of data from individual studies is reported as due to lack of sufficient data, a meta-analysis could not be performed [11]; CI: confidence interval; DCE: dynamic contrast-enhanced; DW: diffusion-weighted; MRSI: magnetic resonance spectroscopy imaging

While these individual imaging modalities have shown the potential to improve PCa detection, results can be further improved by mpMRI, the combination of anatomic T2-weighted MRI with at least 2 of the functional imaging techniques. In addition to T2-weighted MRI, which mainly assesses anatomy, DW-MRI and MRSI add specificity

to lesion characterisation, while DCE-MRI has a high sensitivity in PCa [7].

There is increasing interest for the use of MRI in biopsy targeting. Compared with standard biopsy, MRI-guided biopsy offers a statistically significantly higher cancer detection rate and positive core rate [13]. According to a recent study [14], MRI-guided biopsy is 3 times more likely to diagnose PCa compared with standard transrectal ultrasound (TRUS)-guided biopsy and detects more Gleason sum ≥ 7 PCa (Figure 2).Figure 2

21%

36%

7%

24%

0%

10%

20%

30%

40%

50%

PCa detection rate % of Gleason sum ≥ 7 PCa of all detected tumours

MRI-guided biopsy 12-core systematic biopsy

P = 0.001

P = 0.037

Figure 2. Magnetic resonance imaging (MRI)-targeted biopsies were more likely

to reveal prostate cancer (PCa) than systematic biopsies and the distribution

of Gleason sum ≥ 7 tumours among all detected tumours was also greater for

MRI-guided biopsies [14]

Another study confirmed that MRI-guided biopsy detects more (16%) Gleason grade 4/5 PCa [15]. Many efforts have been made to investigate the ability of MRI to predict high-grade PCa. The combination of T2-weighted MRI and MRSI, MRSI alone and DW-MRI have shown potential for differentiating between high-grade and low-grade tumours, and low-suspicion lesions on mpMRI have been associated with either negative biopsies or low-grade tumours [10,16-18]. The clinical advantages of a MRI-guided biopsy may thus be that fewer men are being biopsied overall, a greater proportion of men with clinically significant PCa are biopsied and fewer men are attributed a diagnosis of clinically insignificant PCa [19]. It can be concluded that MRI can aid in PCa diagnosis by aiding in better targeting of biopsies which may lead to an improved positive biopsy yield and potentially also help to differentiate between high-grade and low-grade PCa.

The role of imaging in staging of prostate cancer

Once PCa has been diagnosed, management decisions rely on staging and risk of progression of the disease. T2-weighted MRI was the first imaging technique that was used to perform PCa staging and remains to this day the most widely used. Prostate zonal anatomy and tumours are best observed

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on multiplanar T2-weighted MRI. DW-MRI, DCE-MRI and MRSI are available, but are evolving techniques and can be considered as a part of a mpMRI protocol for imaging of the prostate gland. Indeed, mpMRI seems to be particularly useful in T1 and T2 stage disease for assessing the extent of disease. In addition, for assessing metastatic status, mpMRI may be implemented at the level of dedicated organ coverage as well as the whole body for assessing skeletal metastases [20]. DW-MRI has shown potential in detecting metastatic bone disease and monitoring response to therapy [20]. Assessing nodal status with imaging still has limitations and is based on size criteria only.

The role of imaging in treatment planning

After PCa diagnosis and staging a decision on further management can be taken. As mpMRI has been suggested to be able to differentiate between clinically significant and insignificant PCa [10,16-18], MRI can for example guide the decision whether active surveillance is an option in case of no significant PCa. In a retrospective study, 953 patients referred for biopsy had a pre-biopsy mpMRI, a 12-core TRUS-guided biopsy and 2 targeted biopsies at any mpMRI area that was suspicious for malignancy [21]. It showed that 14% of patients eligible for active surveillance based on biopsy criteria were reclassified to higher risk by mpMRI with targeted biopsy. Moreover, the presence of adverse pathological parameters in the RP specimens was higher in the reclassified group vs. active surveillance group (83% vs. 26%, respectively). These and other data suggest that mpMRI may have a role in the selection of patients suitable for active surveillance.

MRI may also provide information on location and contours of tumours for guiding focal therapy, and provide information about tumour contact with the gland surface in case of whole-gland therapy. In most men the PCa is multifocal and bilateral [22]. However, high-grade disease is mostly confined to the index lesion and most of the contralateral cancer foci to the index lesion have characteristics that are associated with indolent or clinically insignificant cancer. Treating only the index lesion by means of focal therapy therefore seems a reasonable option to radical treatment. The ability of MRI to locate suspicious areas in the prostate may offer significant opportunities for focal therapies such as high-intensity focused ultrasound (HIFU).

Although the role of imaging, and in particular of mpMRI, in treatment planning offers significant opportunities, this needs to be further studied and trial methods need to be further defined. As mpMRI is increasingly being used in clinical practice, guidelines concerning its use in treatment planning are also needed.

The role of imaging in prostate cancer treatment follow-up

There has been increasing interest in the role of imaging in follow-up of patients after primary treatment of PCa. Whole-body imaging may be performed in case of biochemical recurrence (BCR) after radical therapy to determine whether this is a local, regional or bone recurrence and/or if salvage therapy is indicated. Imaging of the prostate bed may be performed in case of local recurrence after radical therapy, e.g. to plan a salvage focal therapy, or in case of active surveillance to monitor the progression of the tumour.

Imaging for the detection of distant metastases generally consisted of a bone scan and/or a computed tomography (CT) scan, but this is currently being challenged by a whole-body MRI and/or a choline positron emission tomography (PET)-CT scan. The advantages of a whole-body MRI are that it is routinely available and that e.g. a T1-weighted combined with a DW-MRI protocol (skull to mid-femur) does not involve radiation and no injection of contrast fluid is necessary. This protocol also enables the evaluation of both skeleton and soft tissues. The choline PET-CT scan is more widely used in clinical practice. When looking at the diagnostic accuracy of bone scintigraphy, whole-body MRI and choline PET-CT scan in detecting bone metastases (Table 2), it appears that choline PET-CT scan may have a somewhat lower sensitivity than whole-body MRI [23].

Table 2. Sensitivity and specificity of bone scintigraphy, whole-body magnetic

resonance imaging (MRI) and choline positron emission tomography-computed

tomography (PET-CT) scan in detecting bone metastases [23,24]

Sensitivity Specificity

Bone scintigraphy [23] 70%-100% 75%-100%

Bone scintigraphy + targeted X-ray [24]

86% 98%

Whole-body MRI [24] 98%-100% 98%-100%

Choline PET-CT scan [23] 89% 98%-100%

The use of imaging in the detection of lymph node metastases remains an unresolved challenge. The evaluation of the accuracy of MRI for detection of lymph node metastases after primary treatment is hampered by the fact that there is no gold standard. However, a study in newly diagnosed PCa patients at risk of harbouring lymph node metastases using extended pelvic lymph node dissection (PLND) as the reference standard showed a 18.8% sensitivity and a 95% specificity for choline PET-CT scan and a 42.9% sensitivity and a 81.8% specificity for DW-MRI for detecting pelvic lymph node metastases [25].

The role of imaging in the detection of distant metastases during follow-up after treatment can consist of a whole-body MRI, which, if the outcome is normal, can obviate further imaging investigation. In case of a positive whole-body MRI,

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a choline PET-CT scan could be a second-line examination to increase the specificity of the positive MRI.

MRI of the prostate bed can be used to evaluate whether there is local recurrence after primary therapy in men with BCR. Liauw et al. [26] have evaluated the utility of MRI in detecting local recurrences after RP in 88 men with rising PSA levels but without palpable disease. MRI consisted of T2-weighted, DW-MRI and DCE-MRI. Local recurrence was identified in 21 men (24%). Abnormalities were best appreciated on T2-weighted axial MRI and recurrence locations were peri-anastomotic (67%) or retrovesical (33%). Local recurrence on MRI was significantly associated with the PSA level: recurrence was seen in 37% of men with PSA > 0.3 ng/mL vs. 13% if PSA ≤ 0.3 ng/mL (P < 0.01). This shows that MRI can define areas of local recurrence after RP in a minority of men without clinical evidence of disease, with yield related to the PSA level. This may also help to individualise further salvage RT with regard to the radiation dose and volume.

In the follow-up of patients with BCR after primary RT, DCE-MRI seems to perform better than T2-weighted MRI. T2-weighted MRI seems to depict the intraprostatic distribution of recurrent cancer after external beam RT (EBRT) less accurately and with more interobserver variability than DCE-MRI [27]. The sensitivity of T2-weighted MRI also seems to be lower (38%) than that of DCE-MRI (72%) in detecting local recurrences after EBRT while specificities were comparable (80% and 85%, respectively) [28].

The correlation between DW-MRI and Gleason sum [10] and the observation that repeat biopsy findings showed a higher histologic progression rate in tumours with low ADCs [29] suggests a role of MRI in the selection and follow-up of candidates for active surveillance. Patients having tumours with a low ADC value may not be candidates for active surveillance.

It can be concluded that regarding the role of imaging for follow-up after treatment, whole-body MRI may be used to detect distant metastases. If there are no abnormal findings further evaluation can be avoided. In case of abnormal findings, a choline PET-CT scan may be used as a second test to increase the specificity of a positive MRI. Local recurrence is best evaluated by a mpMRI of the prostate bed. The role of MRI in active surveillance is not yet defined and should be further evaluated.

Summary box• The different techniques in MRI (T2-weighted

MRI, DW-MRI, DCE-MRI, MRSI) each have specific characteristics and performances

• While these individual imaging modalities have shown the potential to improve PCa detection, results can be further improved by mpMRI, the combination of anatomic T2-weighted MRI with at least 2 of the functional imaging techniques

• MRI can aid in PCa diagnosis by aiding in better targeting of biopsies which may lead to an improved positive biopsy yield and potentially also help to differentiate between high-grade and low-grade PCa

• For PCa staging, T2-weighted MRI remains to this day the most widely used technique. mpMRI seems most useful for assessing the extent of disease and metastases. DW-MRI has shown potential in detecting metastatic bone disease. Assessing nodal status with imaging still has limitations

• mpMRI may play a role in treatment planning, such as in selecting patients eligible for active surveillance or for targeting of focal therapy. However, this needs to be further studied

• There has been increasing interest in the role of imaging in follow-up of patients after primary treatment of PCa. Whole-body imaging may be performed in case of BCR after radical therapy to determine whether this is a local, regional or distant/bone recurrence and/or if salvage therapy is indicated. If there are no abnormal findings, further evaluation can be avoided. In case of abnormal findings, a choline PET-CT scan may be used as a second test to increase the specificity of a positive MRI. Imaging of the prostate bed may be performed to evaluate whether there is a local recurrence after radical therapy, and potentially aid in the planning of salvage therapy

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Quality of care in prostate cancer: does volume matter?

MRI, excellent tool but only in very dedicated hands?

mpMRI has been reported to be a very sensitive and specific tool for PCa imaging [30]. It may also predict tumour aggressiveness [10] and in patients with elevated PSA and one or more negative TRUS-biopsies, mpMRI may aid in the detection of (clinically significant) PCa [31]. However, the routine use of mpMRI in diagnosis and staging of PCa has been questioned because of economical reasons and its accuracy depending on the experience of the radiologist [32]. Indeed, with MRI, volume or experience does matter for an accurate performance. Guidelines, such as the ESUR prostate MRI guidelines 2012 [7], may aid in establishing a good and constant quality of MRI. These guidelines provide guidance concerning the most optimal technique and give 3 protocols for the use of MRI in PCa detection, PCa staging (detection of minimal extracapsular extension [ECE]) and detection of lymph node and bone metastases. To standardise the interpretation, reporting and communication of MRI data, the PI-RADS score has been developed which indicates the probability of clinically significant PCa on a 5-point scale (Table 3) [7]. PI-RADS stands for Prostate Imaging and Reporting Archiving Data System. In this scoring system every parameter (T2-weighted MRI, DW-MRI, DCE-MRI and MRSI) is scored on a 5-point scale with a higher score predicting a higher PCa risk. Additionally, each lesion is given an overall score, to predict its chance of being a clinically significant cancer. Next to guidelines, education of radiologists is key to establishing a good and constant quality of MRI. In this perspective, educational courses, hands-on sessions and reference centres that allow education, certification and quality control are of utmost importance. It can be concluded that volume/experience does matter in the quality of MRI but with the aid of guidelines and continuous education, every radiologist can become competent, resulting in good and constant quality of care.

Table 3. PI-RADS classification system [7]. Table reproduced from: Barentsz JO,

Richenberg J, Clements R, et al. 2012 ESUR prostate MR guidelines 2012. Eur Radiol

22(4):746-57

Score T2-weighted MRI Criteria for peripheral zone (PZ) and transition zone (TZ) separate

1 PZ: uniform high signal intensity (SI) TZ: heterogeneous TZ adenoma with well-defined margins

2 PZ: linear or geographic areas of lower SI TZ: areas or more homogeneous low SI, however, well marginated

3 Intermediate appearances not in categories 1-2 or 4-5

4 PZ: discrete, homogeneous low signal focus/mass confined to the prostate TZ: areas of more homogeneous low SI, ill defined: “erased charcoal sign”

5 PZ: discrete, homogeneous low SI focus with extracapsular extension/invasive behaviour or mass effect on the capsule (bulging), or broad (> 1�5 cm) contact with the surface TZ: same as 4, but involving the anterior fibromuscular stroma or the anterior horn of the PZ, usually lenticular or water-drop shaped

Score DW-MRI

1 No reduction in ADC compared with normal glandular tissue� No increase in SI on any high b-value image (≥ b800)

2 Diffuse, hyper SI on ≥ b800 image with low ADC; no focal features, however, linear, triangular or geographical features are allowed

3 Intermediate appearances not in categories 1/2 or 4/5

4 Focal area(s) of reduced ADC but iso-intense SI on high b-value images (≥ b800)

5 Focal area/mass of hyper SI on the high b-value images (≥ b800) with reduced ADC

Score DCE-MRI

1 Type 1 enhancement curve



+1 For focal enhancing lesion with curve type 2–3

+1 For asymmetric lesion or lesion at an unusual place with curve type 2–3

Score MRSI

1 Citrate peak height exceeds choline peak height > 2 times

2 Citrate peak height exceeds choline peak height times > 1, < 2 times

3 Choline peak height equals citrate peak height

4 Choline peak height exceeds citrate peak height > 1, < 2 times

5 Choline peak height exceeds citrate peak height > 2 times

Score 1 = clinically significant cancer is highly unlikely to be present; Score 2 = clinically significant cancer is unlikely to be present; Score 3 = clinically significant cancer is equivocal; Score 4 = clinically significant cancer is likely to be present; Score 5 = clinically significant cancer is highly likely to be present; ADC: apparent diffusion coefficient; DCE: dynamic contrast-enhanced; DW: diffusion-weighted; MRI: magnetic resonance imaging; MRSI: magnetic resonance spectroscopy imaging

Radical prostatectomy, excellent results only in high-volume centres?

RP is a first-line therapy for the treatment of localised PCa. Surgical expertise may decrease the complication rates of RP and improve cancer cure [33]. Experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease positive surgical margin (PSM) rates and improve cancer control. A prospective study assessed 521 PCa patients scheduled for RP by surgeons with high (> 50), medium (20-50) or low annual volume (< 20) at 14 urological departments in Norway. It was shown that the overall PSM rate was 26%, with differences between the high- (18%), medium- (28%) and low-volume (44%) groups (Figure 3) [34]. A similar pattern was observed for pT2 and pT3 patients.

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Figure 3

18%

8%

36%

28% 21%

42% 44%

30%

68%

0%

20%

40%

60%

80%

All patients (N = 521) pT2 patients (N = 339) pT3 patients (N = 182)

% of

men

with

pos

itive

sur

gica

l mar

gins

High volume (N = 296) Medium volume (N = 94) Low volume (N = 131)

P < 0.001 P < 0.001 P = 0.001

Figure 3. The positive surgical margins rate with radical prostatectomy was

statistically significantly higher in low-volume surgeons [34]

Robot-assisted RP (RARP) is replacing open RP as standard surgical approach for clinically localised PCa in the US and is also being increasingly used in Europe [33]. A US study using the Nationwide Inpatient Sample (NIS) compared the rates of blood transfusion, intra-operative and post-operative complications, prolonged length of stay, increased hospital charges and mortality between RARP and open RP, according to volume [35]. An estimated 77,616 men underwent RP, including a robot-assisted and an open procedure in 63.9% and 36.1% of patients, respectively. Overall, patients treated with RARP experienced a lower rate of adverse outcomes than those treated with the open procedure for all measured categories. However, low-volume institutions experienced inferior outcomes relative to the highest volume centres, irrespective of approach. These data were confirmed by another study using NIS data to analyse laparoscopic RARP outcome by hospital volume [36]. It was shown that higher volume hospitals showed fewer complications and lower costs than low-volume hospitals on a national basis. It thus seems that RP performed in high-volume centres or by high-volume surgeons is associated with a lower risk of PSM, an improved cancer control, a lower complication rate and lower costs.

External beam radiotherapy excellent results: a matter of quality control?

For good outcomes of EBRT in PCa, quality indicators are necessary. An evaluation of the feasibility of using indicators to assess RT quality in PCa management was performed among academic and non-academic US institutions [37]. Indicators used to represent surrogates for EBRT quality included established measures, such as the use of prescription doses ≥ 75 Gy for intermediate- and high-risk EBRT patients and androgen deprivation therapy (ADT) in conjunction with EBRT for patients with high-risk disease. It appeared that adherence to defined quality performance indicators (QPIs) was observed in a majority of patients.

Approximately 90% of high-risk patients were treated with ADT plus EBRT and ~80% of intermediate- and high-risk patients receive prescription doses ≥ 75 Gy, consistent with the published results of randomised trials. To ensure a good performance of RT, it is important that quality indicators are evidence-based. In addition, at individual centres, structure, such as good equipment, trained staff and high volume of performed procedures is needed. The processes of patient assessment, decision making and technical details need to be monitored. In addition, the outcomes of therapy, in terms of cancer-free survival, complications, patient satisfaction and quality of life need to be analysed and compared. These control measures will ensure a high quality of cancer care.

Quality indicators in prostate cancer

To measure quality of care, QPIs have to be available or developed. These must be explicitly defined, measurable and preferably actionable. In the US, the RAND cooperation developed a set of possible QPIs for early stage PCa [38]. These include indicators on structure (infrastructural characteristics of the care provider), process (diagnostic, therapeutic and follow-up procedures) and on outcome (results following medical care). The combination of the indicators in these 3 domains provides insight regarding variations in healthcare quality. However, the QPIs are limited in the fact that there is a lack of high-level evidence that links individual structure or process-of-care measures to specific cancer control and/or functional outcomes. The development and use of QPIs to ensure quality of cancer care remains a process in development for many countries. Many different parties, such as the government, cancer societies, healthcare inspectors, insurance companies, healthcare providers and patient organisations may all contribute to the development of QPIs. However, this may also lead to different points of attention, different views and different indicators. It can be argued that healthcare providers should stay in the lead when developing QPIs, using high-quality evidence, and get a better insight in the current care given to PCa patients.

Quality indicators in genitourinary cancer

To make sure that patients are receiving high-quality care it is necessary to establish quality indicators. These should not only measure healthcare activities, but also quality of care, healthcare outcomes and patient satisfaction. In the UK, the National Health Service (NHS) has focused on time lines rather than on quality, such as waiting times, times to see a doctor, time to admission, time to diagnosis and time to treatment. It is important that quality indicators in cancer care include targets for specific parameters as well as patient satisfaction surveys. For example the NHS in Scotland

1111 HIGHLIGHTS

has issued QPIs focusing on 3 goals: most appropriate investigations, high standard of treatment and partnership with patient and doctor. Data are to be collected for all patients and published annually. For instance, their goal is that 70% of patients with metastatic renal cancer receive systemic therapy and that the 30-day mortality after surgery for renal cancer is < 5% [39]. Similar goals are defined for other GU cancers such as PCa (Table 4) and bladder cancer. Another example comes from the British Association Urology Surgeons (BAUS) which recommends a prospective collection of data related to renal surgery, such as blood transfusions and hospital stay. It should be noted that there are also disadvantages to data collection. Data collection is very resource intensive and the outcomes are only as good as the quality of the data submitted. Moreover, their main goal may be the pursuit of pre-established targets rather than on improving quality of care. It can be concluded that quality indicators are essential to providing high-quality care and evaluating working practices. They are likely to result in a more uniform healthcare and may identify areas of concern. However, a careful selection of indicators is essential.

Table 4. Example of prostate cancer (PCa) clinical quality performance indicators

established by the NHS Scottish Cancer Taskforce [39]

Quality indicator Goal

At least 10 cores taken at TRUS biopsy 90%

MRI and bone scan staging in intermediate- and high-risk PCa patients undergoing radical treatment

100%

Positive surgical margin rate in pT2 PCa patients undergoing RP < 25%

Experienced surgeon ≥ 12 RP/year

Metastatic PCa patients receiving immediate hormone therapy 100%

% of patients using > 1 pad per day for incontinence 1 year after RP < 10%

PSA relapse rate after radical therapy < 20%

MRI: magnetic resonance imaging; PSA: prostate-specific antigen; RP: radical prostatectomy; TRUS: transrectal ultrasound

Summary box• Volume/experience does matter in the quality of

MRI but with the aid of guidelines, such as the 2012 ESUR guidelines, and continuous education every radiologist can become competent, resulting in good and constant quality of care

• Volume also does matter in RP outcomes. Surgical expertise, consisting of experience and careful attention to surgical details, adjusted for the characteristics of the cancer being treated, can decrease PSM rates and improve cancer control. RP performed in high-volume centres or by high-volume surgeons are also associated with a lower complication rate and lower costs

• For good outcomes of EBRT in PCa, quality indicators are necessary. These should be evidence-based and at individual centres, structure, such as good equipment, trained staff and high volume of performed procedures is needed. The processes of patient assessment, decision making and technical details need to be monitored. In addition, the outcomes of therapy, in terms of cancer-free survival, complications, patient satisfaction and quality of life need to be analysed and compared

• To make sure that patients are receiving high-quality care it is necessary to establish QPIs. These should not only measure healthcare activities, but also quality of care, healthcare outcomes and patient satisfaction. QPIs must be explicitly defined, measurable and preferably actionable. They are likely to result in a more uniform healthcare and may identify areas of concern. However, a careful selection of indicators is essential. It can be argued that healthcare providers should stay in the lead when developing QPIs, using high-quality evidence, and get a better insight in the current care given to PCa patients

1212HIGHLIGHTS

What is the future of local treatment in localised prostate cancer

Is a robot useful or not?

RP is the standard therapy for localised PCa and the performance by means of robotic surgery is becoming increasingly popular. The goal is to cure the patient while obtaining early continence and preserving erectile function. However, RARP has its advantages and disadvantages. The problem in assessing its true value is that different surgical techniques cannot be compared in randomised, double-blind studies and often only results from single-centre studies are available which are difficult to compare. There is also the problem of self-promotion in the era of internet counselling. The outcome of RP is largely determined by the surgical technique and the biology of the tumour. Advocators of RARP mention amongst others that the surgical technique will be improved as there is a 3D-vision with magnification and depth perception, an improved precision as hand tremors are filtered out and the possibility of intuitive movements with increased grades of freedom. Peri-operative outcomes of RARP seem better than those of open RP, with less blood loss, a lower transfusion rate and potentially less intra- and post-operative complications. Incontinence rates and impotency rates are also reported to be better after RARP compared with open RP. However, opponents of RARP argue that RARP has not yet demonstrated improved value compared with open RP with regard to survival outcomes and PSM rates. In addition, RARP is very costly and it remains to be established whether its high costs are balanced by its benefits. Further well-designed, prospective, large size, multicentre studies should evaluate the benefits and cost-efficiency of RARP vs. open RP to answer the question whether RARP is useful or not.

Active monitoring: yes or no?

A major goal of active surveillance is to reduce the overtreatment of clinically insignificant PCa. Active surveillance is appropriate for patients with the lowest risk of cancer progression: cT1-2a, PSA < 10 ng/mL, biopsy Gleason sum < 6 (at least 10 cores), < 2 positive biopsies, minimal biopsy core involvement (< 50% cancer per biopsy) [33]. However, although active surveillance may reduce overtreatment, patients followed with active surveillance are also exposed to some risks. These concern amongst others the risk associated with repeat biopsies which include the potential for infections and/or other biopsy-related complications, pain/discomfort and increased costs. Men on active surveillance may also be more anxious because of the uncertainty of harbouring cancer and its

progression. Markers of PCa progression and triggers for intervention include serum (PSA kinetics) and urinary biomarkers (PCA3) but their validity has been questioned. In addition, the timing and value of periodic imaging studies for progression of PCa in active surveillance have not yet been established. Therefore it may occur in certain patients that the window for cure with active therapy is missed. Although active surveillance is a good option for certain patients, it is thus also associated with some disadvantages. In the future, improvements in imaging and biomarkers may enable us to better diagnose clinically insignificant PCa and to monitor PCa progression. This may decrease the risks associated with active surveillance such as the need for serial biopsies, and aid in establishing better triggers for intervention.

High-dose brachytherapy: the best option for dose escalation?

Before the advent of 3D-conformal RT (3D-CRT), RT doses to the prostate were usually in the order of 64 Gy in 2-Gy fractions, or equivalent. With 3D-CRT, and more recently intensity-modulated external beam RT (IMRT), dose escalation beyond this limit has been possible. Several randomised studies have shown that dose escalation (range 76-80 Gy) has a significant impact on the 5-year survival without BCR [33]. These trials have generally included patients from several risk groups, and the use of neoadjuvant/ adjuvant hormone therapy has varied. To date, no trials have shown that dose escalation results in an overall survival (OS) benefit, they have all reported improvements in freedom from biochemical progression in patients treated with dose-escalated RT [33]. The best way to deliver high-dose RT is under debate. High-dose brachytherapy has been suggested as the optimal method for dose escalation of RT. It can deliver the adequate dose accurately, with a low toxicity, a high patient acceptance and appears to be cost effective. A study assigned 218 patients with localised PCa to EBRT alone (N = 108) or EBRT followed by a temporary high-dose brachytherapy implant (N = 110) [40]. The biochemical/clinical relapse-free survival was significantly higher in patients treated with EBRT plus high-dose brachytherapy than in patients treated with EBRT alone (P = 0.04). Although high-dose brachytherapy appears less costly than e.g. IMRT, no comparison regarding its efficacy has been performed so far. Other parties have suggested stereotactic body RT (SBRT) as the optimal way to deliver high-dose RT. This may result in a better dose distribution, be radiobiologically more reliable, is less invasive and also less expensive. However, its efficacy remains to be confirmed. Further studies evaluating high-dose RT are needed to establish what the best option is for dose escalation in RT.

1313 HIGHLIGHTS

Focal therapy: still utopia?

Focal therapy, such as cryosurgical ablation of the prostate (CSAP) and HIFU have emerged as alternative therapeutic options in patients with clinically localised PCa. They have been developed as minimally invasive procedures, which have potentially the same therapeutic efficacy as established surgical and non-surgical options, with reduced therapy-associated morbidity. HIFU is still considered to be an experimental treatment, however, CSAP is recommended as a possible alternative treatment by the European Association of Urology (EAU) guidelines for patients who are unfit for surgery, or with a life expectancy < 10 years [33]. The goals of focal therapy in PCa are to control cancer, but to treat only tumours that merit treatment, using precise imaging and targeting, causing minimal functional and psychological morbidity while definitive treatment possibilities are still possible. To have success, a favourable cancer biology, a meticulous patient selection and a reliable technical intervention is necessary. The advantages of focal therapy are good functional outcomes with regard to erectile function and urinary incontinence and improved quality of life outcomes. Although short to medium term cancer control seems good, long-term results are lacking. With CSAP, 5-year BCR-free survival rates were inferior to those achieved by RP in low-risk patients [33]. A concern with focal therapy is that PCa is typically multifocal and that treatment of only the index lesion may not be sufficient to prevent progression. In addition, imaging, such as MRI, is often used for focal therapy targeting, however, there is no accepted standard for disease localisation for the purpose of delivering focal therapy. The current standard for characterising men considering focal therapy is transperineal prostate biopsy using a template-guided approach. However, a transperineal template prostate mapping biopsy is associated with complications which are added to those of the initial diagnostic biopsy. It also remains to be established how success and failure of focal therapy are to be defined as PSA kinetics may not be a good marker. Although focal therapy is currently not yet standard of care for men with organ-confined PCa, it is a therapeutic approach with a high future potential [33]. Therefore further long-term prospective studies into focal therapy are needed. As the skills and competencies to deliver focal therapy are also difficult to achieve and rare in current daily urology practice, education is very important.

Summary box• The benefits of RARP include an improved

surgical technique which may result in better peri-operative and functional outcomes. However, RARP has not yet demonstrated improved value compared with open RP with regard to survival outcomes and PSM rates. In addition, RARP is very costly and it remains to be established whether its high costs are balanced by its benefits. Further studies are needed to answer the question whether RARP is useful or not

• Although active surveillance may reduce the risk of overtreatment, it is also associated with some risks such as those associated with serial biopsy testing and increased anxiety. The validity of markers of PCa progression and triggers for intervention in active surveillance has been questioned. In the future, improvements in imaging and biomarkers may enable us to better diagnose clinically insignificant PCa and to monitor PCa progression. This may decrease the risks associated with active surveillance and aid in deciding when intervention in needed

• High-dose RT has been suggested to improve BCR-free survival. Further, large size, prospective, well-designed studies are needed to establish the best method to deliver high-dose RT, e.g. by means of high-dose brachytherapy or SBRT

• Focal therapy was developed to treat localised PCa with potentially the same therapeutic efficacy as established treatments, but with reduced morbidity. HIFU is still considered to be experimental, however, cryotherapy is recommended as a possible alternative treatment for patients who are unfit for surgery, or with a life expectancy < 10 years. A concern with focal therapy is that treatment of only the index lesion may not be sufficient to prevent progression. In addition, there is no accepted standard for MRI for targeting of focal therapy. Transperineal template prostate mapping biopsy for characterisation of patients is associated with complications. It also remains to be established how success and failure of focal therapy are to be defined. Further long-term prospective studies into it is efficacy and morbidity are needed

1414HIGHLIGHTS

Dealing with prostate cancer in seniors; be prepared for the pappy boom!

The pappy boom in prostate cancer

An analysis from the Surveillance, Epidemiology and End Results (SEER) database shows that in the US from 2006-2010 about 20% of men diagnosed with PCa were aged 75 years or over [41]. The diagnosis of PCa largely depends on elevated PSA levels and/or a suspicious DRE potentially leading to a prostate biopsy. A Swedish population-based study evaluated the prevalence of PSA testing and retesting [42]. It appeared that among men aged 70-89 years about 1/4 had a PSA test last year, 1/3 had a PSA test during the last 2 years, 2/3 had a PSA test during the last 5 years and 3/4 had a PSA test during the last 9 years. The prevalence of having a PSA test within the previous 12 months was highest among men aged 70–79 years (Figure 4). PSA testing is thus very common in older men. However, a significant proportion of these men, especially those with PSA levels < 10 ng/mL and no symptoms, will have clinically insignificant cancer. It may be argued that in older men, only those with a PSA level > 10 ng/mL should have a biopsy. When diagnosed with PCa, older men are more likely to have high-risk disease [43]. Older men also have a lower OS, however, PCa-specific survival was shown to be similar in all ages when controlling for treatment and risk [43]. It can be concluded that, by performing less PSA tests in asymptomatic older men and performing less biopsies in men with PSA levels < 10 ng/ mL, overdiagnosis and treatment of the pappy boom may be prevented.Figure 4

5.6%

16.5%

26.9% 30.5%

23.4%

0%

10%

20%

30%

40%

50%

40-49 50-59 60-69 70-79 80-89

% of

men

hav

ing

a PS

A te

st

Age (years)

Figure 4. Prevalence of prostate-specific antigen (PSA) testing in the last

12 months for men in Stockholm County, Sweden [42]

How to define an elderly patient?

How can we define an elderly patient that should or should not have treatment for his PCa? To answer this question, several clinical variables such as life expectancy, health status, comorbidity and the aggressiveness of the tumour should be taken into consideration. Over the years the median life expectancy has increased for older men. However, life expectancy may vary greatly among elderly men of the same age, which mainly reflects differences in health status [44]. Health status is determined by several factors including comorbidity, nutritional status, and dependence in daily life activities. Comorbidity does influence life expectancy and also seems to influence outcome after treatment for PCa. A Dutch study showed that after adjustment for age, PCa patients with comorbidity were not treated differently, did not suffer from more complications but had a worse prognosis, compared with those without comorbidity [45]. A Swedish study showed that among men with locally advanced PCa managed with non-curative intent, the PCa-specific mortality was the highest among the older age groups [46]. According to the authors this suggests undertreatment in the older treatment groups. This was confirmed in a population-based study in Sweden evaluating the use of chemotherapy in men with castration-resistant PCa (CRPC) [47]. It was shown that among the 2,677 men who died from CRPC and were included in the study, 21% had received chemotherapy. Specifically, 61% of men < 70 years had received chemotherapy, 30% of men between 70 and 79 years and 5% men older than 80 years (Figure 5). According to the authors the low use of chemotherapy in older men with CRPC may be caused by concerns about tolerability of treatment, as well as treatment decisions based on chronological age rather than global health status.

Figure 5

21.0%

61.0%

30.0%

5.0%

0%

20%

40%

60%

80%

All ages < 70 70-79 > 80

% of

men

rece

ivin

g ch

emot

hera

py

Age (years)

Figure 5. Chemotherapy treatment was twice as common in castration-resistant

prostate cancer patients aged < 70 years vs. 70-79 years [47]

1515 HIGHLIGHTS

To answer the question how to define an elderly patient that should have treatment for his PCa, one should look at his life expectancy and take the health status into consideration. The International Society of Geriatric Oncology (SIOG) has proposed recommendations that should provide the highest standard of care for older men with PCa [48]. Older men with PCa should be managed according to international recommendations such as the EAU guidelines, National Comprehensive Cancer Network (NCCN) guidelines, and American Urological Association (AUA) guidelines but these need to be adapted to the patient’s health status. The SIOG recommendations have classified patients into 4 groups: healthy patients, vulnerable patients, frail patients and patients with terminal illness. Healthy patients may receive the standard therapy recommended for their disease, while frail elderly need adapted treatment.

Summary box• PCa screening is very common among older men,

however, the risk of significant PCa is low in case of absence of symptoms and a PSA < 10 ng/mL. By performing less PSA tests in asymptomatic older men and performing less biopsies in men with PSA levels < 10 ng/mL, overdiagnosis and treatment of the pappy boom may be prevented

• An elderly patient that should have treatment for his PCa may be defined by looking at his life expectancy and health status. Health status is determined by several factors including comorbidity, nutritional status, and dependence in daily life activities. Older men with PCa should be managed according to international recommendations such as the EAU guidelines, but these need to be adapted to the patient’s health status. Healthy patients may receive the standard therapy recommended for their disease, while frail elderly need adapted treatment

High-risk prostate cancer: what’s in a name?

Current role of radiation, hormone therapy and chemotherapy in high-risk localised prostate cancer

The treatment options for high-risk localised PCa include amongst others RT and ADT, alone or in combination, and the use of chemotherapy is under evaluation. A single-centre cohort study showed that high-risk PCa patients treated with EBRT had a higher risk of metastatic progression and PCa-specific mortality than those treated with RP [49]. However, as noted by the authors, these results may have been confounded by amongst others differences in the use and timing of salvage therapy. There have been several advances in RT and currently there is increasing interest in the use of SBRT (CyberKnife) for treatment of high-risk PCa. This delivers high-dose radiation with the intention of more accurate targeting than standard RT and also allows for hypofractionated treatment. Compared with high-dose RT, SBRT is less invasive, uses less anaesthesia, has less risk of bleeding and infection, requires less pain medication and seems to result in a reduced hospital stay. However, studies evaluating the survival outcomes of SBRT have generated conflicting results and its true efficacy therefore remains unproven.

Several studies have shown that the addition of long-term adjuvant ADT to EBRT prolongs the survival for patients with high-risk or locally advanced PCa [50-53]. Studies evaluating short-term ADT combined with RT compared with RT alone or long-term ADT alone suggest that there is no evidence that (neo)adjuvant ADT for more than 4 months is of benefit for patients with intermediate-risk PCa [53-56]. Another study including 1,979 patients with stage T1b-2b PCa receiving RT alone (N = 992) or RT combined with 4 months ADT (N = 987) also showed that PCa-specific survival was somewhat better for patients receiving RT plus short-term ADT vs. RT alone, particularly in men with intermediate-risk PCa (Table 5) [57].

Table 5 . Radiation therapy (RT) with short-term androgen deprivation therapy (ADT)

provides a better prostate cancer (PCa)-specific survival than RT alone,

particularly in men with intermediate-risk PCa [57]

PCa-specific survival (%) RT + 4 months ADT (N = 987)

RT (N = 992)

Low risk 97% 99%

Intermediate risk 97% 90%

High risk 88% 86%

Low-risk disease was defined as a Gleason sum ≤ 6, a PSA level ≤ 10 ng/mL, and a clinical stage ≤ T2a; intermediate-risk disease as a Gleason sum of 7 or a Gleason sum ≤ 6 with a PSA level > 10 - 20 ng/mL or clinical stage T2b; and high-risk disease as a Gleason sum of 8 to 10

1616HIGHLIGHTS

A lthough many studies have and are evaluating chemotherapy for high-risk PCa, more research is needed before this can play a role in the current treatment of men with high-risk disease. It can be concluded that the combination of RT and ADT is better than RT alone in patients with intermediate- and high-risk localised PCa. Although high-risk patients seem to benefit from long-term ADT, those with intermediate-risk disease may require only 4 months of ADT adjuvant to RT. SBRT and chemotherapy can currently not yet be recommended for the treatment of high-risk PCa and need to be further evaluated.

Radical prostatectomy for patients with high-risk prostate cancer: don’t deny it to your patient

Several definitions are being used to differentiate between low-, intermediate- and high-risk PCa, using different clinical variables such as PSA level, Gleason sum and clinical stage. Survival rates of high-risk PCa patients can differ substantially, depending on the definition used. In addition, the high-risk PCa group is heterogeneous, containing patients who vary widely in prognosis. It has been shown that within the group of patients with clinically locally advanced PCa, about 20%-30% of patients have pathologically organ-confined disease [58]. In these patients, RP may decrease the risk of overtreatment. A recent single-centre, cohort study assessed the outcomes of 369 PCa patients with lymph node metastases treated with RP and lymph node dissection (LND) [59]. A considerable subset of men with lymph node metastases remained free of disease 10 years after RP and extended LND (Table 6). Patients with pathologic Gleason sum < 8 and low nodal metastatic burden represented a favourable group.

Table 6. 10-year survival outcomes for men with lymph node metastatic prostate

cancer (PCa) treated with radical prostatectomy and lymph node dissection [59]

10-year probability 95% confidence interval

Overall survival 60% 49%-69%

PCa-specific survival 72% 61%-80%

Freedom from distant metastases 65% 56%-73%

Freedom from biochemical recurrence 28% 21%-36%

A retrospective review of 6,624 patients with localised PCa who underwent RP from 2000-2010 at the Memorial Sloan-Kettering Cancer Centre (MSKCC) in the US showed that during this time period the proportion of RP-treated patients with intermediate- and high-risk PCa increased, while the proportion of patients with low-risk PCa decreased [60]. Another study showed that high-risk PCa patients treated with RP had a lower risk of metastatic progression and PCa-specific mortality than those treated with EBRT [49]. However, as noted by the authors, these

results may have been confounded by amongst others differences in the use and timing of salvage therapy. Although it seems that surgery clearly has a role in the treatment of high-risk PCa, its sequence, timing and/or combination with other hormonal or systemic therapies remains an area for research. In daily practice, high-risk PCa patients should be managed with a multimodality approach in which surgery could play an important role.

Post-operative radiotherapy for high-risk prostate cancer; to wait or not to wait?

Adjuvant RT to RP is generally given to patients at high risk because of adverse pathological features. Although several non-randomised studies have been published on post-operative RT, there are also 3 recently published phase III randomised studies comparing RP with adjuvant RT vs. observation. These concern the Southwest Oncology Group (SWOG) 8784 trial [61], the European Organisation for Research and Treatment of Cancer (EORTC) trial 22911 [62] and the Arbeitsgemeinschaft Radiologische Onkologie (ARO) 96-02 trial [63]. The SWOG 8784 trial included 431 men with pT3 N0 M0 PCa who were randomised to 60-65 Gy adjuvant RT after RP (N = 214) or observation (N = 211) [61]. Median age was 65 years and median follow-up 12.6 years. The EORTC 22911 included 1,005 patients with pT2-3 N0 PCa aged ≤ 75 years who were randomised to post-RP RT consisting of 60 Gy (N = 502) or observation (N = 503) and who were followed-up for a median of 10.6 years [62]. Finally, the ARO 96-02 trial randomised 385 patients with pT3 N0 PCa aged ≤ 75 years to post-RP RT consisting of 60 Gy (N = 193) or observation (N = 192) who were followed for a median of 53.7 months [63]. All 3 trials demonstrated significant improvements in BCR-free survival with the use of adjuvant RT after RP compared with observation (Table 7) [61-64]. A meta-analysis of BCR data performed as part of a literature review for the American Society for Therapeutic Radiation and Oncology (ASTRO)/AUA guideline on adjuvant and salvage RT after RP yielded a pooled hazard ratio (HR) of 0.48 (95% confidence interval [CI]: 0.42-0.56; P < 0.00001) [64]. Two of the trials demonstrated a statistically significant reduction in the cumulative incidence of locoregional failure in patients treated with adjuvant RT compared with RP only patients [61,62,64]. Only the SWOG 8794 trial demonstrated a significantly improved metastatic recurrence-free survival and OS; 71% and 74% for patients treated with adjuvant RT compared with 61% and 66% for patients managed with observation [61]. It can be concluded from these trials that the outcomes regarding a survival benefit of adjuvant RT to RP are not clear. However, there were consistent findings showing an improved BCR-free survival and reduction in locoregional recurrence with adjuvant RT to RP.

1717 HIGHLIGHTS

When considering adjuvant RT to RP, one must also consider its toxicity. Acute toxicity to the GU system may occur, and late toxicities may manifest cumulatively for several years after RT and persist for many years. The SWOG 8794 trial reported that at a median of 127 months follow-up, urethral stricture was more common among patients receiving adjuvant RT (17.8%) than among patients managed with observation (9.5%) [64]. Proctitis also was more common among RT patients (3.3%) than among observation only patients (0%). The ASTRO/AUA guidelines conclude that patients who are being considered for management of localised PCa with RP should be informed of the potential for adverse pathologic findings which may result in a higher risk of cancer recurrence and that these findings may suggest a potential benefit of additional therapy after surgery [64].

Summary box• The combination of RT and ADT is better than RT

alone in patients with intermediate- and high-risk localised PCa

• Although high-risk PCa patients seem to benefit from long-term ADT, those with intermediate-risk disease may require only 4 months of ADT adjuvant to RT

• SBRT and chemotherapy can currently not yet be recommended for the treatment of high-risk PCa and need to be further evaluated

• RP clearly has a role in the treatment of high-risk PCa, however, its sequence, timing and/or combination with other hormonal or systemic therapies remains an area for research. In daily practice, high-risk PCa patients should be managed with a multimodality approach in which surgery could play an important role

• The results from 3 phase III randomised studies comparing RP with adjuvant RT vs. observation in patients with high-risk PCa do not demonstrate a clear survival benefit of adjuvant RT to RP. However, they do show that adjuvant RT to RP improves BCR-free survival and decreases the incidence of locoregional recurrence

Treatment of patients with newly diagnosed metastatic disease

Preventive treatment of the primary tumour and treating local complications

RP is the first-line treatment for localised PCa. The long-term risk of death due to PCa after RP seems modest. A multi-institutional cohort of 12,677 patients treated with RP from 1987-2005 showed that the 15-year PCa-specific mortality and all-cause mortality were 12% and 38%, respectively [65]. Considering the 7,403 patients treated since 1998, only 4% had a predicted 15-year PCa-specific mortality > 5%. In patients with high-risk PCa, PCa-specific mortality rates are substantially higher. A cohort study of 12,184 men with locally advanced PCa managed without curative intent (e.g. active surveillance, hormone therapy) showed a PCa-specific mortality rate at 8 years of 52% for patients with Gleason sum 8 and 64% for men with Gleason sum 9-10 [46]. In patients with high-risk or locally advanced PCa, treatment of the primary tumour by means of RP or RT seems to improve survival and is important for prevention of further progression. An analysis of the SEER database showed that patients with localised high-risk PCa ≤ 65 years had the lowest PCa-specific mortality when treated with RP compared with RT or observation [66]. However, RP was equally favourable to RT in patients 70-79 years old and RT appeared better than RP or observation in patients ≥ 80 years old. Retrospective studies analysing data from patients with cT3 PCa who underwent RP within the framework of a multimodality approach have shown 10-year PCa-specific survival rates of around 90% (Table 8).

Table 7. Outcomes of phase III randomised controlled trials evaluating adjuvant radiation therapy (RT) after radical prostatectomy (RP) for patients with pT2-3 prostate

cancer [61-64]

SWOG [61] EORTC [62] ARO [63]

RT (N = 214)

Observation (N = 211)

P RT (N = 502)


P RT (N = 193)


P

BCR-free survival 10 yr: 53% 10 yr: 26% < 0�001 10 yr: 61% 10 yr: 41% < 0�001 5 yr: 72% 5 yr: 54% 0�0015

Locoregional recurrence 10 yr: 8% 10 yr: 22% < 0�01 10 yr: 8�4% 10 yr: 17�3% < 0�0001 - - -

Distant metastases (cumulative) 10 yr: 9�3% 10 yr: 17�5% 0�016 10 yr: 10% 10 yr: 11% 0�94 4�5 yr: 2% 4�5 yr: 3�1% -

Overall survival 10 yr: 74% 10 yr: 66% 0�023 10 yr: 76�9% 10 yr: 80�7% 0�20 - - -

ARO: Arbeitsgemeinschaft Radiologische Onkologie; BCR: biochemical recurrence; EORTC: European Organisation for Research and Treatment of Cancer; SWOG: Southwest Oncology Group; yr: year

1818HIGHLIGHTS

Table 8. Oncological outcomes in retrospective studies analysing data from

patients with cT3a prostate cancer (PCa) who underwent radical prostatectomy

within the framework of a multimodality approach

Author, year N Overall survival PCa-specific survival

5 year 10 year 5 year 10 year 15 year

Ward, 2005 [67] 841 90% 76% 95% 90% 79%

Carver, 2006 [58] 176 - - 94% 85% 76%

Hsu, 2007 [68] 200 96% 77% 99% 92% -

Freedland, 2007 [69] 58 - - 98% 91% 84%

Yossepowitch, 2008 [70] 243 - - 96% 89% -

Stephenson, 2009 [65] 254 - - - 85% 62%

Adjuvant RT to RP seems to improve survival outcomes of patients with ECE, PSM or seminal vesicle invasion (SVI) [61]. Several studies have shown the efficacy of RT in addition to ADT in high-risk PCa. The SPCG-7 study was a phase III randomised trial including 875 patients with locally advanced PCa (cT3, PSA < 70 ng/ mL, N0, M0) treated with ADT alone or ADT with adjuvant RT [71]. Compared with ADT alone, the addition of RT reduced the 10-year PCa specific and overall mortality by 12.0% and 9.8%, respectively. This was confirmed by another phase III randomised controlled trial [72]. The fact that treatment of the primary tumour is very important was shown by a retrospective analysis of 1,469 patients with clinically localised PCa who underwent RT [73]. Local failure defined as PCa recurrence or a positive biopsy, was the strongest predictor of distant metastases in a multivariate model.

ADT is the mainstay treatment for patients with lymph node positive PCa. A study from the mid 1980’s compared delayed ADT with early ADT without local treatment of the primary tumour in patients with T2-3 pN1-3 M0 PCa [74]. The 10-year cumulative incidence of death resulting from PCa was 55.6% in the delayed ADT group vs. 52.1% with immediate ADT. The outcomes of this trial have been challenged because the trial was underpowered. In contrast, a more recent study did show a benefit with respect to OS, PCa-specific survival and progression-free survival for immediate vs. delayed ADT in patients with lymph node positive PCa after RP and LND [75]. Local control of the primary tumour also seems important for patients with lymph node positive PCa. An analysis of the Munich cancer registry included 1,413 PCa patients diagnosed as lymph node positive during PLND and underwent completed or abandoned RP [76]. RP was abandoned in 456 patients, whereas 957 patients underwent RP despite the lymph node positive finding. It was shown that patients with a complete RP had an improved OS and PCa-specific survival compared with patients with an abandoned RP (Table 9).

Table 9. Lymph node positive prostate cancer (PCa) patients who had a complete

radical prostatectomy (RP) demonstrate a better overall and PCa-specific survival

compared with patients with an abandoned RP [76]

Complete RP (N = 957)

Abandoned RP (N = 456)

Overall survival

• 5 year 83�7% 60�1%

• 10 year 63�8% 28�2%

PCa-specific survival

• 5 year 94�9% 70�5%

• 10 year 86�2% 40�5%

This suggests that RP may be associated with a survival benefit also in lymph node positive patients. In addition, a study in 703 consecutive patients with positive lymph nodes treated with RP and LND showed that adjuvant RT plus ADT significantly improved PCa-specific survival and OS [77]. These data reinforce the need for a multimodal approach in the treatment of lymph node positive PCa.

Data on the role of surgery in metastatic PCa are scarce. The SWOG 8894 trial, a randomised phase III trial of 1,286 patients with metastatic PCa who were randomised to orchidectomy vs. orchidectomy combined with flutamide, included an unplanned secondary analysis of the impact of previous RP (N = 148) [78]. It was shown that previous RP was associated with a statistically significant decrease in the risk of death (HR: 0.77; 95% CI: 0.53-0.89) relative to those who did not undergo earlier RP. A single-centre Chinese study including 146 men with newly diagnosed metastatic PCa, receiving ADT as initial systematic therapy, treated 39 patients with transurethral resection of the prostate (TURP) for benign prostatic hyperplasia [79]. The results suggest that TURP resulted in a better and more prolonged response to ADT, with a trend towards positive influence on PCa-specific survival and OS. Local obstructive complications are common in metastatic PCa. Maximal local control by means of surgery may also prevent local obstructions later on during progression to metastatic PCa.

It can be concluded that in locally advanced PCa, the concept of improved outcomes with local control by e.g. RP has been demonstrated in randomised controlled trials. In lymph node positive and metastatic PCa, interesting data exist which support the role of surgery in these settings. Nevertheless, prospective trials are urgently needed to confirm these findings.

Non-systemic therapy in low-volume metastatic disease

Patients with metastatic PCa are considered palliative and the first-line treatment is ADT. While ADT may provide a benefit in deferring progression, it is associated with considerable morbidity such as impaired physical activity, sarcopenic obesity, impotence, loss of libido, metabolic

1919 HIGHLIGHTS

syndrome, osteoporosis and anxiety and/or depression. Considering this, it is questionable whether all patients with asymptomatic metastatic PCa should be offered ADT. In this perspective the concept of oligometastases may prove useful, which has been defined as the state in which the patient shows distant relapse in only a limited number of regions (Figure 6) [80].

Figure 7

Localised prostate cancer Oligometastases Polymetastases

Figure 6. Oligometastases represents the state in which the patient shows only a

limited number of distant recurrences

New imaging techniques, such as 18F-fluorodeoxyglucose (FDG) and 11C-choline PET-CT scans allow earlier identification of these oligometastases. The role of surgery or RT in treating oligometastases and whether this will defer initiation of ADT and improve the patient’s survival is being studied. The evidence concerning salvage surgery or RT for oligometastases after RP is still very limited. One study in 72 consecutive patients with BCR and limited nodal recurrence detected by 11C-choline PET-CT after RP were treated with PLND and/or retroperitoneal salvage LND [81]. A total of 56.9% of patients reached a PSA nadir of < 0.2 ng/ mL. However, in patients with a complete biochemical response after salvage LND who were not treated with adjuvant ADT (N = 29), the BCR-free survival at 5 years was only 10.3%. In the total population, 34% of patients were free from clinical recurrence at 5 years. Further, large size, prospective randomised trials are needed to evaluate the value of salvage LND as a possible treatment option for selected patients with limited nodal recurrent PCa. A centre in Italy evaluated salvage (lineac-based or robotic image-guided) SBRT in patients with isolated single lymph node recurrent PCa after primary therapy and showed that this approach is feasible and safe [82]. The use of image-guided single-fraction, robotic stereotactic radiosurgery for oligometastases has shown actuarial 6-month, 12-month and 24-month local tumour control rates of 95.5% (95% CI: 83.0-98.8%) for all, as defined by MRI and PET-CT scan [83]. A Belgian study investigated whether repeated SBRT of recurrent oligometastases after local therapy was able to defer the initiation of ADT in patients with low-volume (≤ 3) bone and lymph node metastases [84]. This study suggested that salvage SBRT is feasible, well-tolerated and that it defers ADT with a median of 38 months in patients with limited bone or lymph node

metastases. It can be concluded that low-volume metastatic PCa could be a separate entity from polymetastatic disease. Local aggressive treatment seems feasible, safe and may postpone ADT, however, this should be further evaluated.

Systemic treatment of patients with newly diagnosed metastatic disease

Ever since Huggins and Hodges demonstrated > 70 years ago that PCa is an androgen-dependent cancer, ADT has become the mainstay for treatment of (symptomatic) metastatic PCa, usually with a long-lasting luteinising hormone-releasing hormone (LHRH) agonist or antagonist. Two studies performed in the 1990’s showed that there was no difference in survival between orchidectomy and goserelin [85,86]. A meta-analysis of 27 randomised trials has shown that the addition of an anti-androgen to an LHRH agonist for treatment of metastatic or locally advanced PCa improved the 5-year survival by about 2-3%, however, this was associated with an increased rate of adverse events, reduced quality of life and high costs [33,87]. The LHRH antagonist degaralix has been compared with the LHRH agonist leuprolide [88]. Results showed a similar testosterone suppression, but the absence of a testosterone flare with degaralix. Non-steroidal anti-androgen monotherapy (e.g. bicalutamide) is stated by the EAU guidelines as an alternative to castration in well-informed metastatic patients with a low PSA level, however, the expected benefit of bicalutamide for quality of life compared with castration is far from being proven [33].

There is still controversy over the most appropriate time to introduce ADT therapy in non-symptomatic metastatic PCa patients. A review from the Cochrane collaboration showed that early androgen suppression significantly reduced disease progression and complication rates due to progression itself [89]. However, it did not improve PCa-specific survival and provided a relatively small benefit in OS, with an absolute risk reduction of 5.5% after 10 years. Intermittent ADT has been proposed as a means to delay the emergence of CRPC, to improve quality of life and to reduce costs. The SWOG 9346 trial included men with newly diagnosed, metastatic, hormone-sensitive PCa, a PSA level ≥ 5 ng/ mL who received a LHRH agonist for 7 months [90]. A total of 1,535 patients with a PSA decrease ≤ 4 ng/mL were randomised to continuous (N = 765) and intermittent ADT (N = 770). The primary objective was to assess whether intermittent therapy was non-inferior to continuous therapy with respect to OS, with a one-sided test with an upper boundary of the HR of 1.20. The median OS after randomisation was 5.8 years in the continuous therapy group as compared with 5.1 years in the intermittent therapy group (HR for death with intermittent therapy: 1.10; 90% CI: 0.99-1.23; Figure 7). The results of the study were inconclusive as the CI for survival exceeded the upper boundary for non-inferiority, suggesting that a

2020HIGHLIGHTS

20% greater risk of death with intermittent therapy than with continuous therapy could not be ruled out. However, too few events occurred to rule out significant inferiority of intermittent therapy. Intermittent therapy did result in small improvements in quality of life.

Years since Randomisation

No. of Median Deaths Survival (yr)Continuous therapy 445 5.8Intermittent therapy 483 5.1

No. at RiskContinuous therapy 765 325 64Intermittent therapy 770 291 52

0 5 10 15

Surv

ival

(%)

100

90

80

70

60

50

40

30

20

10

0

Figure 7. Median overall survival in men treated with intermittent or continuous

androgen deprivation therapy [90]. Adapted from Hussain M et al. [90] with

permission from the Massachusetts Medical Society

It has recently been investigated whether early chemotherapy might improve the overall outcomes of patients with metastatic non-CRPC [91]. In an open-label phase III study, patients with metastatic PCa were randomised to receive ADT plus docetaxel (N = 192) or ADT alone (N = 193). Median BCR-free survival and clinical progression-free survival were statistically significantly longer in the group treated with ADT plus docetaxel than in the group treated with ADT alone. However, the median OS did not differ between both groups. The authors concluded that docetaxel should not be used as part of first-line treatment for patients with metastatic non-CRPC. Overall, it can be concluded that ADT is the standard therapy for metastatic PCa and aims to prevent or delay symptoms due to disease progression and to improve and maintain quality of life. As ADT may have significant side effects such as impotence, loss of libido, hot flushes, weight gain, loss of muscle, fatigue, cardiovascular risk and a decrease in bone mineral density, treatment-related morbidity should be taken into consideration when managing patients with metastatic PCa.

Newly diagnosed metastatic disease: new data, new perspectives?

Patients with newly diagnosed metastatic PCa represent a heterogeneous population. Various prognostic factors to define this population have been suggested, including general factors, such as pain, Eastern Cooperative Oncology Group (ECOG) score, Gleason sum or biological information (haemoglobin level, C-reactive protein level, alkaline

phosphatase), which still need to be confirmed in large trials [33]. The SWOG 8894 trial has classified patients who have only nodal metastases or pelvic and axial bone metastases as having minimal disease, while those with visceral metastases or appendicular bone metastases have been defined as extensive disease [92]. An updated more precise classification has been published, which discriminates patients into 3 groups according to survival, with a median overall survival in the good, intermediate and poor prognosis groups of 54, 30 and 21 months, respectively (Table 10) [93].

Table 10. Prognostic factors for the heterogeneous metastatic population for

patients with advanced prostate cancer [93]

Prognostic factor Good prognosis

Intermediate prognosis

Poor prognosis

Axial bone metastasis and/or nodes +

Appendicular bone or visceral metastases + + + +

Performance status ≥ 1 - - + +

Gleason sum ≥ 8 - +

PSA ≥ 65 ng/mL - +

PSA: prostate-specific antigen; +: factor present; -: factor absent (i�e�, performance status < 1, Gleason sum < 8 or PSA < 65 ng/mL)

The PSA response, i.e. the speed of PSA decline after the start of ADT therapy has been suggested as another predictive factor of survival [94]. Others have suggested that the circulating tumour count (CTC) may stratify metastatic PCa patients as CTCs have been shown to be an independent prognostic factor for progression-free survival on multivariate analysis and baseline CTC counts were predictive of patient survival [95,96].

The rationale for ADT in patients with metastatic PCa is to suppress serum testosterone levels. Most PCa patients receiving LHRH agonists will achieve serum testosterone values at or below the castration level (< 20 ng/dL). However, about 13%-38% of patients fail to achieve this therapeutic goal, while 2%-17% of patients do not achieve a serum testosterone level below 50 ng/dL [33]. Furthermore, up to 24% of men treated with LHRH agonists may experience testosterone surges (testosterone > 50 ng/dL) during long-term treatment upon re-administration of the agonist drug, i.e., the ‘acute on-chronic effect’ or ‘breakthrough responses’ [33]. The impact on survival of these breakthrough responses is still unknown. To improve castration, LHRH antagonists have been suggested as alternative to LHRH agonists. With LHRH antagonists testosterone suppression seems to be similar to that of LHRH agonists, but no testosterone surge occurs [88]. Other agents, such as those targeting the androgen receptor (enzalutamide) or androgen synthesis, via CYP 17 inhibition (abiraterone), have been used for treatment of hormone-sensitive CRPC, however, these need to be further evaluated for the treatment of metastatic PCa. In addition, non-hormonal therapy such as docetaxel and sipuleucel-T might be considered in metastatic

2121 HIGHLIGHTS

PCa, but more research is definitely needed [91]. It can be concluded that further research should be directed towards the development and evaluation of new agents for treatment of metastatic PCa, in which the disease heterogeneity needs to be considered.

Summary box• In patients with high-risk or locally advanced PCa,

treatment of the primary tumour by means of RP or RT provides survival benefits and is important for prevention of further progression

• In lymph node positive and metastatic PCa, interesting data exist which suggest a survival benefit and support the role of surgery in these settings. Nevertheless, prospective trials are urgently needed to confirm these findings

• Low-volume, limited, metastatic PCa, i.e. oligometastases, could be a separate entity from polymetastatic disease and may be treated differently. Limited data have demonstrated the feasibility and safety of local aggressive treatment and suggest that this may postpone the initiation of ADT, however, this should be further evaluated

• ADT is the standard therapy for metastatic PCa and aims to prevent or delay symptoms due to disease progression and to improve and maintain quality of life. Treatment-related morbidity should be taken into consideration when managing patients with metastatic PCa

• It is still unclear when it is the most appropriate time to introduce ADT in asymptomatic metastatic PCa patients

• The results of a recent non-inferiority study comparing intermittent with continuous ADT were inconclusive. The CI for survival exceeded the upper boundary for non-inferiority, suggesting that a 20% greater risk of death with intermittent therapy than with continuous therapy could not be ruled out

• Chemotherapy cannot be recommended for patients with metastatic non-CRPC

• Metastatic PCa patients are a heterogeneous population. While several prognostic factors to define this population have been suggested, research into this area (e.g. CTC, PSA response to treatment) is ongoing to be able to better stratify this population

• Research in metastatic PCa is also evaluating new therapies, such as hormonal and non-hormonal therapy to provide a more optimal treatment to every patient

Personalised medicine for prostate cancer? Dream or reality?

Beyond PSA: the next generation of prostate cancer biomarkers

Early detection of PCa is currently mainly based on the PSA level and outcome of DRE. However, as both PSA and DRE have a low specificity for PCa, there is a high risk of overdiagnosis and overtreatment. There is an urgent need for novel biomarkers to supplement PSA and other clinical information to aid in the diagnosis of PCa. Many potential new biomarkers are currently under evaluation, e.g. pathways consisting of multiple proteins, protein modifications at expression level or cellular location, genes, RNA, micro-RNA, SNPs, etc. However, their direct clinical relevance still needs to be confirmed. Recently, research has focused on SNPs (i.e. a DNA sequence variation) associated with PCa, which may serve as a germline indication of an individual’s risk for developing cancer. Although each individual SNP is likely to contribute to a minor degree to an individual’s risk of developing cancer, combining multiple SNPs may yield more informative results. In a retrospective study, Zheng et al. [97] evaluated 16 SNPs from 5 chromosomal regions in a Swedish population (2,893 men with PCa and 1,781 controls) and assessed the individual and combined association of the SNPs with PCa. It was shown that 5 SNPs and family history were estimated to account for 46% of the PCa cases. Men with one or more of these 5 SNPs combined with family history had an odds ratio up to 9.5 for developing PCa. The role of SNPs in the future diagnosis of PCa needs to be further evaluated. However, not only diagnostic markers are needed, also markers that can predict disease progression are of utmost importance. Improved patient stratification can allow for a more rational application of current treatments and the selected testing of novel therapeutics. Singh et al. [98], using microarray expression analysis, identified a set of genes that strongly correlated with the Gleason sum of the tumour. Moreover, a model using gene expression data alone, accurately predicted patient outcome following RP. Although these are promising data, they need to be validated in further studies. In the need for biomarkers that improve the ability to predict disease outcome, Cuzick et al. [99] have measured the expression level of 31 genes involved in cell cycle progression (CCP genes), created a predefined score and evaluated its ability to predict PCa outcome. The signature was tested in a retrospective cohort of 366 patients who had undergone RP and in a retrospective cohort of 337 men with clinically localised PCa diagnosed by a TURP and managed conservatively. In the RP cohort, the CCP score predicted BCR in univariate analysis (HR for a doubling in CCP: 1.89; 95% CI: 1.54-2.31; P = 5·6 × 10−9) and multivariate

2222HIGHLIGHTS

analysis (HR: 1.77; 95% CI: 1.40-2.22; P = 4·3 × 10-6). The CCP score and PSA were the most important and most clinically significant variables in the best predictive model. The prognostic value of the CCP score in predicting RP outcomes was recently validated in an external cohort [100]. In the TURP cohort, the CCP score was the dominant variable for predicting PCa-specific mortality in both univariate analysis (HR: 2.92; 95% CI: 2.38-3.57; P = 6.1 × 10−22) and multivariate analysis (HR: 2.57; 95% CI: 1.93-3.43; P = 8·2 × 10−11; Table 11) [99]. When validated in prospective cohorts, the CCP score may thus be a new predictor of PCa outcome and may aid in personalising treatment for PCa.

Table 11. Multivariate analysis predicting prostate cancer (PCa)-specific death in

a cohort of conservatively treated patients who were incidentally diagnosed with

PCa during transurethral resection of the prostate [99]

Variable N Hazard ratio (95% CI) P -value

CCP score 337 2�57 (1�93–3�43) 8�2 x 10-11

Gleason sum

• < 7 172 1 (reference)

• 7 73 2�45 (1�09–5�48) 0�02

• > 7 92 2�72 (1�22–6�08)

log (1+ PSA) [ng/mL] 337 1�84 (1�46–3�32) 6�2 x 10-8

CCP: cell cycle progression genes; CI: confidence interval; PSA: prostate-specific antigen

Another research group aimed to develop a molecular panel for PCa progression by analysing data from a Swedish watchful waiting cohort with up to 30 years of clinical follow-up using a novel method for gene expression profiling [101]. The gene expression profiles of 6,100 genes for 281 men divided in 2 groups were identified: men who died of PCa and men who survived more than 10 years without metastases. None of the predictive models using molecular profiles significantly improved over models using clinical variables only. Additional computational analysis confirmed that molecular heterogeneity within both the lethal and indolent classes was widespread and this may be a limitation in the development of a lethal PCa signature. In contrast, Cheville et al. [102] developed a gene panel model predictive of systemic progression and death from high-grade PCa incorporating gene expression of topoisomerase-2a, cadherin-10, the fusion status based on ERG, ETV1and ETV4 expression, and the aneuploidy status. This model had an area under the receiver operating characteristic curve (AUC ROC) of 0.81 and may, when externally validated, identify men with high-risk PCa who may benefit from more intensive follow-up and adjuvant therapies. Emerging evidence shows that microRNAs (miR) are involved in the pathogenesis of PCa. Spahn et al. [103] showed that miR-221 is progressively downregulated in PCa and PCa metastasis, and has potential as a new biomarker to predict clinical progression in high-risk PCa. It can be concluded that there is much promising data concerning biomarkers for PCa; these concern diagnostic markers, prognostic markers and

predictive markers, however, further research and validation is needed before they can be applied in daily clinical practice.

Personalised medicine: example from non-genitourinary malignancies

Cancer remains the leading cause of death in many countries. Selecting the right therapy for the right patient is very important and is in many cases determined by patient and tumour characteristics. However, patients with apparent similar cancer do not respond the same to therapy; there is absence of efficacy in some patients and some patients experience undue toxicity. Over the years, the diagnosis of various cancers such as lung and breast cancer have gone from a histological perspective to more biological perspective including the detection of mutated molecular pathways. Cancer therapy, which was often organ-based has evolved to molecular classification and molecular-targeted therapy allowing a more personalised medicine. Patients with apparent similar neoplasms can be differentiated by e.g. biomarkers and treatment can be individualised. In breast cancer, colo-rectal cancer and non-small cell lung cancer personalised medicine has already become reality. The important question for the future is whether personalised medicine for PCa will also become reality.

Personalised medicine in genitourinary malignancies: dream or reality for the future?

The current clinical challenge in CRPC is to give the right treatment to the right patient. Important questions are for example if we can predict who benefits from docetaxel rechallenge, who may respond to subsequent endocrine manipulations (e.g. abiraterone, enzalutamide) and if taxanes and abiraterone are cross-resistant? A single-centre, French study including 39 patients diagnosed with metastatic PCa has evaluated the re-administration of docetaxel [104]. Patients were administered subsequent docetaxel after front-line docetaxel-based chemotherapy. It was shown that the interval between the last cycle of first-line docetaxel and progression (median: 3.0 months) was associated with progression-free survival: median progression-free survival was 3.4 months (95% CI: 2.6-4.1) and 6.3 months (95% CI: 3.0-5.6), respectively, in patients with an interval < 3.0 months and an interval ≥ 3.0 months (P = 0.04). It was concluded that the time from the last docetaxel cycle to progression may predict further docetaxel sensitivity and that a docetaxel rechallenge can be done when the progression-free interval is > 3 months.

Molecular classification of PCa patients by means of biomarkers may aid in selecting patients who respond to endocrine therapy such as abiraterone. The recent

2323 HIGHLIGHTS

discovery of TMPRSS2 fusions to the ERG gene in PCa raises the possibility of using alterations at the ERG locus as additional (prognostic) biomarkers. Attard et al. [105] have evaluated a novel stratification of PCa, characterised by duplication of the fusion of TMPRSS2 to ERG sequences together with interstitial deletion of sequences 50 to ERG (called ‘2 + Edel’). The category ‘2 + Edel’ exhibited extremely poor PCa-specific survival compared with other categories or the non-rearranged class (HR: 6.10; 95% CI: 3.33-11.15; P < 0.001; Figure 8). In multivariate analysis, ‘2 + Edel’ provided significant prognostic information (P = 0.003) in addition to Gleason sum and PSA level at diagnosis.

0 1 2 3 4 5 6 7 8 9 10

Surv

ival

from

PCa

(%)

100

75

50

25

0

Class N Class 1 Edel Class 2 + Edel

Figure 8. Kaplan-Meier analysis comparing prostate cancer (PCa)-specific survival

for different classes of ERG gene alterations; Class N: non-rearranged class; Class 1

Edel: cancer containing a single copy of 3’-ERG sequences; Class 2 + Edel: cancer

containing ≥ 2 copies of 3’-ERG sequences [105]. Adapted from Attard G et al. [105]

with permission from Nature Publishing Group

However, a study evaluating the effect of abiraterone on progression-free survival in ‘2 + Edel’ and non-rearranged PCa classes revealed that the ERG subclass including ‘2 + Edel’ was not a relevant predictive marker for efficacy of abiraterone in chemo-naïve metastatic CRPC patients [106]. Another way to identify patients who might benefit from abiraterone was suggested by Efstathiou et al. [107] who evaluated androgen signaling in bone marrow-infiltrating cancer and testosterone in blood and bone marrow after abiraterone therapy, as persistent androgen signaling is implicated in CRPC progression. A total of 57 patients with bone-metastatic CRPC underwent bone marrow biopsy and received abiraterone. A maximal PSA change ≥ 50% occurred in 28 (50%) of 56 patients. Homogeneous, intense nuclear expression of the androgen receptor, combined with ≥ 10% CYP17 tumour expression, was correlated with a longer time to treatment discontinuation (> 4 months) in 25 patients with tumour-infiltrated bone marrow samples. In addition, pre-treatment CYP17 tumour expression ≥ 10% was correlated with increased bone marrow aspirate testosterone. Blood and bone marrow aspirate testosterone concentrations declined to less than picograms-per-milliliter levels and remained suppressed at progression. This shows that abiraterone may achieve sustained suppression of testosterone in both blood and bone marrow aspirate to less than picograms-per-milliliter levels. Responders to abiraterone may thus be identified by

an intense androgen receptor nuclear expression and CYP17 tumour expression in bone marrow during biopsy. Another study in CRPC patients receiving second-line endocrine therapy (e.g. abiraterone, MDV 3100, DES) showed that a previous duration of PCa sensitivity to ADT ≥ 16 months was the only significant predictive factor for efficacy of subsequent endocrine manipulations in patients with CRPC [108]. This suggests that measurement of duration of sensitivity during previous ADT may identify men who may benefit from further ADT.

Abiraterone and docetaxel are both approved treatments for men with metastatic CRPC. In vitro studies indicate that taxanes may act by disrupting androgen receptor signaling which may make them cross-resistant with abiraterone. A retrospective study in 35 patients evaluated the activity of docetaxel in metastatic CRPC patients previously treated with abiraterone [109]. Docetaxel resulted in a PSA decline of ≥ 50% in 26% of patients, with a median time to PSA progression of 4.6 months. The median overall survival was 12.5 months. The authors concluded that the activity of docetaxel appears lower than anticipated in patients pre-treated with abiraterone which suggests a cross-resistance. Further larger size studies should evaluate the potential for a cross-resistance between taxanes and abiraterone. Also in other GU malignancies the potential of individualised treatment is increasingly investigated. Continuing research should focus on identifying biomarkers for diagnosis, prognosis and treatment to make personalised medicine possible in the early future.

2424HIGHLIGHTS

Summary box• There is much promising data concerning

biomarkers for PCa. These concern diagnostic markers, prognostic markers, and predictive markers, however, further research and validation is needed before they can be applied in clinical practice

• The identification and development of these biomarkers, and further studies into variables predictive of treatment success, may aid in selecting the right treatment for the right patient, i.e. personalised medicine

• In CRPC the time from the last docetaxel cycle to progression may predict further docetaxel sensitivity; a docetaxel rechallenge can be done when the progression-free interval is > 3 months

• CRPC patients likely to respond to abiraterone may be identified by an intense AR nuclear expression and CYP17 tumour expression in bone marrow during biopsy. In addition, measurement of duration of PCa sensitivity during previous ADT may identify men who may benefit from further ADT

• The potential for a cross-resistance between taxanes and abiraterone should be further evaluated

• Continuing research should focus on identifying biomarkers for diagnosis, prognosis and treatment to make personalised medicine possible in the early future

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58� Carver BS, Bianco FJ, Jr�, Scardino PT, Eastham JA� Long-term outcome following radical prostatectomy in men with clinical stage T3 prostate cancer� J Urol 2006;176:564-8�

59� Touijer KA, Mazzola CR, Sjoberg DD, et al� Long-term outcomes of patients with lymph node metastasis treated with radical prostatectomy without adjuvant androgen-deprivation therapy� Eur Urol 2013;doi:10�1016/j�eururo�2013�03�053�

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62� Bolla M, Van Poppel H, Tombal B, et al� Postoperative radiotherapy after radical prostatectomy for high-risk prostate cancer: long-term results of a randomised controlled trial (EORTC trial 22911)� Lancet 2012;380:2018-27�

63� Wiegel T, Bottke D, Steiner U, et al� Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostate-specific antigen: ARO 96-02/AUO AP 09/95� J Clin Oncol 2009;27:2924-30�

64� Thompson IM, Valicenti RK, Albertsen P, et al� Adjuvant and Salvage Radiotherapy After Prostatectomy: AUA/ASTRO Guideline� J Urol 2013;doi:0�1016/j�juro�2013�05�032�

65� Stephenson AJ, Kattan MW, Eastham JA, et al� Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era� J Clin Oncol 2009;27:4300-5�

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74� Schröder FH, Kurth KH, Fossa SD, et al� Early versus delayed endocrine treatment of T2-T3 pN1-3 M0 prostate cancer without local treatment of the primary tumour: final results of European Organisation for the Research and Treatment of Cancer protocol 30846 after 13 years of follow-up (a randomised controlled trial)� Eur Urol 2009;55:14-22�

2626HIGHLIGHTS

75� Messing EM, Manola J, Yao J, et al� Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy� Lancet Oncol 2006;7:472-9�

76� Engel J, Bastian PJ, Baur H, et al� Survival benefit of radical prostatectomy in lymph node-positive patients with prostate cancer� Eur Urol 2010;57:754-61�

77� Briganti A, Karnes RJ, Da Pozzo LF, et al� Combination of adjuvant hormonal and radiation therapy significantly prolongs survival of patients with pT2-4 pN+ prostate cancer: results of a matched analysis� Eur Urol 2011;59:832-40�

78� Thompson IM, Tangen C, Basler J, Crawford ED� Impact of previous local treatment for prostate cancer on subsequent metastatic disease� J Urol 2002;168:1008-12�

79� Qin XJ, Ma CG, Ye DW, et al� Tumor cytoreduction results in better response to androgen ablation--a preliminary report of palliative transurethral resection of the prostate in metastatic hormone sensitive prostate cancer� Urol Oncol 2012;30:145-9�

80� Hellman S, Weichselbaum RR� Oligometastases� J Clin Oncol 1995;13:8-10�81� Rigatti P, Suardi N, Briganti A, et al� Pelvic/retroperitoneal salvage lymph node

dissection for patients treated with radical prostatectomy with biochemical recurrence and nodal recurrence detected by [11C]choline positron emission tomography/computed tomography� Eur Urol 2011;60:935-43�

82� Jereczek-Fossa BA, Fariselli L, Beltramo G, et al� Linac-based or robotic image-guided stereotactic radiotherapy for isolated lymph node recurrent prostate cancer� Radiother Oncol 2009;93:14-7�

83� Muacevic A, Kufeld M, Rist C, et al� Safety and feasibility of image-guided robotic radiosurgery for patients with limited bone metastases of prostate cancer� Urol Oncol 2013;31:455-60�

84� Berkovic P, De Meerleer G, Delrue L, et al� Salvage stereotactic body radiotherapy for patients with limited prostate cancer metastases: deferring androgen deprivation therapy� Clin Genitourin Cancer 2012;doi:10�1016/j�clgc�2012�08�003�

85� Kaisary AV, Tyrrell CJ, Peeling WB, Griffiths K� Comparison of LHRH analogue (Zoladex) with orchiectomy in patients with metastatic prostatic carcinoma� Br J Urol 1991;67:502-8�

86� Vogelzang NJ, Chodak GW, Soloway MS, et al� Goserelin versus orchiectomy in the treatment of advanced prostate cancer: final results of a randomized trial� Zoladex Prostate Study Group� Urology 1995;46:220-6�

87� Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials� Prostate Cancer Trialists’ Collaborative Group� Lancet 2000;355:1491-8�

88� Klotz L, Boccon-Gibod L, Shore ND, et al� The efficacy and safety of degarelix: a 12-month, comparative, randomized, open-label, parallel-group phase III study in patients with prostate cancer� BJU Int 2008;102:1531-8�

89� Nair B, Wilt T, MacDonald R, Rutks I� Early versus deferred androgen suppression in the treatment of advanced prostatic cancer�Cochrane Database Syst Rev 2002;1:CD003506�

90� Hussain M, Tangen CM, Berry DL, et al� Intermittent versus continuous androgen deprivation in prostate cancer� N Engl J Med 2013;368:1314-25�

91� Gravis G, Fizazi K, Joly F, et al� Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial� Lancet Oncol 2013;14:149-58�

92� Eisenberger MA, Blumenstein BA, Crawford ED, et al� Bilateral orchiectomy with or without flutamide for metastatic prostate cancer� N Engl J Med 1998;339:1036-42�

93� Glass TR, Tangen CM, Crawford ED, Thompson I� Metastatic carcinoma of the prostate: identifying prognostic groups using recursive partitioning� J Urol 2003;169:164-9�

94� Hussain M, Tangen CM, Higano C, et al� Absolute prostate-specific antigen value after androgen deprivation is a strong independent predictor of survival in new metastatic prostate cancer: data from Southwest Oncology Group Trial 9346 (INT-0162)� J Clin Oncol 2006;24:3984-90�

95� Resel Folkersma L, San José Manso L, Galante Romo I, et al� Prognostic significance of circulating tumor cell count in patients with metastatic hormone-sensitive prostate cancer� Urology 2012;80:1328-32

96� Amato RJ, Melnikova V, Zhang Y, et al� Epithelial Cell Adhesion Molecule-positive Circulating Tumor Cells as Predictive Biomarker in Patients With Prostate Cancer� Urology 2013;81:1303-7�

97� Zheng SL, Sun J, Wiklund F, et al� Cumulative association of five genetic variants with prostate cancer� N Engl J Med 2008;358:910-9�

98� Singh D, Febbo PG, Ross K, et al� Gene expression correlates of clinical prostate cancer behavior� Cancer Cell 2002;1:203-9�

99� Cuzick J, Swanson GP, Fisher G, et al� Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: a retrospective study� Lancet Oncol 2011;12:245-55�

100� Cooperberg MR, Simko JP, Cowan JE, et al� Validation of a cell-cycle progression gene panel to improve risk stratification in a contemporary prostatectomy cohort� J Clin Oncol 2013;31:1428-34�

101� Sboner A, Demichelis F, Calza S, et al� Molecular sampling of prostate cancer: a dilemma for predicting disease progression� BMC Med Genomics 2010;3:8�

102� Cheville JC, Karnes RJ, Therneau TM, et al� Gene panel model predictive of outcome in men at high-risk of systemic progression and death from prostate cancer after radical retropubic prostatectomy� J Clin Oncol 2008;26:3930-6�

103� Spahn M, Kneitz S, Scholz CJ, et al� Expression of microRNA-221 is progressively reduced in aggressive prostate cancer and metastasis and predicts clinical recurrence� Int J Cancer 2010;127:394-403�

104� Loriot Y, Massard C, Gross-Goupil M, et al� The interval from the last cycle of docetaxel-based chemotherapy to progression is associated with the efficacy of subsequent docetaxel in patients with prostate cancer� Eur J Cancer 2010;46:1770-2�

105� Attard G, Clark J, Ambroisine L, et al� Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer� Oncogene 2008;27:253-63�

106� Attard G, De Bono JS, Li W, et al� ERG rearrangements and association with clinical outcome in patients (pts) receivingabiraterone acetate (AA): results from the COU-AA-302 study in chemotherapy (chemo)-naïve metastatic castration-resistant prostate cancer (mCRPC)� J Clin Oncol 2013;31(Suppl):abs� 5004�

107� Efstathiou E, Titus M, Tsavachidou D, et al� Effects of abiraterone acetate on androgen signaling in castrate-resistant prostate cancer in bone� J Clin Oncol 2012;30:637-43�

108� Loriot Y, Massard C, Albiges L, et al� Personalizing treatment in patients with castrate-resistant prostate cancer: A study of predictive factors for secondary endocrine therapies activity� J Clin Oncol 2012;30(Suppl 5):abs� 213�

109� Mezynski J, Pezaro C, Bianchini D, et al� Antitumour activity of docetaxel following treatment with the CYP17A1 inhibitor abiraterone: clinical evidence for cross-resistance? Ann Oncol 2012;23:2943-7�

27 ABSTRACTS

TABLE OF CONTENTS

Abstracts accepted for oral presentation � � � � � � � � � � � � � � � � � � � � � � � � � � � � 28-30 Abstracts accepted for poster presentation � � � � � � � � � � � � � � � � � � � � � � � � � � 31-79Authorlist � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 80-83

ABSTRACTS OF THE GLOBAL CONGRESS ON PROSTATE CANCER, 2ND EDITION12-14 June 2013 – Marseille, France

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28ABSTRACTS

Abstracts accepted for oral presentationThe 3 winning abstracts are presented during the main session in Auditorium 1.

1Choice between prostatectomy and radiotherapy: RCT with a patient decision aid for localized prostate cancer

van Tol-Geerdink Julia, Radiation Oncology, Radboud UMC, Nijmegen, NetherlandsLeer Jan Willem, Radiation Oncology, Radboud UMC, Nijmegen, Netherlandsvan Oort Inge, Urology, Radboud UMC, Nijmegen, NetherlandsWijburg Carl, Urology, Rijnstate Hospital, Arnhem, NetherlandsVergunst Henk, Urology, Canisius Wilhelmina Hospital, Nijmegen, Netherlandsvan Lin Emile, Radiation Oncology, Radboud UMC, Nijmegen, NetherlandsWitjes Fred, Urology, Radboud UMC, Nijmegen, NetherlandsStalmeier Peep, Health Evidence, Radboud UMC, Nijmegen, Netherlands

Introduction & Objectives: For prostate cancer different treatment options are available, of which the most common are prostatectomy and radiotherapy (either external beam or brachytherapy). These treatments yield a comparable likelihood of cure. Guidelines indicate that patients’ preferences should be taken into account in the treatment choice. Some clinicians may fear that the advantages of increased patient participation could be counteracted by e.g. increased anxiety and treatment-related regret. This study examined the effect of increased patient involvement, by means of a patient decision aid.

Methods: Based on a literature study, a decision aid for prostate cancer treatment was developed, in collaboration with urologists and radiation oncologists. The decision aid provided evidence based information on the pros and cons of different treatment options.

From 2008 to 2011, 240 patients with localized prostate cancer (T1-3aN0NxM0) were enrolled from three hospitals. Only patients who were eligible for both prostatectomy and external beam radiotherapy were included. Brachytherapy was offered as a third option for eligible patients only, i.e. about half of the patients. Patients were randomized to 1) a usual care group, that discussed the treatment choice with their urologist and 2) a decision aid group, that, in addition, was offered a decision aid by a researcher. All patients were asked to fill out questionnaires before and shortly after the treatment choice and at 6 and 12 months after treatment.

Results: The treatment choice was affected by the use of the decision aid (p=0.03) and by the hospital (p<0.001). The decision aid left fewer people undecided (p<0.05) and led to more people choosing brachytherapy (p=0.02). Prostatectomy was the most preferred treatment in both arms.

The decision aid caused patients to feel better informed (p=0.006) and to participate more actively in decision making (p=0.002). It did not increase anxiety or regret. If anything, for patients with serious side effects at 12 months, a trend towards less regret was found (p=0.06) when a decision aid was used.

Conclusions: The decision aid, with evidence based information on the pros and cons of different treatments, was effective in increasing patient participation in the treatment choice for prostate cancer without causing anxiety or regret later on. It even appeared to lower the risk of regret in an important patient group, i.e. the patients faced with serious treatment-related side effects.

29 ABSTRACTS

2Extended pelvic lymph node dissection can increase survival in prostate cancer patients with positive lymph nodes

Andrianov Andrey, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian FederationAlekseev Boris, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian FederationNyushko Kirill, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian FederationVorobyev Nikolay, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian FederationKrasheninnikov Alexey, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian FederationKaprin Andrey, Oncourology, Moscow Hertzen Oncology Institute, Moscow, Russian Federation

Introduction & Objectives: The aim of the study was to assess biochemical progression-free survival (b-PFS) in lymph node (LN) positive PC pts after radical prostatectomy (RPE) in subject to anatomical boundaries of pelvic lymph node dissection (PLND) performed and number of LN metastases (MTS) revealed.

Material & Methods: Retrospective analysis of database from 1148 pts after RPE and PLND was performed. 680 pts with exactly established anatomical extent of PLND and known follow-up survival status were included. According to anatomical regions of PLND performed, pts were divided in to 2 groups: standard (S-PLND) was performed in 289 (42.5%) patients; extended (E-PLND) – in 391 (57.5%). Mean PSA level was 13.6±11.7 ng/ ml in S-PLND group and 16.1±15.6 ng/ ml in E-PLND group (p<0.001); mean percentage of positive biopsy cores was 47.8±31.1% and 53.9±30.7% respectively (p=0.02). Clinical stage (p<0.001) and biopsy Gleason score (p<0.001) were significantly more favorable in S-PLND group of patients. Biochemical recurrence (BR) was assessed as elevation of PSA>0.2 ng/ ml on 3 consecutive measurements.

Results: Mean number of LN removed was 14±6 (4-37) in S-PLND and 26±8 (8-61) in E-PLND group (p<0.001). LN metastases were verified in 34 (11.7%) and in 80 (20.5%), p=0.003. ADT was administered in 22 (19.3%) pts. Median follow up time was 30.5±28 months (3-156 months). During this period BR were observed in 22 (78.6%) pts in S-PLND group and in 21 (32.8%) pts in E-PLND group (p<0.001). Cumulative 3-year b-PFS rate was 20.1±8.3% for pts with LN MTS in S-PLND group and 49.6±8.7% in E-PLND group (p=0.005). Cumulative 3-year b-PFS in pts with 1 positive LN and with ≥2 positive LN was 36.6±13.3% and 10.3±9.4% in S-PLND group and 75.8±9.7% and 29.8±10.8% in E-PLND group (p<0.05).

Conclusions: E-PLND could be associated with better b-PFS even in PC pts with LN MTS. Probably better results could be achieved by more extensive PLND in pts with minimal LN invasion. S-PLND is associated with worse survival and should not be performed especially in pts with intermediate and high risk PC.

3Subgroup analyses of efficacy and safety of radium-223 dichloride (Ra-223) in patients (Pts) who did or did not receive prior docetaxel (pD) in the phase 3 ALSYMPCA trial

Hoskin Peter, Clinical Oncology, Mount Vernon Hospital Cancer Centre, Middlesex, United KingdomLogue John, Clinical Oncology, Christie Hospital, Manchester, United KingdomBottomley David, Clinical Oncology, St� James Hospital, Leeds, United KingdomNilsson Sten, Oncology-Pathology, Karolinska University Hospital, Stockholm, SwedenFang Fang, Global Clinical Statistics, Bayer HealthCare, Montville, NJ, United StatesGarcia-Vargas Jose, Global Clinical Development Oncology, Bayer HealthCare, Montville, NJ, United StatesStaudacher Karin, Clinical Research, Algeta ASA, Oslo, NorwayPawar Vivek, Global HEOR, Bayer HealthCare, Montville, NJ, United StatesReuning-Scherer Jonathan, Statistics, Yale University, New Haven, CT, United StatesParker Christopher, Clinical Oncology, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Sutton, United Kingdom

Introduction & Objectives: In the ALSYMPCA trial in castration-resistant prostate cancer (CRPC) pts with bone metastases (mets), Ra-223, a first-in-class alpha-emitting pharmaceutical, significantly prolonged overall survival (OS) (median: 14.9 vs 11.3 mo; HR=0.695; P=0.00007), significantly delayed time to first skeletal-related event (SRE) (median: 15.6 vs 9.8 mo; HR=0.658; P<0.001), and was associated with better preservation of quality of life (QOL), compared with placebo (Pbo) (Parker et al. IPCU 2013. Abstr). Data from predefined subgroup analyses assessing efficacy and safety of Ra-223 in pts who did or did not receive pD are presented.

Methods: Eligible pts had progressive, symptomatic CRPC with ≥2 bone mets; had no known visceral mets; were receiving best standard of care; and had received pD, or were unfit for or declined D (npD). Pts were randomized 2:1 to 6 injections of Ra-223 (50 kBq/ kg IV) q4wk or matching Pbo and stratified by prior D use, baseline alkaline phosphatase level, and current bisphosphonate use. The primary endpoint was OS. Secondary endpoints included SRE and QOL. Subgroup efficacy data were compared using a log-rank test. Interaction of prior D use with treatment effect on QOL was compared using a mixed-effects linear regression model.

Results: 395/ 921 (43%) randomized pts had npD (Ra-223, n=262; Pbo, n=133); 526/ 921 (57%) had received pD (Ra-223, n=352; Pbo, n=174). Irrespective of prior D use, median OS was prolonged in the Ra-223 vs Pbo group (npD, HR=0.75; pD, HR=0.71). There was a trend toward risk reduction in time to first SRE with Ra-223 vs Pbo, regardless of prior D use (npD, HR=0.74; pD, HR=0.62). Similarly, the treatment effect on QOL with Ra-223 was generally not influenced by prior D use. Overall, there was a low incidence of myelosuppression in both subgroups. Incidences of grade 3/ 4 neutropenia and thrombocytopenia were higher in pD vs npD pts.

30ABSTRACTS

Conclusions: Regardless of prior D use, Ra-223 prolonged OS and, in general, showed QOL benefit. The safety profile of Ra-223 was highly favorable; pD pts had a higher incidence of grade 3/ 4 hematologic AEs than npD pts.

npD pD

No. (%) Pts With

Grade 3/ 4 AEs*

Ra-223

n=253

Pbo

n=130

Ra-223

n=347

Pbo

n=171

Hematologic

Anemia 27(11) 15(12) 50(14) 24(14)

Neutropenia 2(1) 1(1) 11(3) 1(1)

Thrombocytopenia 7(3) 1(1) 31(9) 5(3)

*Safety population

31 ABSTRACTS

Abstracts accepted for poster presentation

4Laparoscopic radical prostatectomy in prostate cancer of low-risk tumors D’Amico. Evolution

Saez Felipe, Urology, Virgen de la Victoria, Málaga, SpainCastillo Elisabeth, Urology, Hospital Virgen de la Victoria, Málaga, SpainYañez Ana, Urology, Hospital Virgen de la Victoria, Málaga, SpainHerrera Bernardo, Urology, Hospital Virgen de la Victoria, Málaga, SpainMachuca Francisco Javier, Urology, Hospital Virgen de la Victoria, Málaga, Spain

Introduction & Objectives: Localized prostate cancer at low risk includes in its management options (observation, active surveillance, radiotherapy and radical surgery). However, a subgroup of these patients did not present the expected cancer evolution. With this review we try to quantify this subgroup.

Material & Methods: Retrospective, descriptive and inferential of 191 low-risk tumors D’Amico for a total of 354 cancer PRL analyzing the behavior of the same in terms of organoconfination, variability between the Gleason score of biopsy and surgical specimens, and surgical margins biochemical progression (PBQ).

Results:

Frequency of descriptive: Mean age was 61 years (46-73). Mean PSA 6.33 ng/ dl.

Inferential Analysis:

• Organoconfination: 86% of low risk tumors corresponded to organ confined tumors in the surgical specimen (pT2a, T2b and pT2c). 11% has fallen to pT3a and 3% for pT3b (p 0.006).

• Variability of biopsy Gleason score versus Gleason score of the piece: In the low risk group by 23.5% and 1.8% have been shown as a Gleason score 7 and 8 respectively as in the surgical specimen (p 0.7)

• PBQ: The group of low-risk tumors has shown a 5% PBQ (7 cases). 42% (3 cases) criteria has recurred with distant disease and 58% (4 cases) with local recurrence criteria.

• Surgical margins: 19%.

Considering any of the above criteria, 25% of tumors initially classified as low risk have not been.

Conclusions: LRP offers a high rate of cancer control in low-risk tumors. However, up to 25% of these tumors may not behave as such to follow up more by the variability between the biopsy Gleason score and specimen.

32ABSTRACTS

5Are peri-urethral prostate core biopsies necessary when performing transperineal template biopsies?

Hussain Muddassar, Urology, Frimley Park Hospital, Surrey, United KingdomPereira Nicola, Urology, Frimley Park Hospital, Surrey, United KingdomBott Simon, Urology, Frimley Park Hospital, Surrey, United Kingdom

Introduction & Objectives: To investigate whether periurethral biopsies (PUB) taken at the time of transperineal template biopsy (TTB) contribute to the diagnosis and management of patients with prostate cancer.

Patients & Methods: 270 patients underwent transperineal TTB by a single surgeon between November 2010 and November 2012. Criteria for inclusion included an elevated PSA, an abnormal DRE of the prostate, a diagnosis of ASAP or high-grade PIN on a previous biopsy, and/ or as part of an active surveillance protocol. The prostate gland was divided into 10 regions, including a separate periurethral region defined as within 1cm of the urethra: right (R), left (L), medial (m), lateral (l), posterior (p), anterior (a), and peri-urethral (pu).

Results: The median patient age was 65 years (range 40-78) with a median PSA of 7.1 ng/ mL (range 0.5-36) and a median prostate volume of 41.0cm3 (range 8-140). Patients had undergone a median of 1 (range 0-3) prior negative TRUS and prostate biopsies and/ or TTB. Prostate cancer was diagnosed in 123 patients (45.6%). The prostate cancer core distribution rates are as follows: Rmp 18.0%, Rma 28.7%, Rlp 50.8%, Rla 37.7%, Lmp 30.3%, Lma 34.4%, Llp 47.5%, Lla 30.3%, Rpu 21.3%, Lpu 24.6%. 46.7% patients had unilateral disease (left 23.0%, right 23.8%). 13.9% of prostate cancer was found exclusively in the anterior regions. Prostate cancer was diagnosed in 123 patients (45.6%). PUB were positive in 34.4% of patients diagnosed with prostate cancer. In three patients the Gleason grade was higher in PUB vs. other positive regions, potentially altering management. One patient had Gleason 3+3 tumour exclusively in PUB involving 2mm of a single core and went onto active surveillance. In one further case, 4 out of 6 positive cores were from PUB (maximum core length 4mm, Gleason grade 3+3) influencing the patient’s decision to pursue radical treatment. 10.0% of patients went into urinary retention following TTB.

Conclusions: Considerable anatomic variability in the prostate cancer distribution was documented. Prostate cancer was found in the periurethral zone in a third of cases, however it was only found exclusively in this region in one case. The volume of disease in the PUB affected management choice in one patient. By avoiding the periurethral area when performing TTB fewer biopsies may be taken without significantly effecting diagnostic power but potentially reducing morbidity including urinary retention.

6HIFU: the challenge in individualized prostate cancer treatment for the next decade. Less=more. Review of over 1000 single center patients treated in the past decade with HIFU

D’Hont Christiaan, Urology - Urologic Oncology, ZNA Middelheim, Antwerp, BelgiumVan Erps Peter, Urology, ZNA Middelheim, Antwerp, BelgiumSorber Marc, Urology, ZNA Middelheim, Antwerp, BelgiumCortvriend Jim, Urology, ZNA Middelheim, Antwerp, BelgiumDebacker Tibaut, Urology, ZNA Middelheim, Antwerp, BelgiumToussaint Nele, Urology, ZNA Middelheim, Antwerp, Belgium

Introduction & Objectives: To report biochemical and biopsy outcomes + Quality of Life of 1000 fully evaluable patients treated with HIFU as a primary treatment for T1-T3aNxM0 prostate cancer. Full and individualized nerve sparing/ focal treatments will be reported.

Methods: Patients treated by Ablatherm (EDAP-TMS, Lyon, France) with single HIFU treatment strategy for localized prostate cancer. Salvage treatments were excluded. Patients were stratified according to D’Amico’s 2003 risk group definitions. Kaplan-Meier analysis was performed to determine biochemical survival with failure defined according to the 2006 Phoenix definition (nadir+2).

Results: A total of 695 consecutive fully evaluable patients met the inclusion criteria for full treatment/ 295 had a more individualized nerve sparing treatment. The average age was 63.0/ 60.2 ± 7.6 years. Pretreatment PSA was 10,8/ 9,3 ± 7,8 ng/ ml, the median Gleason sum was 7 (6:56.8%, 7:30.7%, 8 and up:11%) and 9,8/ 17,7%, 37,7/ 49,4% and 52,7/ 32,9% of patients were in the low, moderate and high+T3a risk groups, respectively. 8% T1, 68,2%T2 and 23,3%T3a. Patients were followed for 4.3 ± 2.2 years (range: 1 to 11 years). The median PSA nadir was 0.11 which was reached 14.6 ± 14.2 weeks after HIFU (67,4% < 0,2 ng/ ml; 32,6% 0,2-1ng/ ml). Biochemical failure free survival rates at 5,6 and 7 years are 78%, 75% and 73% respectively. 5YBFSR is 88%,86% and 63% for the low, intermediate and high+T3a risk groups (p=0,012). No significant difference between Full and Individualized treatments. A 2nd HIFU treatment is offered in case of bx proven local recurrence (9.2 %). Side effects are extremely low (3,8/ 1,3% SI gr 1, 5.4/ 5,1% UTI, 6/ 3,8%TUR/ BNI, 0,6%AUR). Potency preservation (IFFE-5>20) is 85%, 55%, 8% in unilateral nerve sparing, full and T3a treatment (outside capsula) groups resp. The comorbidity difference is significant: Less treatment = More QuOL for Same QuOTreatment.

Conclusions: HIFU provides good biochemical control through > 7 years of follow-up combined with a relatively low rate of side effects and meets the results of classical treatments as primary PCA treatment. Equal results on cancer control can be obtained with more individualized nerve sparing/ focal procedures in carefully selected patients. Extremely low comorbidity and repeatability of the procedure make HIFU a first choice safe treatment for prostate cancer both in primary as in salvage curative settings for any Gleasonscore or age.

33 ABSTRACTS

7Parameters influencing continence recovery after endoscopic extraperitoneal radical prostatectomy

Hermans Tom, Urology, Maastricht University Medical Center, Maastricht, NetherlandsJacobs Rens, Urology, Maastricht University Medical Center, Maastricht, NetherlandsFossion Laurent, Urology, Maxima Medical Center, Veldhoven, Netherlands

Introduction & Objectives: To assess the influences of age, body mass index (BMI), prostate volume (PV), tumor stage (pT), bilateral preservation of the neurovascular bundle (BPNVB) and posterior musculofascial plate reconstruction (PMPR) on short- and long-term continence recovery in endoscopic extraperitoneal radical prostatectomy (EERPE).

Methods: From May 2008 until October 2012, 183 consecutive patients underwent EERPE performed by a single surgeon, having previous experience with 81 EERPE procedures. Median age, BMI, PSA, and PV were 65.0y, 26.1kg/ m2, 9.0µg/ l and 38.0cc, respectively. Clinical tumor stages were: cT1c 62 (33.9%) patients, cT2c 92 (50.3%), cT3 29 (15.8%). The last 83 patients underwent PMPR as described by Rocco.

All patients followed the same continence rehabilitation program. Patients were considered continent using 0-1 pad daily. Data on continence recovery after 3 and 12 months were gathered prospectively and analyzed in a retrospective manner. Univariate logistic regression analysis was performed to evaluate the relationship between variables and continence recovery.

Results: Continence recovery rates after EERPE

Conclusions: In this series patients undergoing EERPE+PMPR acquire better short- and long- term continence recovery rates. More randomized controlled trails are needed to confirm the value of PMPR in radical prostatectomy.

Reached

3mo FU,

n

Conti-

nent

3mo,

n(%)

Miss-

ing

3mo,

n(%)

Reached

1y FU,

n

Conti-

nent 1y,

n(%)

Miss-

ing

1yr,

n(%)

Overall 183 52(28.7) 2(1.1) 154 78(52.7) 6(3.9)

PMPR+ 83 30(36.0) 0(0.0) 54 34(67.3) 2(3.7)

PMPR- 100 22(22.4) 2(2.0) 100 43(44.8) 4(4.0)

OR(95%-CI) 2.0(1.0-

3.8)

2.5(1.3-

5.1)

pT1-2 Pca 121 35(29.4) 2(1.7) 103 52(53.1) 5(4.9)

pT3 Pca 62 17(27.4) 0(0.0) 53 26(52.0) 1(2.0)

OR(95%-CI) 0.9(0.5-

1.8)

1.0(0.5-

1.9)

PV < 50cc 124 38(31.1) 2(1.6) 106 54(53.5) 5(4.7)

PV > 50cc 49 10(20.4) 0(0.0) 38 18(47.4) 0(0.0)

PV X 10 4(40.0) 0(0.0) 10 6(66.7) 1(10.0)

OR(95%-CI) 0.6(0.3-

1.3)

0.8(0.4-

1.7)

BPNVB+ 35 12(34.4) 0(0.0) 29 19(65.5) 0(0.0)

BPNVB- 148 40(27.4) 2(1.4) 125 59(49.6) 6(4.8)

OR(95%-CI) 1.4(0.6-

3.0)

1.9(0.8-

4.5)

Age < 65y 88 26(30.2) 2(2.3) 75 33(47.1) 5(6.7)

Age ≥ 65y 95 26(27.4) 0(0.0) 79 45(57.7) 1(1.3)

OR(95%-CI) 0.9(0.5-

1.7)

1.5(0.8-

2.9)

BMI 18.5–

25kg/ m2

56 17(30.4) 0(0.0) 49 27(57.4) 2(4.1)

BMI 25–

30 kg/ m2

110 29(26.9) 2(1.8) 91 43(48.9) 3(3.3)

OR(95%-CI) 0.8(0.3-

2.5)

0.8(0.2-

3.0)

BMI ≥

30kg/ m2

17 6(35.3) 0(0.0) 14 1(7.1)

OR(95%-CI) 0.7(0.2-

2.0)

0.6(0.2-

2.0)

CI=Confidence interval, OR=Odds ratio, Pca=Prostate cancer, X=Unknown.

34ABSTRACTS

8Choline PET/ CT in staging and restaging at biochemical recurrence for prostate cancer: a systematic review and meta-analysis of cohort studies

Center Finn, Office, Center of Tobacco Control Research, Odense, DenmarkKairemo Kalevi, Department of Molecular Radiotherapy and Nuclear Medicine, International Comprehensive Center Docrates, Helsinki, Finland

Introduction & Objectives: The clinical value of choline PET/ CT for staging and restaging of patients with prostate cancer is not well established. In the present meta-analysis, we aimed to evaluate benefits and harms from choline PET/ CT scans.

Methods: The search by 1 author extracted records from PubMed and Embase databases and from a hand search. We selected cohort studies from 1998 to January 2013 for patients with prostate cancer at staging or restaging at biochemical recurrence. The meta-analysis pooled positive findings of the individual articles.

Results: Across 89 articles, 3,364 (58%) of 5,757 patients had lesions by PET/ CT scans. Of the patients, 1,248 (22%) had lesions in the prostatic bed, 910 (16%) had lesions in pelvic lymph nodes, 676 (12%) had lesions in distant organs, and 530 (9%) had lesions in two or more regions. Sensitivity of choline PET/ CT for pelvic lymph node metastases was 0.58 (95% CI 0.51 to 0.65) using 176 patients. Specificity was 0.91 (95% CI 0.88 to 0.94). Choline PET/ CT detected lesions better than bone scan, present for 124 (46%) versus 56 (21%) of 272 patients, and detected lesions better than 18F-FDG PET/ CT, present for 187 (63%) versus 99 (33%) of 298 patients. The scans changed treatment for 323 (38%, 95% CI 35% to 41%) of 854 patients, and improved outcome for 103 (27%, 95% CI 22% to 32%) of 380 patients.

Conclusions: Choline PET/ CT had appropriate clinical efficacy for patients with prostate cancer and biochemical recurrence.

9The effectiveness of salvage stereotactic body radiation therapy for recurrent prostate cancer

Favretto Maria Silvia, Radiotherapy, San Bortolo, Vicenza, ItalyBolzicco Giampaolo, Radiotherapy, San Bortolo, Vicenza, ItalySatariano Ninfa, Medical Physics, San Bortolo, Vivenza, ItalyScremin Enrico, Urology, San Bortolo, Vicenza, ItalyBaiocchi Cristina, Radiotherapy, San Bortolo, Vucenza, ItalyTasca Andrea, Urology, San Bortolo, Vicenza, Italy

Introduction & Objectives: Radiation therapy is a common practice in cases of biochemical recurrence of prostate cancer after surgery. We evaluated the safety and efficacy of CyberKnife-Stereotactic Body Radiation Therapy (CK-SBRT) in a series of 22 patients with measurable local recurrence of prostate cancer.

Methods: Twenty-two patients with a mean age of 71 years (range 61-81) have been treated with Cyberknife robotic radiosurgery (Accuray Inc., Sunnyvale, CA, USA). Evidence of recurrence was performed with biopsy in 8 patients and with PET and MRI in 14. Ten patients had had a relapse after prostatectomy, 9 after radical radiotherapy and 3 after prostatectomy plus adjuvant radiotherapy. In all patients three or four gold fiducial seeds were implanted in the prostate gland or in the prostatic bed under transrectal ultrasound guidance; a CT and PET/ RMN images fusion was performed for clinical target volume delineation. Half of the patients (11pts) had a Foley catheter placed for better identification of the urethra. The mean volume of disease recurrence was 7.8 cc. The planning treatment volume (PTV) ranged from 4 to 35.8 cc. (median 18.23 cc). Prescription dose ranged from 24 to 30 Gy in 3-5 fractions, depending on whether the lesion was in surgical bed following radical prostatectomyor intraglandular.

Results: The median follow up was 24 months (range 3-102 months). Seven patients had Grade 1-2 acute genitourinary (GU) toxicity and 1 Grade 3; one patient developed Grade 2 acute rectal toxicity, no patients experienced Grade 3 acute rectal toxicity. Late GU toxicity occurred in 5 patients (22.7%): GU Grade 1 in 4 patient (18%) and GU Grade 2 in 1 (4.5%); only 1 patient had Grade 1 late rectal toxicity. After salvage-CK-SBRT, local recurrences occurred in 3 patients (13,6%): one had had surgery, one radiotherapy and one surgery plus radiotherapy. Four patients (18% developed distant metastases (1 bone, 1 lymph nodes and 2 bone plus lymph node metastases) (Table 1). One patient with bone and lymph-node metastasis died of related disease, the other patients with clinical progression are alive in androgen deprivation therapy (ADT) or chemotherapy.

35 ABSTRACTS

Conclusions: CyberKnife-Stereotactic Body Radiation Therapy is a feasible approach for local measurable recurrence of prostate cancer with good control and low acute or late toxicity. A longer follow-up and a larger number of patients are necessary to evaluate its effectiveness.

10Patients’ decision making after the diagnosis of prostate cancer

Bellardita Lara, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyVilla Silvia, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyMagnani Tiziana, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyVilla Sergio, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyBedini Nice, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyBiasoni Davide, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyStagni Silvia, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyValdagni Riccardo, Prostate Cancer Program, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Introduction & Objectives: According to international guidelines, patients receiving a diagnosis of prostate cancer (PCa) should be informed of the different appropriate therapeutic/ observational options. To date, it is not completely clear how concerns about side effects influence patients’ choice and what the core landmarks of patients’ decision making (DM) process are. The aim of our study was to explore the experience of DM in patients diagnosed with PCa.

Patients & Methods: Between February and May 2012, 10 patients (mean age 64.8) were recruited for an observational, qualitative study. Patients had low or intermediate risk PCa. A decision aid (DA, Ottawa Personal Decision Guide) was used to increase the patients’ awareness of the DM process after a multidisciplinary visit. The DA focused on three main areas: a) clarify the decision; b) identify patients’ decision making needs and c) explore these needs. A further set of questions was added in order to explore patients’ emotions. Interviews were audio-recorded and verbatim transcriptions were made. Content analysis was performed by using a text analysis software (T-LAB).

Results: Text analysis showed the following results: a) all patients reported to be informed of the available options; 3 of them reported not to be prone toward a particular treatment option; b) 8 out of 10 patients stated they did not clearly understand benefits and risk of each option; all of them reported to know what mattered the most to them in terms of personal priorities; 9 out of 10 patients reported to have enough support and advice from their family; c) 9 out 10 patients felt to be supported mainly by their partners even if their partners wanted them to make the final choice; all patients considered physician’s point of view as a crucial factor for the choice; 8 out 10 patients mentioned their need to clarify some doubts and expand their knowledge as a necessary step to finalize their choice. All the patients mentioned fear and concern about the issue of recovery and/ or about the potential threats of quality of life.

Conclusions: The use of a decision aid helped to highlight that patients experienced the choice of treatment for PCa as a complex process, involving the evaluation of medical information as well as of psycho-social factors. A better knowledge and understanding of patients’ subjective experience may help to reach an informed and aware choice and to promote a patient-centred approach to PCa care.

36ABSTRACTS

11The quality of life of patients on active surveillance: two years follow-up

Bellardita Lara, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyAlvisi Maria Francesca, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyRancati Tiziana, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyVilla Silvia, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori,,Marenghi Cristina, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyNicolai Nicola, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyAvuzzi Barbara, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyVilla Sergio, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalySalvioni Roberto, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyMagnani Tiziana, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyValdagni Riccardo, Prostate Cancer Program, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Introduction & Objectives: The distress that men may experience due to living with untreated prostate cancer (PCa) when choosing Active Surveillance (AS) is still an open issue. Research showed that most patients did not report psychological burden; nonetheless, longer term follow-up is still needed. The aim of this study was to investigate the changes in quality of life (QoL) over the first two years on AS.

Patients & Methods: Between Nov 2007 and Jan 2013, 208 patients completed questionnaires at enrolment in the AS protocol (T0). Evaluations after 10 months (T1) from diagnostic biopsy, 12 months (after the first re-biopsy- T2) and 24 months (T3) were completed by 156, 109 and 62 patients, respectively. Validated self-report questionnaires were administered, including: a) Functional Assessment of Cancer Therapy – Prostate Version (FACT-P), measuring physical wellbeing, social wellbeing, emotional wellbeing, functional wellbeing, and wellbeing related to prostate cancer symptoms (PCS); b) Mini Mental Adjustment to Cancer (Mini-MAC), evaluating the strategies of coping with cancer: fighting spirit, helplessness/ hopelessness, fatalism, anxious preoccupation and avoidance. Descriptive analyses were performed. Repeated measure analyses of variance (ANOVA) were performed to test changes over time and Bonferroni correction was used for pair time comparisons.

Results: The mean age of study population at T0 was 66.2 years (median 66, range 42-79). ANOVAs showed the following significant changes over time: social wellbeing decreased from T0 to T3 (p = 0.001); PCS decreased between T0 and T3 (p = 0.014); emotional wellbeing increased between both T0 and T2 (p = 0.016) as well as T0 and T3 (p = 0.001). Anxious preoccupation and avoidance significantly decreased from T0 and T2 (p = 0.0001 and p = 0.035, respectively).

Conclusions: Patients on AS reported high levels of physical and psychological wellbeing throughout the first two years. QoL was not impaired by the idea of living with an untreated cancer. It is particularly interesting that anxious preoccupation, i.e.worry about disease progression, decreased over the first year on AS and then remained stable. The decrease in the perception of social wellbeing could be related to the fact that support from family/ friends is likely to be higher in the period immediately following the diagnosis. The increase of PCa-related symptoms is unexpected and needs to be further detailed. Acknowledgements to Foundations I. Monzino and ProADAMO.

37 ABSTRACTS

12Prostate cancer screening in men 50 to 70 years old in Fasa in 2012

Abbasfard Adnan, Anesthetist in Shiraz Hospital, Mir Shiraz Hospital, Shiraz, Iran, Islamic Republic ofBiegmohamadlo Hossein, Specialist in Kidney and Urinary Tract in Fasa University of Medical Science, Shariati Hospital, Tehran, Iran, Islamic Republic ofShabbooie Zohre, Student of Research Committee in Fasa University of Medical Science, Fasa, Iran, Islamic Republic ofNaghizade Mohammad, Expert Stats in Fasa University of Medical Science, Fasa University of Medical Science, Fasa, Iran, Islamic Republic of

Introduction & Objectives: Cancer is one of the leading causes of deaths worldwide. Prostate cancer occurs in older men. Screening clinical trials are conducted in many parts of the world. According to the importance of men’s health and the lack of comprehensive researches we decided to do prostate cancer screening for men aged 50 to 70years in Fasa to improve health and reduce mortality of men.

Methods: This cross-sectional study (descriptive -analytical) was done in order to screen men for prostate cancer. At first the comments were explained to the volunteers and each patient was taken to interview after reading the informed consent. The data collected were analyzed by SPSS software, version17.

Results: Of the 921 men who participated, mean age was 58.9±7.9. From 760 people took a rectal examination, prostate size in 558 patients (73.4%) was normal, in 198 men (26.1%) was bigger than normal and in 4 men (0.5%) was so bigger than normal. The mean of prostate-specific antigen (PSA) in men was 1.55±3.28. This factor in 697 men (91.7%) was lower than 3.5 ng/ ml and normal, in 12 men (1.6%) was edgy 3.5-4.5ng/ ml and in 51 men (6.7%) was increased.

Conclusions: The study showed that men with PSA above 4 and formidability of hard or semi-hard in rectal examination, are suspected for prostate cancer that need to have a biopsy to confirm the diagnosis. It is recommended for men over 50 to visit for prostate exam every year and if they have abnormal rectal examination and PSA above 4 apply for biopsy and treatment.

13EphB4 as a new prognostic marker in prostate cancer

Stonier Thomas, Medicine, Bristol Royal Infirmary, Bristol, United KingdomWall Joshua, Medicine and Dentistry, University of Bristol, Bristol, United KingdomNobes Kate, Biochemistry, University of Bristol, Bristol, United Kingdom

Introduction: The Gleason scoring method currently used to diagnose prostate cancer is poor at determining cancer aggressiveness and thus prognosis. With over 40% of men over the age of 50 having a well-differentiated form of prostate cancer, this is a major issue. The Eph receptors are the largest family of tyrosine kinase receptors and have been shown to have increased expression in association with prostate cancer, in particular EphB4.

Methods & Results: Using immunohistochemistry we have shown that the EphB3 receptor has a similar increase in expression in prostate cancer when compared with benign prostate gland (p<0.0001), and thus is a potential diagnostic biomarker. We also investigate a possible correlation between increase in the expression of these receptors and cancer grade, as determined by the current Gleason scoring method. We find that increasing EphB4 expression directly correlates with increasing cancer grade (Gleason 6-7) (p<0.05). We also observe a trend for a similar correlation with the EphB3 receptor.

Conclusions: Our results pave the way for a follow-up study, with a larger sample size and clinical outcome data, to determine whether the level of EphB3 and EphB4 expression could give an indication of prostate cancer aggressiveness and thus become a prognostic marker.

38ABSTRACTS

14Strontium-89 for prostate cancer with bone metastases: the potential of cancer control and improvement of overall survival

Kuroda Isao, Urology, Ibaraki Medical Center, Tokyo Medical University, Ami,Inashiki,Ibaraki, JapanAoyagi Teiichiro, Urology, Ibaraki Medical Center, Tokyo Medical University, Ami,Inashiki,Ibaraki, JapanShimodaira Kenji, Urology, Ibaraki Medical Center, Tokyo Medical University, Ami,Inashiki,Ibaraki, Japan

Introduction & Objectives: Strontium-89 (Sr89) has been thought to have a tumoricidal effect with minimal adverse events. However, there have not been many reports on it. In this study, we examined the tumoricidal and pain-relief effects of Sr89 on prostate cancer with bone metastasis and also survivals.

Methods: A retrospective study was performed involving 31 prostate cancer patients with bone metastasis treated with Sr89. Using PSA as an evaluation criterion of cancer control, patients were divided into PSA responder and non-responder groups, and the survival rates were compared. In addition, using the total amount of pain killers as an evaluation criterion of pain relief, patients were divided into pain responder and non-responder groups, and the survival rates were compared. As secondary investigation items, age, PSA (ng/ ml), pain site, extent of the disease (EOD), the presence or absence of castration-resistant prostatic cancer (CRPC), the presence or absence of a past medical history of treatment with docetaxel (DTX) in CRPC cases, Gleason Score (GS), hemoglobin (Hb) (g/ dL), platelet (Plt) (/ µl), serum carboxyterminal telopeptide of type I collagen(ICTP) (ng/ ml), and bone-alkaline phosphatase (BAP) (U/ L) were investigated.

Results: Longer survival was expected for the PSA responder than the PSA non-responder group,and, as predictors of this, whether the spine was the pain site or not and the presence or absence of CRPC were useful. Plt, ICTP, and BAP were suggested to be useful indicators; however, no significant difference was noted. Furthermore, the survival time was significantly longer in the pain responder than in the pain non-responder group, and whether the pain site was present in the spine was considered to be a predictor, but no significant difference was noted in any of the items assumed to be biomarkers.

Conclusions: Sr89 has a potency to control PSA and prolong the survival. A large-scale prospective study of the therapeutic effect of Sr89 is expected.

15The occurrence of high-grade prostatic intraepithelial neoplasia in transition zone of prostate

Gordeev Vasily, Department of Urology, Railroad clinical hospital at Khabarovsk-1 station, Khabarovsk, Russian FederationAntonov Alexander, Department of Urology, Far Easern state medical university, Khabarovsk, Russian FederationEvseev Alexey, Department of Pathology, Far Easern state medical university, Khabarovsk, Russian FederationMasaltseva Natalia, Department of Urology, Railroad clinical hospital at Khabarovsk-1 station, Khabarovsk, Russian Federation

Introduction: It is generally accepted that high-grade prostatic intraepithelial neoplasia (HG PIN) is mainly localized in the peripheral zone of the prostate, which corresponds to the characteristics of the zonal location of prostate cancer. Considered that incidence of HG PIN in transition zone significantly lower. These conclusions were based mainly on the results obtained during the prostate needle biopsy and monopolar transurethral resection of the prostate (TURP). But, during prostate needle biopsy ordinarily less specimens takes from transition zone then from peripheral zone. The analysis of benign prostate hyperplasia (BPH) surgery specimens can give more correct data about HG PIN incidence in transition zone of prostate.

Objective: To evaluate the occurrence of HG PIN in transition zone of prostate.

Material & Methods: The incidence of HG PIN was studied among patients who had prostate needle biopsy or BPH surgery. A bipolar TURP were performed at 57 cases (group 1), monopolar TURP were performed at 130 patients (grour 2), simple prostatectomy were performed at 128 man (group 3), and 617 patients had prostate needle biopsy (group 4). The comparison of groups was performed by Chi-square test using. Results: The occurrence of HG PIN in group 1 was 22,8% in group 2 – 6,9% in group 3 – 14,8% in group 4 – 16%. Statistically significant differences in the detection of HG PIN between simple prostatectomy, prostate needle biopsy groups and bipolar TURP group were absent (chi-square = 1.9; p=0.37). At the same time, the frequency of HG PIN with bipolar TURP was higher than in the monopolar TUR (chi-square = 8.16; p=0.004).

Conclusions: These results show the same prevalence of the HG PIN in peripheral and transition zones of the prostate. The conclusion of a preferential occurrence of HG PIN in the peripheral zone of the prostate, based on the worst representation of the material obtained by biopsy or by monopolar TURP.

39 ABSTRACTS

16Risk of hernia complications after minimally invasive and open radical prostatectomy

Eastham James, Urology, Memorial Sloan-Kettering Cancer Center, New York, United StatesCarlsson Sigrid, Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, United StatesEhdaie Behfar, Urology, Memorial Sloan-Kettering Cancer Center, New York, New York, United StatesElkin Elena, Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United StatesAtoria Coral, Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Introduction: Increased incidence of prostate cancer, largely as a result of widespread prostate cancer screening, has led to a rise in the number of radical prostatectomies. Many urologists have shifted from an open surgical approach to minimally invasive techniques. It is not clear whether the risk of incisional hernia varies by surgical approach.

Objective: To estimate the impact of surgical approach on the incidence of post-prostatectomy incisional hernia.

Design, Setting, Participants: We used the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare dataset to identify men age 66 and older who had minimally invasive (MIRP) or open radical prostatectomy (ORP) for prostate cancer diagnosed 2003-2007.

Main Outcome Measures: Incisional hernia repair identified in Medicare claims following prostatectomy. We also examined the frequency of umbilical, inguinal and other hernia repairs.

Results: We identified 3,199 patients who had MIRP and 6,795 who had open radical prostatectomy ORP. The frequency of incisional hernia repair was 5.3% (median follow-up 3.1 years) in the MIRP group and 1.9% (median follow-up 4.4 years) in the ORP group, corresponding to incidence rates of 16.1 and 4.5 per 1000 person-years for MIRP and ORP, respectively. Compared with ORP, MIRP was associated with a more than 3-fold increased risk of incisional hernia repair, controlling for patient and disease characteristics (adjusted hazard ratio 3.39, 95% CI, 2.63–4.38, p <0.0001). MIRP was associated with an attenuated but increased risk of any hernia repair compared with ORP (adjusted hazard ratio 1.48, 95% CI 1.29–1.70, p <0.0001).

Conclusions: In this population-based cohort of older men treated surgically fro prostate cancer, MIRP was associated with a significantly increased risk of incisional hernia compared with ORP. This is a potentially remediable complication of prostate cancer surgery that warrants increased vigilance with respect to surgical technique.

17Infective complications following TRUS-Bx - a tale of two cities

Venugopal Suresh, Department of Urology, Royal Hallamshire Hospital, Sheffield, United KingdomJames Nicola, Department of Urology, Chesterfield Royal District Hospital, Chesterfield, United KingdomBoucher Nigel, Department of Urology, Chesterfield Royal District Hospital, Chesterfield, United KingdomRosario Derek, Academic Unit of Urology, Royal Hallamshire Hospital, Sheffield, United Kingdom

Introduction & Objectives: There is a recognised but variable rate of infective complications reported following TRUS-Biopsy. There remain concerns regarding antibiotic resistance with no level I evidence as to best antibiotic prophylaxis. The aim of this study was to compare prospectively the infective morbidity within 30 days of TRUS-Bx across two neighbouring cities with different antibiotic protocols, using data from the prospective PROBE study as the reference population.

Material & Methods: Group 1 (reference population, IV Co-amoxiclav pre-biopsy and 5 doses of ciprofloxacin 500 mg post-biopsy) consisted of 282 men undergoing first-time biopsy within the PROBE study. Group 2 consisted of 172 consecutive men from a neighbouring centre (single dose 500mg Ciprofloxacin and Metronidazole 1mg pre-biopsy and 5 doses ciprofloxacin 500 mg post-biopsy). All men had standard 10-12 core biopsies.

Results: There were no deaths in either group. Hospital admission for sepsis was required for 1 man (0.4%) and 5 men (2.9%) in groups 1 and 2 respectively (95% CI for difference 0.2 to 6.3% favouring centre 1), (χ2 p = 0.059). Group 2 had 1 man with a positive blood culture demonstrating an organism with quinolone resistance.

Conclusions: Serious sepsis rates between protocols are more indicative of pharmacokinetic differences than sensitivities per se. Parenteral administration improves reliability of cover and may contribute to reduction of serious infectious complications following TRUS-Bx.

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18Complications following prostate biopsy – a retrospective audit

Iyer Subrmanian, Urology, Nobles (IOM), Douglas, Isle of Man, United KingdomUpsdell Stephen, Urology, Nobles(IOM), Douglas, Isle of man, United KingdomRai Hem, Urology, Nobles Hospital, Douglas, Isle of Man, United Kingdom

Introduction: Prostate cancer is the no 1 cancer in man(1) and no 2 cause of mortality in all male cancers(2). Trans rectal ultrasound guided biopsy (TRUSB) of the prostate is the gold standard for localising, volume measurement and tissue acquisition for prostate cancer. Infective sequel, form a significant part of the complications, sometimes serious or even fatal (rare).

Methods: We present a retrospective audit on 100 consecutive TRUSB patients and analyse their infective complication rate.

Results: We are pleased to announce that our complication rates are well within the accepted (7%) as per world wide guidelines.

Conclusions: In our study, TRUSB of prostate is a safe procedure.

References:

1. Cancer Research UK.http:/ / www.cancerresearchuk.org/ cancer-info/ cancerstats/ types/ prostate/ incidence/

2. Cancer Research UKhttp:/ / www.cancerresearchuk.org/ cancer-info/ cancerstats/ types/ prostate/ mortality/

3. The British Association of Urological Surgeonshttp:/ / www.baus.org.uk/ Resources/ BAUS/ Documents/ PDF%20Documents/ Patient%20information/ TRUSP.pdf

4. European Association of Urology Nurseshttp:/ / www.uroweb.org/ fileadmin/ EAUN/ guidelines/ EAUN_TRUS_Guidelines_EN_2011_LR.pdf

19RANKL pathway proteins as risk parameters for biochemical recurrence in prostate cancer patients

Todenhöfer Tilman, Urology, University Hospital Tübingen, Tübingen, GermanyHennenlotter Jörg, Urology, University Hospital Tübingen, Tübingen, GermanyAufderklamm Stefan, Urology, University Hospital Tübingen, Tübingen,Blumenstock Gunnar, Biometry and Statistics, University Hospital Tübingen, Tübingen, GermanyStenzl Arnulf, Urology, University Hospital Tübingen, Tübingen, GermanySchwentner Christian, Urology, University Hospital Tübingen, Tübingen, Germany

Introduction & Objectives: The development of bone metastases from prostate cancer is closely linked to the activity of the receptor activator of the NF-kB Ligand (RANKL) pathway. Recent evidence exists that this pathway might play a role for tumor biology before metastatic disease becomes manifest. We aimed to assess the prognostic impact of proteins of the RANKL pathway in serum samples of patients undergoing radical prostatectomy (RP).

Patients & Methods: 178 patients undergoing RP between 2004 and 2006 were included. Serum concentrations of soluble RANKL (sRANKL) and osteoprotegerin (OPG) were determined retrospectively using Enzyme Linked Immunosorbent Assay (ELISA). Results of serum measurements were correlated to clinical and patient follow-up data using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis.

Results: Increased sRANKL (p=0.01), decreased OPG (p=0.01) and an increased sRANKL/ OPG Ratio (p=0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis adjusted for classical risk factors for BCR, sRANKL and sRANKL/ OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with classical histopathologic factors such as pT, pN, PSA, Gleason score or R status.

Conclusions: Increased activity of the RANKL pathway in serum of patients with prostate cancer undergoing RP is a risk factor for biochemical recurrence. The RANKL pathway seems to contribute to the biologic behavior of prostate cancer already in an organ-confined stage of the disease. Whether serum proteins of this pathway are also able to predict response to RANKL-inhibition in patients without bone metastases remains to be elucidated.

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20Quantification of multiparametric prostate MR data to predict adverse pathologic features: preliminary findings

Acar Ömer, Urology, VKF American Hospital, Istanbul, TurkeyVural Metin, Radiology, VKF American Hospital, Istanbul, TurkeyAkpek Sergin, Radiology, VKF American Hospital, Istanbul, TurkeyCezayirli Fatin, Urology, VKF American Hospital, Istanbul, TurkeyEsen Tarık, Urology, VKF American Hospital, Istanbul, Turkey

Introduction & Objectives: PI-RADS (prostate imaging, reporting, and data system) scoring system quantifies multiparametric prostate MRI (Mp-MRI) data and it is being used to estimate the probability of a lesion to be malignant. In this preliminary study, we aimed to analyze the correlation between the total score of radiologically detected index lesions and pathologic outcome in those patients who were operated due to clinically localized prostate cancer.

Material & Methods: Between November 2011 and March 2013, a total of seventeen patients have undergone Mp-MRI of the prostate before radical prostatectomy. Anatomic T2-weighted sequences, diffusion weighted and dynamic contrast-enhanced images were available for all of the patients. Twelve patients had additional spectroscopic evaluation. Two radiologists assessed all images to identify the lesion most suspicious of being the index lesion. Total score of each index lesion was calculated by adding the individual scores of the studied parameters. Histopathologic evaluation was conducted by the whole-mount step-section technique. The relationship between PI-RADS score and pathologic outcome was investigated.

Results: Mean age and mean PSA value of the study population were 63.5 ± 4,8 years and 11.3 ± 15.8 ng/ ml, respectively. Gleason score in the prostatectomy specimen was 6 in 3, 7 in 9, 8 in 2 and 9 in 3 patients. Disease was confined to the prostate in 12 patients while 4 patients had extracapsular extension (pT3a). Mean tumor volume was 2.5 ± 1.9 cm3. Surgical margins were clear.

Since spectroscopy score was absent in 5 patients, we did not use it while making comparisons. Index lesions were represented as the most voluminous tumor focus in the prostatectomy specimens. Tumor volume in the prostatectomy specimens and PI-RADS score exhibited a weak but insignificant correlation (r: 0.292). Patients with a primary Gleason grade of ≥ 4 had a significantly higher mean total score than those with a primary Gleason grade of 3 (15.7 ± 2.2 vs. 12.5 ± 1.6, p= 0.003). Mean total score was insignificantly higher for those with pathologically confirmed extracapsular extension than those who had organ-confined disease (13.8 ± 0.4 vs. 12.5 ± 1.7, p= 0.148).

Conclusions: Quantification of Mp-MRI data by PI-RADS scoring system may provide discriminative information regarding histopathologic variables. Higher scores might be associated with adverse pathologic outcomes and may be utilized while counseling patients.

21Prostate protein glycosylation profile may serve as a diagnostic biomarker for prostate cancer

Vermassen Tijl, Department of Medical Oncology, University Hospital Ghent, Ghent, BelgiumLumen Nicolaas, Department of Urology, University Hospital Ghent, Ghent, BelgiumVan Praet Charles, Department of Urology, University Hospital Ghent, Ghent, BelgiumVanderschaeghe Dieter, Unit for Medical Biotechnology, Department for Molecular Biomedical Research, Flemish Institute for Biotechnology, Ghent University, Ghent, BelgiumCallewaert Nico, Unit for Medical Biotechnology, Department for Molecular Biomedical Research, Flemish Institute for Biotechnology, Ghent University, Ghent, BelgiumHoebeke Piet, Department of Urology, University Hospital Ghent, Ghent, BelgiumVan Belle Simon, Department of Medical Oncology, University Hospital Ghent, Ghent, BelgiumRottey Sylvie, Department of Medical Oncology, University Hospital Ghent, Ghent, BelgiumDelanghe Joris, Department of Clinical Chemistry, University Hospital Ghent, Ghent, Belgium

Introduction: Prostate cancer (PCa) is the most common malignancy in men. Prostate specific antigen (PSA) assays are widely used for early detection of PCa. However, those analyses are associated with considerable sensitivity and specificity problems complicating the distinction between various forms of prostate disease. Moreover, there is a risk of over-diagnosing indolent PCa and missing potentially aggressive PCa’s.

Material & Methods: We determined the N-glycan profile of prostatic proteins in the urine after digital rectal examination of healthy volunteers (n = 21), patients with benign prostate hyperplasia (BPH; n = 61), PCa patients (n = 42) and patients with prostatitis (n = 17) by means of DNA sequencer-assisted Fluorophore-assisted carbohydrate electrophoresis. Statistical analyses were performed to examine whether differences in N-glycan profile were statistically significant between the 4 subject groups.

Results: N-glycan profile analyses have pointed out differences between patients with BPH and PCa patients, associated with a decrease in triantennary structures and a decrease in fucosylation of biantennary structures. The isolated test was not statistically better than sPSA measurement (AUC after ROC curve analyses are 0.795 ± 0.047 and 0.710 ± 0.053 for sPSA screening and the glycosylation marker respectively). It gives however an added value to sPSA screening. Combination of these assays reached a diagnostic performance of 0.863 ± 0.040 for all patients. In the diagnostic gray zone of sPSA between 4 and 10 ng/ mL sPSA was not retained in the logistic regression model.

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Conclusions: We have found a statistically significant difference in the glycosylation patterns of patients with BPH versus PCa patients. These changes in N-glycosylation could lead to the discovery of a new biomarker for PCa. A larger sample size and subsequent validation will show us if this glycosylation marker can be used as a clinically usable assay in the future.

22Predictors of biochemical progression after RARP: oncological outcome and salvage therapy three years after robot assisted radical prostatectomy

Collette Eelco, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, NetherlandsVan den Ouden Dies, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, NetherlandsKlaver Sjoerd, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, Netherlands

Introduction & Objectives: Goal of this analysis is to analyse the oncological outcome three years after RARP (robot assisted radical prostatectomy) and to evaluate predictors of biochemical progression (BCR) after RARP.

Material & Methods: Prospective registration and retrospective analysis. Between January 2009 and April 2010, 207 patients (pts) underwent RARP in our hospital for clinically localized prostate cancer, performed by one single surgeon. At time of analysis all pts were minimal 36 months in follow-up. pTumor-stadium, pGleason score, surgical margin status, BCR and salvage therapy were evaluated. Time between RARP and onset of salvage therapy was listed, as well as type of salvage therapy; external radiotherapy (EBRT), androgen deprivation therapy (ADT) or a combination. BCR is defined as PSA >0.2 ng/ ml. None of the pts received adjuvant therapy (<3 months) after RARP.

Results: Of the total group of 207 pts, 55 (27%) revealed BCR within three years after initial treatment. All pts with BCR received salvage therapy. Within this group 35/ 55 (64%) pts received EBRT, 8/ 55 (14%) pts ADT and 12/ 55 (22%) pts initially EBRT and later ADT. The peri-operative and three years oncological outcomes are listed in the table. In multivariate logistic regression analysis adjusted for initial PSA, prostate volume and nerve sparing surgery, pGleason score 8-10 (OR 5,760; p<0.001) and pT3ab-stadium (OR 4,924; p<0.001) appeared as strong significant predictors for BCR. Positive surgical margin (p=0.53) was not significantly associated. Mean time between RARP and salvage therapy was 15,4 (n=55) months.

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Conclusions: RARP showed acceptable oncologic outcomes. Three years after surgery 73% of pts is free of biochemical recurrence, despite the first 150 pts concerned the oncologic learning curve of the surgeon (demonstrated at GCPC 2012). The largest predictors for BCR were pGleason score 8-10 and pT3ab-stadium. More accurate imaging concerning local staging and evaluating metastases is needed to prevent local treatment in the metastatic setting and to perform a wide excision in locally advanced tumors in combination with an eLND.

Table: Proportion of patients with BCR three years after RARP stratified to pT and surgical margin

BCR in Margin-

BCR in Margin+

Total subgroup

pT2ab, n= 33 3/ 29 (10%) 0/ 4 (0%) 3/ 33 (9%)

pT2c, n=121 13/ 97 (13%) 7/ 24 (29%) 20/ 121 (17)

pT3a, n=22 5/ 16 (31%) 4/ 6 (67%) 9/ 22 (41%)

pT3b, n=31 13/ 20 (65%) 10/ 11 (91%) 23/ 31 (74%)

Total group, n=207

34/ 162 (21%) 21/ 45 (47%) 55/ 207 (27%)

23Survival, continence and potency (SCP) outcomes three years after robot assisted radical prostatectomy

Collette Eelco, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, NetherlandsVan den Ouden Dies, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, NetherlandsKlaver Sjoerd, Department of Urology, Maasstad Hospital, Rotterdam, Zuid-Holland, Netherlands

Introduction & Objectives: Objective is to evaluate oncological and functional outcomes three years after RARP (robot assisted radical prostatectomy) and to identify different patient groups by means of the survival, continence and potency (SCP) classification.

Material & Methods: Prospective registration and retrospective analysis by means of validated questionnaires. Between January 2009 and April 2010, 207 patients (pts) underwent RARP in our hospital for clinically localized prostate cancer, performed by one single surgeon. At time of analysis all pts were minimal 36 months in follow-up. Biochemical recurrence, continence and potency were evaluated accordant to the SCP-classification. S(urvival): Sx = adjuvant therapy <3 months after RARP, S0 = PSA ≤0.2, S1 = PSA >0,2 or salvage therapy. C(ontinence): Cx = pre-op incontinent, C0 = no pad use, C1 = 1 (security) pad per day, C2 = >1 pad per day. P(otency): P0 = SHIM ≥17 without medication, P1 = SHIM ≥17 with medication, P2 = SHIM <17, Px = pre-op impotent, no nerve-sparing surgery, no sexual activity or no partner. Group A concerned pre-op continent and potent pts who underwent nerve-sparing surgery. Group B concerned all the other pts.

Results: The SCP outcomes are listed in the table. Within the entire cohort a pT2-tumor was found in 154 pts (74%) and pT3-tumor in 53 pts (26%).

44ABSTRACTS

Conclusions: The SCP-classification differentiates outcome between patient categories. RARP reached favourable oncological and functional outcome at a follow-up of three years. Explanation for the results may be due to the first 150 pts concerning the oncologic learning curve of the surgeon (demonstrated at GCPC 2012), no adjuvant pts, no psa screening cohort and large portion of pT3 tumors. Higher numbers and longer oncological follow-up is needed.

Table: SCP outcomes of entire cohort three years after RARP

Outcome Entire cohort;

(n=207; 100%)Group A: (n=81; 39%)

Group B: (n=126; 61%)

Survival Sx= 0 (0%)

S0= 152 (73%) S0= 64 (79%) S0= 88 (70%)

S1= 55 (27%) S1= 17 (21%) S1= 38 (30%)

Continence Cx = 5 (2%) Cx = 5 (4%)

C0 = 157 (76%) C0= 67 (83%) C0= 90 (72%)

C1 = 40 (20%) C1= 12 (15%) C1= 28 (22%)

C2 = 5 (2%) C2= 2 (2%) C2= 3 (2%)

Potency Px= 126 (61%) Px= 126 (100%)

P0= 39 (19%) P0= 39 (48%)

P1= 7 (3%) P1= 7 (9%)

P2= 35 (17%) P2= 35 (43%)

Oncologic success,

functional success

- 37/ 81 (46%) 88/ 126 (70%)

Oncologic success,

functional failure

- 27/ 81 (33%) 0/ 126 (0%)

Oncologic failure,

functional success

- 7/ 81 (9%) 35/ 126 (28%)

Oncologic failure,

functional failure

- 10/ 81 (12%) 3/ 126 (2%)

24Prolaris®: A Novel Genetic Test for Prostate Cancer Prognosis

Brawer Michael, Urology, Myriad Genetic Laboratories, Inc�, Salt Lake City, UT, United StatesCuzick Jack, Centre for Cancer Prevention, Queen Mary, University of London, London, United KingdomCooperberg Matthew, Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United StatesSwanson Greg, Radiation Oncology and Urology/ Radiology, University of Texas Health Science Center San Antonio, San Antonio, TX, United StatesFreedland Stephen, Surgery, Durham VA Medical Center and Duke University School of Medicine, Durham, NC, United StatesReid Julia, Informatics, Myriad Genetics, Inc�, Salt Lake City, UT, United StatesFisher, Centre for Cancer Prevention, Queen Mary, University of London, London, United KingdomLanchbury Jerry, Administration, Myriad Genetics, Inc�, Salt Lake City, UT, United StatesGutin Alexander, Informatics, Myriad Genetics, Inc�, Salt Lake City, UT, United StatesKing Gary, MGI International, Myriad Genetics, Inc�, Salt Lake City, UT, United StatesStone Steven, Research, Myriad Genetics, Inc�, Salt Lake City, UT, United StatesCarroll Peter, Urology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States

Introduction & Objectives: The natural history of prostate cancer is highly variable and difficult to predict accurately. Improved tools are needed to match treatment more appropriately to a patient’s risk of progression. Therefore, we developed an expression signature composed of genes involved in cell cycle progression (CCP) and tested its utility in prostate cancer.

Methods: We’ve developed an expression signature composed of 31 cell cycle progression and 15 housekeeper genes. An expression score (CCP score) was derived as the mean of all cell cycle progression genes. The signature was tested at disease diagnosis in two conservatively managed cohorts (N=337 and 349), after radical prostatectomy in an additional two cohorts (N=366 and 413), and after external beam radiation therapy (N=141) in a final cohort. All studies were retrospective.

45 ABSTRACTS

Results: The cell cycle progression signature was a highly significant predictor of outcome in all five studies. In conservatively managed patients, the CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (p = 6.1 x 10-22 after diagnosis by TURP and p = 8.6 x 10-10 after diagnosis by needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis, and in fact, was a stronger predictor of disease-specific mortality than other prognostic variables. After radical prostatectomy, the CCP score predicted biochemical recurrence (BCR) in univariate analysis (p = 5.6 x 10-9 and p= 2.23 x 10-6) and provided additional prognostic information in multivariate analysis (p = 3.3 x10-6 and p = 9.5 x10-5). After external beam radiation therapy, the CCP score predicted BCR (Phoenix) in univariate (p=0.0017) and multivariate analysis (p=0.034). In all five studies the HR per unit change in the CCP score was remarkably similar, ranging from 1.89 to 2.92, indicating that the effect size for the CCP score is robust to clinical setting and patient composition.

Conclusions: This CCP score test predicts prostate cancer outcome in multiple patient cohorts and diverse clinical settings. In all cases, it provides information beyond clinicopathologic variables to help differentiate aggressive from indolent disease.

25Diagnostic accuracy of MRI and MRI targeted biopsies for patient’s selection for active surveillance for low risk prostate cancer

Marliere François, Urology, Claude Huriez, Université Lille 2, Lille, FranceOuzzane Adil, Urology, Claude Huriez, Université Lille 2, Lille, FranceVillers Arnauld, Urology, Claude Huriez, Université Lille 2, Lille, France

Introduction & Objectives: Although the rationale for active surveillance (AS) in patient with low risk prostate cancer is well established, there are limits in the ability of AS criteria to predict the correct pathologic stage of insignificant prostate cancer at radical prostatectomy. A strategy of targeted biopsies based on pre-biopsy multiparametric resonance imaging (mp-MRI) is associated with a high sensitivity, specificity and negative predictive value for prostate cancer identification and staging. We retrospectively measured the role of mpMRI-targeted biopsies for reclassification to higher risk in patients eligible for AS based on 12 systematic biopsies in our center.

Material & Methods: From 1763 patients biopsied in one center in the period 2008 to 2012, 1103 were diagnosed for prostate cancer. Out of them, 922 underwent pre-biopsy mp-MRI and 12 transrectal ultrasound-guided systematic biopsies plus two targeted biopsies at any mp-MRI area suspicious for malignancy.The criteria for AS, based on 12 systematic biopsies, were clinical stage T1-2 tumor, PSA ≤10ng/ ml, biopsy Gleason sum ≤6 with no pattern of grade 4 or 5, < 3 biopsies, with maximum cancer core length of 5mm. mp-MRI comprised T2 weighted, diffusion weighted and dynamic contrast enhanced imaging with either 1.5 or 3 Tesla magnetic field strengths. Suspicious areas were ranked on a 5 point scale. Criteria for the likelihood of maligancy were classified as either non suspicious (score of 1 or 2) or suspicious (score of 3, 4 or 5). Two targeted biopsies at any mp-MRI lesion (score of 3, 4 or 5) were performed using fusion software or by visual targeting. Both systematic and targeted biopsies were performed during the same biopsy session in that order. Patients were reclassified if targeted prostate biopsies showed cancer core length > 5mm or Gleason score >6.

Results: Of the 922 patients, 220 (24%) fulfilled all clinicobiological criteria and biopsy criteria based on 12 systematic biopsies for AS. The median (range) age was 63 (60-68) years ; median PSA level was 6 (4.8-7.2)ng/ ml ; median PSA density was 0.12 (0.08-0.16) ng/ ml/ cc. Out of the 220 patients eligible for AS, 10 %(22/ 220) were reclassified to higher risk by mp-MRI with targeted biopsy.

Conclusions: The risk of misclassification of patients eligible for AS from the currents criteria can be reduced by 10% with pre-biopsy mp-MRI and targeted biopsies at any MRI area suspicious for malignancy.

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26Preliminary experience with a novel method of three-dimensional co-registration of prostate cancer digital histology and in vivo multi-parametric MRI

Orczyk Clement, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceRusinek Henry, Radiology, NYU Medical Center, New York City, New York, United StatesRosenkrantz Andrew, Radiology, NYU Medical Center, New York City,Mikheev Artem, Radiology, NYU Medical Center, New York City, New York, United StatesDeng Feng-Ming, Pathology, NYU Medical Center, New York City, New York, United StatesMelamed Jonathan, Pathology, NYU Medical Center, New York City, New York, United StatesTaneja Samir, Division of Urologic Oncology, Department of Urology, NYU Medical Center, New York City, New York, United States

Introduction & Objectives: To assess a novel method of three-dimensional (3D) co-registration of prostate cancer digital histology and in vivo Multi-parametric MRI for clinical usefulness.

Material & Methods: We developed a software platform to achieve 3D co-registration. We prospectively applied this method to three patients who underwent radical prostatectomy. Data were comprised of in vivo MpMRI (T2WI, ADC, DCE), ex vivo T2WI, 3D-rebuilt pathologic specimen, and digital histology. Internal landmarks from zonal anatomy served as reference for assessing co-registration accuracy and precision.

Results: Applying a method of deformable transformation based upon 22 internal landmarks, we reached a 1.6mm accuracy to align T2-weighted images and 3D-rebuilt pathologic specimen, improving over the rigid approach by 32% (p=0.003). The 22 zonal anatomy landmarks were more accurately mapped using the deformable transformation than the rigid one (p=0.0008). An automatic method based on Mutual Information, permitted us to automate the process and include perfusion and diffusion MR images. Evaluation of coregistration accuracy by volume overlap index (Dice index) met clinically relevant requirements, ranging from 0.81 to 0.96 for sequences tested. Ex vivo images of the specimen did not significantly improve co-registration accuracy in our specific workflow.

Conclusions: This preliminary analysis suggests that deformable transformation based on zonal anatomy landmarks is accurate in co-registration of mpMRI and histology. Including diffusion and perfusion sequences in the same 3 dimensional space as histology is essential further clinical implication. The ability to localize the cancer in 3D space may improve targeting for image-guided biopsy, focal therapy and disease quantification in surveillance protocols.

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27Long-term quality of life after open and robot assisted laparoscopic radical prostatectomy

De Bruyne Peter, Urology, UZ Gent, Gent, BelgiumVan Praet Charles, Urology, UZ Gent, Gent, BelgiumDe Smet Jens, Urology, UZ Gent, Gent, BelgiumAspeslagh Barbel, Urology, UZ Gent, Gent, BelgiumOosterlinck Willem, Urology, UZ Gent, Gent, BelgiumVerbaeys Anthony, Urology, UZ Gent, Gent, BelgiumLumen Nicolaas, Urology, UZ Gent, Gent, Belgium

Introduction & Objectives: We examined and compared quality of life (QoL) and continence after open radical prostatectomy (ORP) versus a robot assisted laparoscopic procedure (RALP) for clinically located prostate cancer (cT1-T2).

Material & Methods: We invited 244 persons who underwent ORP between 1997 and 2011 to fill in EORTC QLQ-C30, EORTC QLQ-PR25, and ICIQ-mLUTS questionnaires. We retrieved 108 (44%). Starting in 2009 the same questionnaires were prospectively offered to RALP patients (n=78) after 1, 3 and 12 months. The ORP group was compared to the RALP group and to a literature-reported reference population of healthy males. Univariate linear regression was performed to identify determinants of QoL and symptoms.

Results: Patient characteristics are listed in the table below.

ORP (n = 108)

RALP (n = 78)

P < x

Age 61,4 (±6,7) 63,4 (±6,6) 0,08

Follow-up 55,6 (±37,4) 18,5 (±10,6) 0,001

PSA (ng/ ml) 10,9 (±8,5) 12,1 (±18,9) 0,97

Gleason ≤6: 37 (34%) ≤6: 21 (31%) 0,74

7: 50 (46%) 7: 35 (52%)

≥8: 21 (19%) ≥8: 11 (16%)

pT T2: 69 (64%) T2: 51 (66%) 0,5

T3: 39 (36%) T3: 23 (29%)

Nerve sparing 63/ 108: 75/ 78: 0,001

None: 30(48%)

None: 15(20%)

Unilateral: 16(25%)

Unilateral: 39(52%)

Bilateral: 17(27%)

Bilateral: 21(28%)

Adjuvant or salvage radiotherapy

54/ 107 (51%) 15/ 65 (23%) 0,001

Hormonal therapy 33/ 107 (31%) 8/ 64 (13%) 0,007

BMI 25,9 (±3,1) 27,6 (±4,1) 0,07

Age-stratification and comparison of the open group to a healthy Dutch reference population illustrated that only patients between 60-69 (n=47) and ≥70 years old (n=37) had a significant lower QoL (P<0,001). There were no significant differences in QoL and continence of the robot versus the open group. Univariate analysis in the latter demonstrated an advantage of nerve sparing but disadvantage of radiotherapy in terms of QoL (P<0,035 and P<0,041 respectively). Hormonal therapy increases incontinence (P<0,005). Bilateral nerve sparing in the robot group was associated with better continence on the 3rd and 12th month of follow up (P<0,013 and P<0,05). The BMI however is detrimental to overall continence on the 12th month of follow up (P<0,008).

Conclusions: Overall QoL several years after radical prostatectomy is excellent and shows only a minor decrease in comparison to a Dutch elderly reference population. Radiotherapy was associated with worse QoL. Hormonal therapy and BMI contribute to incontinence. As opposed to other published literature there were no significant differences between open and robotic surgery. However, longer follow-up is needed.

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28Can we localize the prostate cancer index lesion at our office? Performances of TRUS saturation biopsies confronted to radical prostatectomy specimen

Orczyk Clement, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceDoerfler Arnaud, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceComoz François, Pathology, University Hospital of Caen, Caen,Le Gal Sophie, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceDesmonts Alexis, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceBazille Celine, Pathology, University Hospital of Caen, Caen,Secco Michael, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceTillou Xavier, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceBensadoun Henri, Urology and Renal Transplantation, University Hospital of Caen, Caen, France

Introduction & Objectives: Index lesion should be defined as the one within the gland that leads cancer prognosis. With perspective of active surveillance (AS) and focal therapy (FT), localize and identify this index lesion is critical. While TRUS saturation biopsy (TRUS SB) is controversial for raw detection, increased sample of tissue may improve qualitative information about cancer foci. Objective is to assess the ability of TRUS SB, as an office based procedure, to detect and localize the index lesion confronted to radical prostatectomy specimen.

Material & Methods: We retrospectively reviewed the charts of patients who underwent radical prostatectomy after TRUS SB at our institution in 2010 and 2011. TRUS SB with 22 cores is offered for baseline biopsy at our center (scheme figure1). Each core was sent to pathology in separate jar. Biopsy analysis included core-by-core analysis and a report using a scheme with tissue length and cancer extension. Grouping contiguous positive cores made up lesions. Specimens underwent step section analysis and were reviewed by senior uropathologists with reporting on a standardized scheme of the sliced gland (figure 1). Specimen index lesion was the one with extra prostatic extension, if not the largest. Correlation was done on a sextant basis as described in figure 1.

Results: We included 50 patients, median age 62 years old (51-72), median PSA 6.64 ng/ ml (2.69-18.73), mean Gleason score 6.1(5-7). Median number of cores was 22, with median cancer involvement of 9 mm by patient. 88% of patient presented an index lesion at biopsy. Sensitivity (Se) for detection and localization of index lesion as such was 87% and positive predictive value (PPV) of 61%.

Conclusions: Intrinsic performance was high with sensitivity of 87% for detection and localization of the index lesion. Results are temperated by moderate PPV. TRUS SB is useful for detection and localization of the index lesion in this population of patient treated by radical prostatectomy. Clinical value of this technique depends of the treatment option offered to patient such as AS and FT. Our results need further controlled studies for validation. Improvement will rise with 3D US core registration in space and conjunction with modern imaging like Multiparametric MRI.

49 ABSTRACTS

29Stratification of prostate cancer: the benefit of TRUS saturation biopsy for predicting final Gleason score

Orczyk Clement, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceDoerfler Arnaud, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceComoz François, Pathology, University Hospital of Caen, Caen, FranceLe Gal Sophie, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceBazille Celine, Pathology, University Hospital of Caen, Caen, FranceDesmonts Alexis, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceSecco Michael, Urology and Renal Transplantation, University Hospital of Caen, Cane, FranceTillou Xavier, Urology and Renal Transplantation, University Hospital of Caen, Caen, FranceBensadoun Henri, Urology and Renal Transplantation, University Hospital of Caen, Caen, France

Introduction & Objectives: Risk stratification of prostate cancer needs accurate determination of Gleason score (GS). TRUS extended biopsy are known to under evaluate GS in 25% up to 35% of cases. TRUS SB may identify aggressiveness by maximizing tissue sampling.The objective is to assess performance of TRUS SB, as an office base method, to predict the Gleason score at radical prostatectomy analysis.

Material & Methods: We retrospectively reviewed the charts of patients who underwent radical prostatectomies after TRUS SB at our institution in 2010 and 2011 and for which biopsy and specimen pathology were assessed by one identified senior uropathologist. TRUS SB with 22 cores is offered for baseline biopsy in our center and performed under local anesthesia. Each core was sent to pathology in separate jar. Biopsy analysis included core-by-core analysis and a report using a scheme with tissue length, cancer extension and GS. Specimen underwent a step section analysis and final GS was recorded. We used Wilcoxon signed rank test for paired data with p significance at 0.05 to compare GS between biopsy and specimen.

Results: We included 41 patients median age 61.5 years old, median PSA 6.58ng/ ml, normal DRE rate of in 61%, median Gleason score 6, median prostate weight 50.5 gr. Median number of cores was 22, with median tissue length of 289 mm, median cancer involvement of 10.5 mm by patient and median rate of involvement of 3.2%. There was no significant difference (p=0.03) between TRUS SB and final GS. Exact match for GS was observed in 87% of cases. Performance for GS 6 and 7 are reported in table 1.

Conclusions: We report high performance for TRUS SB, office based procedure, for stratification of prostate cancer. High NPV at 92% for GS 7 is critical for patient enrolled in AS. By increasing number of cores, this technique may samples more tissue from cancer foci than TRUS extended biopsy. TRUS SB has to be evaluated with other techniques that aim to optimize sampling the gland like MRI guided biopsy.

Table 1. TRUS SB performance

TRUS SB with GS of 6

Sensitivity (Se) % 93

Specificity (Sp) % 79

Positive predictive value (PPV) % 89

Negative Predictive Value (NPV) % 85

TRUS SB with GS of 7

Sensitivity (Se) % 62

Specificity (Sp) % 100

Positive predictive value (PPV) % 100

Negative Predictive Value (NPV) % 92

50ABSTRACTS

30Correlation between prostate volume measured by transrectal and suprapubic ultrasound: can we do without TRUS ?

Van Praet Charles, Urology, Ghent University Hospital, Ghent, BelgiumDecaestecker Karel, Urology, Ghent University Hospital, Ghent, BelgiumMortier Margarete, Radiology, Ghent University Hospital, Ghent, BelgiumHoebeke Piet, Urology, Ghent University Hospital, Ghent, BelgiumLumen Nicolaas, Urology, Ghent University Hospital, Ghent, Belgium

Introduction & Objectives: Transrectal ultrasound (TRUS) is established as the gold standard prostate imaging tool in daily clinical practice to determine prostate volume (Pvol). Pvol is important for decision-making in prostate cancer to determine prostate-specific antigen density (PSAD, with a suspicious threshold of >15%) as well as in benign prostate hyperplasia (BPH), with a threshold of >80 mL not to perform transurethral resection of the prostate (TURP). TRUS however is not as widely available as suprapubic ultrasound (SPUS), more expensive and rather unpleasant for the patient. We investigate whether Pvol measurement with TRUS or SPUS differ significantly.

Material & Methods: We included 55 patients who underwent TRUS at Ghent University Hospital from March until May 2012. All SPUS measurements were performed by a urology resident, who also performed 18 (33%) of TRUS measurements. In 37 cases (67%) TRUS was performed by another urologist blinded to results from SPUS. In both examinations Pvol was calculated with the ellipse formula after measurement of all three prostate diameters (anteroposterior, transversal and craniocaudal). Correlation between Pvol by TRUS and SPUS was determined with Pearson correlation coefficient. Univariate and multivariate linear regression was performed to account for influence of body mass index (BMI), bladder volume and blinding on the ratio Pvol(TRUS)/ Pvol(SPUS).

Results: Median Pvol was 32,1 mL (range 8,4-154,0) with SPUS and 35,5 mL (range 10,1-117,0) with TRUS. Overall Pearson correlation coefficient was 0,919 (P<0.001). All three prostate diameters showed good correlation (range 0,739-0,875, all P<0.001). However, in 31% of patients there was a difference of >30% between SPUS and TRUS Pvol (range 0,5%-58,1%). SPUS and TRUS were inconclusive in 5 patients (9%) for a PSAD threshold of 15% and in 2 patients (4%) for a TURP threshold of 80mL. Both on uni- and multivariate linear regression lower BMI (univariate P=0.006) and blinding between observers (univariate P=0.008) predicted for lower ratio Pvol(TRUS)/ Pvol(SPUS).

Conclusions: Although there is a strong correlation between Pvol measurement by SPUS and TRUS, in almost one in three patients both measurements will differ >30%. Lower BMI predicted for more accurate SPUS measurement.

31Toxicity of postoperative high-dose pelvic radiotherapy and androgen deprivation for N+ prostate cancer compared to postoperative prostate bed-only radiotherapy: a matched case analysis

Van Praet Charles, Urology, Ghent University Hospital, Ghent, BelgiumOst Piet, Radiation therapy and oncology, Ghent University Hospital, Ghent, BelgiumLumen Nicolaas, Urology, Ghent University Hospital, Ghent, BelgiumDe Meerleer Gert, Radiation therapy and oncology, Ghent University Hospital, Ghent, BelgiumVandecasteele Katrien, Radiation therapy and oncology, Ghent University Hospital, Ghent, BelgiumVilleirs Geert, Radiology, Ghent University Hospital, Ghent, BelgiumDecaestecker Karel, Urology, Ghent University Hospital, Ghent, BelgiumFonteyne Valérie, Radiation therapy and oncology, Ghent University Hospital, Ghent, Belgium

Introduction & Objectives: Lymph node metastasized (N1) prostate cancer (PC) patients may benefit from trimodality therapy i.e. radical prostatectomy (RP) with pelvic lymph node dissection (PLND) plus high-dose whole-pelvis radiotherapy (RT) and androgen deprivation therapy (ADT). We assess acute and early late RT-induced toxicity compared to patients receiving postoperative prostate-only RT.

Material & Methods: Forty-eight N1-PC patients were treated with adjuvant (n=19) or salvage (n=29) intensity-modulated arc therapy and 2-3 years of ADT (median follow-up 12 months). Mean dose to the prostate bed and lymph node regions (including common, internal and external iliac vessels, obturator fossa and presacral nodes) was 76 Gy and 54 Gy respectively in 36-37 fractions. Patients were matched with 48 N0-PC patients receiving prostate-only RT following RP-PLND from 239 eligible patients. RT doses to the prostate bed were equivalent. Prospective end points are acute and late genito-urinary (GU) and gastro-intestinal (GI) toxicity. Late toxicity was restricted to patients with ≥12 months follow-up. An in-house developed toxicity scale was used based on RTOG/ CTCAE/ SOMA-LENT scales for GU and a modified RTOG scale for GI toxicity.

Results: Patient and tumor characteristics did not differ significantly in both groups, except for follow-up (pelvic RT 17 ± 16,1 vs. prostate-only RT 43 ± 30,2 months; p<0.001) and ADT use (pelvic RT 98% vs. prostate-only RT 71%; p<0.001). Toxicity outcomes are presented in the table. While GU toxicity did not differ significantly, acute and late GI toxicity was higher in patients receiving pelvic RT compared to prostate-only RT (p≤0.007). In the pelvic RT group 59% of ≥grade 2 GU toxicity recuperated and 100% of ≥grade 2 GI toxicity. Two patients developed lymphedema.

51 ABSTRACTS

Conclusions: Postoperative high-dose pelvic RT plus ADT comes at the cost of a temporary increase in grade 2 GI toxicity.

Acute toxicity Late toxicity

GI Pelvic RT

(n=48)

Prostate-

only RT

(n=48)

P

value

Pelvic RT

(n=28)

Prostate-

only RT

(n=38)

P

value

Grade 1 20 (42%) 24 (50%) 0.007 16 (57%) 14 (37%) 0.006

Grade 2 20 (42%) 7 (15%) 7 (25%) 3 (8%)

GU Pelvic RT

(n=48)

Prostate-

only RT

(n=48)

P

value

Pelvic RT

(n=28)

Prostate-

only RT

(n=38)

P

value

Grade 1 20 (42%) 23 (48%) 0.558 11 (39%) 14 (37%) 0.229

Grade 2 17 (35%) 12 (25%) 10 (36%) 9 (24%)

Grade 3 2 (4%) 2 (4%) 2 (7%) 1 (3%)

Grade 4 0 0 1 (4%) 2 (5%)

32Increased number of high-risk factors following radical prostatectomy is associated with decreased biochemical recurrence-free survival in high-risk prostate cancer

Van Praet Charles, Urology, Ghent University Hospital, Ghent, BelgiumDecaestecker Karel, Urology, Ghent University Hospital, Ghent, BelgiumFonteyne Valérie, Radiation therapy and oncology, Ghent University Hospital, Ghent, BelgiumOosterlinck Willem, Urology, Ghent University Hospital, Ghent, BelgiumVerbaeys Antony, Urology, Ghent University Hospital, Ghent, BelgiumLumen Nicolaas, Urology, Ghent University Hospital, Ghent, Belgium

Introduction & Objectives: High-risk (HR) prostate cancer (PC) is associated with less favourable biochemical recurrence (BCR) rates and cancer control outcomes following radical prostatectomy. However, HR-PC represents quite a heterogeneous patient group. We evaluate whether number and type of HR factors predicts for BCR-free survival.

Materials & Methods: We identified 143 patients with HR-PC who underwent radical prostatectomy (116 open, 27 robot-assisted) at Ghent University Hospital from 1997 until 2012. HR-PC was defined by at least one of 3 HR factors: prostate-specific antigen (PSA) >20 ng/ mL, Gleason score ≥8 or stage pT3-4. Mean age was 62,6 (± 5,92) years, mean follow-up was 57 (±43,2) months. Mean PSA was 16,2 (±18,54) ng/ mL. Pathological Gleason score was ≤6 in 29 patients (20%), 7 in 62 (43%) and ≥8 in 52 patients (36%). Twenty-one patients (15%) had pT2 PC, 91 (64%) had pT3a, 28 (20%) pT3b and 3 patients (2%) pT4. Adjuvant RT was delivered in 64 patients (45%) because of PSM (n=51), stage pT3b (n=19) or pN1 (n=8). Kaplan-Meier analyses were performed with multivariate Cox regression to correct for delivery of adjuvant RT.

Results: Five-year BCR-free survival was 59,4% for the total group and 64,0%, 48,6% and 53,3% for patients with 1, 2 and 3 HR factors respectively. On multivariate Cox regression (figure 1), presence of ≥2 HR factors was associated with worse BCR-free survival (hazards ratio 2,13 [1,12-4,06]; p=0.021). When all HR factors were put in the multivariate regression model, only PSA≥20 ng/ mL was independently associated with worse BCR-free survival (hazards ratio 2,11 [1,03-4,31]; p=0.041).

52ABSTRACTS

Conclusions: Presence of >1 HR factor predicts for less favourable BCR-free survival. HR-PC should be further stratified according to number of HR factors.

33Quality of life (QoL) in patients with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel: interim analysis of a prospective non-interventional trial (QoLiTime)

Hofheinz Ralf, Hematology/ Oncology, University Hospital Mannheim, Mannheim, GermanyAl-Batran Salah-Eddin, Hematology/ Oncology, Krankenhaus Nordwest, Frankfurt, GermanyHammerer Peter, Urology, Academic Hospital Braunschweig, Braunschweig, GermanyKienitz Carsten, Oncology, Sanofi-Aventis Germany, Berlin, GermanyKloß Susanne, Urology, DRK Hospital Luckenwalde, Luckenwalde, GermanyLange Carsten, Urology/ Oncology, Medical Practice for Urology and Oncology, Bernburg, Germany

Introduction: Cabazitaxel (Caba) combined with Prednisone or Prednisolone is approved for second-line treatment of mCRPC after Docetaxel. Potential toxicity of chemotherapy may impact on patient s QoL and counterbalance treatment benefits. Thus QoL data are becoming more important from patients and regulatory perspective.

Methods: Patients with mCRPC receiving Caba are asked to fill in EORTC QLQ C30 QoL questionnaires every three weeks. Here we describe QoL results of the first 131 patients of 480 planned in total.

Results: 131 patients who had finished 4 cycles of Caba treatment are evaluated. Median age was 72 years with generally good performance status (ECOG 0, n=51; ECOG 1, n=70). Bone metastases (n=106 (82%)) and lymph node metastases (n=66 patients (51%)) are most common. 114 patients have been pretreated with Docetaxel (6 cycles mean). Mean baseline functioning scales were (n=119 patients): cognitive 80, emotional 65, physical 64, social 63, role 53. QoL questionnaire compliance was excellent: 114 patients (96%) reporting QoL data in cycle 4. Mean functioning values and global health status remained unchanged during the first 12 weeks of treatment. Mean baseline values for symptom scales are: fatigue 50, pain 42, sleep disturbance 39, appetite loss 32, dyspnea 31, constipation 24, financial difficulties 15, diarrhea 13, nausea/ vomiting 9. A significant improvement of pain between baseline and cycle 4 (mean 35) (p=0.03) and a trend regarding improvement of sleeping disturbance (cycle 4 mean 33) (p=0.15) were noticed, while diarrhea significantly increased (cycle 4 mean 21; p<0.01). Other parameters remained unchanged.

Conclusions: This interim analysis is the largest prospective non-interventional analysis of QoL in patients receiving Cabazitaxel for mCRPC. QoL questionnaire compliance was excellent. A significant improvement of pain and a trend for improved sleep quality were shown, for the price of increased diarrhea. Importantly, mean global health status was maintained during the 12-week observation period. Results need to be confirmed by final analysis.

This research is funded by Sanofi-Aventis.

53 ABSTRACTS

34Cancer volume is an independent predictor for biochemical recurrence in high-risk prostate cancer patients following radical prostatectomy: a validation of Leuven’s cohort

Hakim Lukman, Urology, University Hospitals Leuven, Leuven, BelgiumTosco Lorenzo, Urology, University Hospitals Leuven, Leuven, BelgiumChun Felix K�H�, Urology, University Hospital Hamburg - Eppendorf, Hamburg, GermanySpahn Martin, Urology, Inselspital, Bern, SwitzerlandGontero Paolo, Urology, Vita-Salute San Raffaele Hospital, Milan, ItalyAlberts Arnout, Urology, University Hospitals Leuven, Leuven, BelgiumBriganti Alberto, Urology, Vita-Salute San Raffaele Hospital, Milan, ItalyHsu Chao Yu, Medical and Research Education, Puli Christian Hospital, Puli, Taiwan, Province of ChinaKarnes R Jeffrey, Urology, Mayo Clinic, Rochester, MN, United StatesGraefen Markus, Urology, Martini Klinik, Hamburg, GermanyVan Poppel Hein, Urology, University Hospitals Leuven, Leuven, BelgiumJoniau Steven, Urology, University Hospitals Leuven, Leuven, Belgium

Introduction & Objectives: We have previously shown that CV is an independent predictor for biochemical recurrence in a single center at the University Hospitals of Leuven – Belgium (UZL). This study aimed to validate the UZL observations using the Martini Clinic Hamburg-Germany (MCH) data.

Material & Methods: We retrospectively collected the 370 high-risk PCa patients treated with RRP and bilateral lymphadenectomy at UZL and validated them towards 492 data from MCH between 1987-2010. Patients were diagnosed either cT 3-4, or PSA > 20 ng/ ml, or biopsy Gleason score (bGS) 8-10. Staging was based on TNM 2002. Biochemical recurrence (BCR) was considered as a confirmed increase PSA>0.2 ng/ ml, while adjuvant treatment was defined as either hormonal and or radiotherapy treatment given within 90 days following RRP. Kaplan-Meier survival analysis was used to calculate the biochemical progression-free survival (BPFS), cancer-specific survival (CSS), and overall survival (OS), meanwhile log-rank test was used to compare between survival curves. Univariate and multivariate cox-proportional hazard were used to determine the predictive ability of cancer volume models, corrected for prostate specific antigen (PSA), pathological staging (pT), surgical Gleason score (fGS), lymph node invasion (LNI), surgical margin status (SM), adjuvant hormonal therapy (AHT) and adjuvant radiotherapy (ART). Cancer volume were stratified into non-fixed intervals (quartiles) and fixed intervals (≤ 2.5, 2.5-5, > 5-7.5, > 7.5-10, > 10 ml) in both cohorts, to identify the strongest predictor and critical cancer volume.

Results: Biochemical progression-free survival at 5 years were 61.3% and 46.3% at UZL and MCH respectively, while at 10 years it was 49.6% and 35%. Cancer-specific survival at 5 years were 97.7% and 97.3% respectively, while at 10 years it was 97.3% and 95.7%. The overall survival were 92.9% and 93.7% respectively, meanwhile at 10 years it were 76.3% and 87.6%.

logCancer volume was proven to be an independent predictor for BCR at UZL cohort (HR 1.86; 95% CI 1.26-2.76; p=0.002) and MCH cohort (HR 2.15; 95% CI 1.4-3.29; p=0.0004). The highest quartile of CV at UZL (> 8.2 ml) and MHC (> 17 ml) were shown to be the only independent predictor among other quartiles, yielding 1.61-fold (p=0.01) and 1.69-fold increased (p=0.009) respectively, compared to the lowest quartile. Further stratification into fixed intervals showed critical cancer volume of 10 ml in UZL cohort and 7.5-10 ml in MCH cohort.

In this series, fGS 8-10 was shown to be the strongest independent predictor for BCR in UZL (HR 2.67; 95% CI 1.58-4.51; p=0.0003) and MCH (HR 7.99; 95% CI 3.61-17.69; p<0.0001) cohorts.

Conclusions: This validation study consistently showed CV as an independent predictor for BCR. Critical cancer volume in this series is about 10 ml in both cohorts. This emphasize the importance of CV measurement in a routine histopathology of high-risk PCa specimens following RRP.

54ABSTRACTS

35Cancer and precancerous lesions risk in patients with probably precancerous processes of the prostate

Zakharava Viktoryia, Pathology, Belarusian State Medical University, Minsk, BelarusLiatkouskaya Tatsiana, Pathology, Belarusian State Medical University, Minsk, BelarusCherstvoy Eugeniy, Pathology, Belarusian State Medical University, Minsk, BelarusMasansky Igar, Oncosurgery, Minsk City Clinical Oncologic Health Center, Minsk, BelarusNitkin Dmitry, Urology, Belarusian Medical Academy of Postgraduate Education, Minsk, BelarusDosta Nikolay, Urology, Belarusian Medical Academy of Postgraduate Education, Minsk, Belarus

Introduction: According to the results of recent studies, postatrophic hyperplasia (PAH), proliferative inflammatory atrophy (PIA) and adenosis of the prostate demonstrate overlapping histological and biological features with prostatic intraepithelial neoplasia (PIN) and prostatic adenocarcinoma (PCa).

Methods: PCa risk in patients with probably precancerous lesions (PAH/ PIA and adenosis) has been assessed in biopsies material from 172 patients having clinically suspicious PCa. Suspicious foci were estimated with use of cocktail AMACR+HWC+p63.

Results: According to our results, within the first 6 years the overall incidence of precancerous lesions and PCa on re-biopsy in the PAH/ PIA and adenosis group makes 4% and 6% respectively. Median lifetime in this group without precancerous lesions and PCa made 5.8-years with no reliable difference between groups (P=0,06). Thus, the cumulative share of patients without precancerous lesions/ PCa in the probably precancerous group made 98/ 99%-96/ 95%-94/ 93%-90/ 91%-88/ 89%-85/ 84% at the end of the first-second-third-fourth-fifth-sixth year of supervision respectively with no reliable difference between groups PAH, PIA and adenosis of the prostate.

Conclusions: Within the 6 years precancerous lesions and PCa risk in the PAH/ PIA and adenosis group makes 4% and 6% respectively. Cumulative share of patients in the group of probably precancerous lesions of the prostate without precancerous lesions and PCa in re-biopsy specimens decreased from 98-99% to 85-84% during these six years respectively.

366-month hormonotherapy in advanced prostate cancer: what is new about anxiety?

De La Taille Alexandre, Urology Department, Henri Mondor Hospital, Creteil, FranceMardoyan Séta, Urology Department, Henri Mondor Hospital, Creteil, FranceDuclos-Morlaes Bénédicte, Medical Department, Laboratory Astellas, Levallois-Perret, FranceLafaye Anaïs, Laboratory Epsilon EA 4556, Dynamics of Human Abilities and Health Behaviors, University de Monpellier, Montpellier, France

Introduction & Objectives: Significant levels of anxiety were found in patients suffering from prostate cancer (PCa), due to the diagnosis and their treatment. The primary objective of this study was to describe the level of anxiety associated with disease in patients receiving leuprorelin acetate 45mg for the treatment of advanced PCa, taking into account the exclusive or combined nature of hormonotherapy.

Methods: This was an observational, non-interventional, multicenter study conducted among 172 specialists practicing in France (may 2010-april 2011). Patients completed questionnaires at inclusion and 6 months after starting their treatment. PCaspecific anxiety was assessed with the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and quality of life (QoL) with SF-12.

High MAX-PC (range 0-54) scores indicate greater anxiety while high SF-12 scores (range 0-100) represent a better QoL.

Results: A total of 145 physicians (urologists 91%) included 813 patients, of whom 575 and 315 were evaluable at inclusion and 6 months, respectively. Median age of patients was 77 years, and median time to PCa diagnosis was 5.3 months. In half of cases, PCa was at intermediate risk (Gleason score 7, PSA ≤ 15 mg/ mL).

Initially, the 575 analyzed patients were little anxious, as 75% of them had a MAX-PC score <27, limit of clinically significant anxiety.

Anxious patients were likely to be younger (with lymphatic invasion/ nodal metastasis (OR=2.2, p=0.002), and metabolic disorders (OR=1.7, p=0.049). However, PCa had an impact on QoL, especially on physical and mental (SF-12 scores ≤ 49).

At 6 months, the 315 patients were less anxious than at baseline with a significant decrease in the MAX-PC total score of -2.0 ± 10.4 (95% CI [-3.2, -0.8], p<0.001), mainly due to improved anxiety related to PCa diagnosis. Similarly, the vitality SF-12 subscore significantly increased (1.2 ± 9.8 ; p=0.014). An improving trend was also found with regard to generic anxiety and mental health.

Conversely, physical condition was significantly deteriorated after 6 months of treatment (p<0.001) as well as pain (p=0.003) and social functioning (p<0.001).

Regarding the modalities of LHRH intake, there was no significant difference between both groups (alone or combined), except for a greater improvement in generic anxiety when associated (p=0.013).

Conclusions: PCa-related anxiety estimated at 25% at baseline improved after 6 months of hormonotherapy.

55 ABSTRACTS

37Was information provided by urologists when patients started androgen blockade for advanced prostate cancer, well-understood, sufficient, appreciated?

Lebret Thierry, Department of Urology, Foch Hospital, Suresnes, FranceDuclos-Morlaes Bénédicte, Medical Department, Laboratory Astellas, Levallois-Perret, FranceComet Denis, Medical Department, Axonal, Nanterre, FranceDroupy Stéphane, Department of Urology, University Hospital, Nimes, France

Introduction & Objectives: Communication and information have increasingly been considered important in helping people to cope with cancer. The primary objective of this study was to compare information given by the physician when starting androgen deprivation therapy [adT] for prostate cancer (PCa) with that perceived by the pt overall, and according to the main circumstances of care (metastatic [M] stage, recurrence [R], adjuvant therapy [AT]).

Material & Methods: An observational, non-interventional, multicenter study was conducted among French urologists between September 2011 and June 2012. Physicians completed questionnaires about the information they gave to the patients (pts) concerning their PCa, prognosis and treatment the day they intiate adT. Patients filled in self-questionnaires one day after the consultation about messages they understood. Concordance between physician and pt answers was assessed using pourcentage of condordance, overestimed, underestimated by pts and kappa indexes (k).

Results: A total of 165 physicians included 915 pts. 770 pts had evaluable questionnaires (M: 40%, AT: 27%, R: 33%). Mean age of pts was 75 years. At inclusion, the majority of pts had an advanced PCa T3N0M0, Gleason≥ 7. A total of 55% of pts went accompanied to the consultation, mainly by their wife.

When physicians informed patients of the nature of the prostate disease, respectively 77% of pts understood the information related to disease extension, 82% the palliative nature of treatment and duration of treatement and 92% information on adverse event (AE).

The best concordance between responses from physicians and pts was found for treatment (nature, duration, AE; k 0.54-0.68). Concordance was not significantly changed according to the presence/ absence of an accompagnist unlike the pts’s status: More M pts overestimated the response regarding the nature (severity) of the disease than pts with AT (respectively 17% vs 7%, k= 0.37 vs 0.17). In contrast, pts with AT underestimated the duration of treatment compared with M pts (respectively 8% vs 14%, k= 0.56 vs 0.55).

Conclusions: Key information delivered to pts at consultation is not always well grasped and may be improved. Especially in the domain of the disease (stage, severity) while for domains linked to treatments, patients’ understanding is better.

38Our way for treatment of locally advanced prostate cancer

Haxhiu Isa, Urology, University Clinical Center of Kosovo, Prishtina, AlbaniaQuni Xhevdet, Urology, University Clinical Center of Kosovo, Prishtina, Kosovo, AlbaniaHyseni Sabri, Urology, University Clinical Center of Kosovo, Prishtina, Kosovo, AlbaniaHaxhiu Anduena, Consultant Department, Family Medical Center, Shtime, Kosovo, AlbaniaHaxhiu Emirjon, Medical Faculty, University of Prishtina, Prishtina, Kosovo, Albania

Introduction & Objectives: Prostate cancer develops primarily in men over fifty. Our purpose was to give a full information about the incidence of prostate cancer in Kosova, the methods of treatment, especially those for locally advanced prostate cancer, focusing more on the radical prostatectomy as a favorable choice.

Material & Methods: This is a perspective - retrospective study. The material gives information about the incidence and the type of surgical intervention applied to the patients diagnosed with prostate cancer which were admitted to our Urological Center (the only tertiary center in Kosova). 157 cases with prostate cancer are processed, considering their age, the Gleason score and the type of intervention. We have been more focused on monitoring and the course of disease to the patients with locally advanced prostate cancer.

Results: We have applied radical prostatectomy in 47 patients. Before these interventions the sextant biopsy was performed and the Gleason score resulted from 1-10. In seven of them Gleason score was 10, with the infiltration of the seminal vesicles, and in four of them this score was 9 respectively. The course of disease was followed for two, respectively five years and it is seen that the five cases had the levels of PSA normal inside two months and there was no tendency for these values to increase. In two cases, after surgery, the PSA level were jet high and we decided to treat with Androcuror, for three months. After that we see that PSA level was normalized.

Conclusions: Their course of disease was followed by performing the CT and measuring the PSA levels every four months, which showed us that there was no relapse, and their condition was good, so we came to the conclusion that radical prostatectomy can be considered as a favorable choice even for the patients with highly advanced prostate cancer, and even when the Gleason score is 10.

56ABSTRACTS

39Prostate carcinoma in solid organ transplant recipients

Tillou Xavier, Urology and Transplantation, CHU de Caen, Caen, FranceGuleryuz Kerem, Urology, CHU de Caen, Caen, FranceOrczyk Clement, Urology, CHU de Caen, Caen, FranceHurault de Ligny Bruno, Nephrology, CHU de Caen, Caen, FranceChiche Laurence, Abdominal Surgery, CHU de Bordeaux, Bordeaux, FranceBensadoun Henri, Urology, CHU de Caen, Caen, FranceDoerfler Arnaud, Urology and Transplantation, CHU de Caen, Caen, France

Introduction & Objectives: Improvements in immunosuppression and anti-infection drugs in solid organ transplantation have led to a significant survival increase for patients and grafts. Prostate cancer (PC), being the most common tumor in men and given the increasing number of old male recipients, should show an increasing incidence in solid organ transplant recipients (SOTR). The aim of this study was to analyze retrospectively our Liver (LTR) and Kidney transplant recipients (KTR) treated for a PC.

Material & Methods: Between 1993 and 2012, we found 33 PC in SOTR. 12 PC in LTR and 21 in KTR. Age at diagnosis was 64,4±5,9 (51,7-76,7) years old and the interval from transplantation to diagnosis was 79,4±59,5 (9,1-241,5) months. Mean PSA level was 12±12.7 (0.5-53) ng/ ml. Clinical stages were T1, T2 and T3 in respectively 11, 19 and 3 patients. Diagnosis was suspected during screening, because of prostatitis or bone pain in respectively 29, 1 and 1 patients. Two PC were discovered after prostate transurethral resection.

Results: 24 patients (15 KTR and 9 LTR) with a localized disease underwent radical prostatectomy (RP). Histological findings were 16 pT2 and 8 pT3 tumors, with 5 positive surgical margins. Gleason score (GS) was 5 in 1 case, 6 in 17 cases, 7 in 5 cases and 9 in 1 case. One patient with positive pelvic lymph nodes was given hormonotherapy. Another had a biochemical recurrence at 10 months and was treated with salvage radiotherapy. With a mean follow-up of 51,7 ±38,2 (0,6-151,6) months, two KTR died 3 and 11 years after Hormonotherapy and RP respectively.

Conclusions: Prevalence of PC in SOTR remains controversial, even though a significant increase can be expected in the coming decades. It is therefore recommended to systematically screen male transplant recipients after 50 years of age because outcome is much better if PC is diagnosed and treated early. Radical prostatectomy is feasible in KTR as well as in LTR. HIFU should be an alternative curative treatment for small-localized PC in older patients. Despite a poor prognosis for metastatic disease, hormonotherapy is still indicated.

57 ABSTRACTS

40Stage III prostate cancer surgical treatment after neoadjuvant androgen deprivation therapy

Zakharava Viktoriya, Pathology, Belarusian State Medical University, Minsk, BelarusPuchinskaya Marina, Pathology, Belarusian State Medical University, Minsk, BelarusLiatkouskaya Tatsiana, Pathology, Belarusian State Medical University, Minsk, BelarusMasansky Ihar, Oncosurgery #3, Minsk City Clinical Oncologic Health Center, Minsk, Belarus

Introduction & Objectives: Prostate cancer (PCa) is one of the most widespread cancers in men throughout the world and affects mostly elderly people. Surgical treatment, i. e. radical prostatectomy (RPE) is used for treatment of localized disease, but nowadays patients with locally advanced PCa are also treated surgically in some cases. Before operation neoadjuvant (NA) androgen deprivation therapy (ADT) is often used to lessen the size of the tumor. Such treatment gives the opportunity of radical operation even in stage III PCa patients.

In our country surgical treatment of PCa with NA ADT is used for a relatively low period of time, but gives good results. So, the aim of the study is to analyze the current experience of PCa surgical treatment after NA ADT.

Methods: We retrospectively analyzed the medical data of 23 patients, operated between 2009 and 2013. All of them had stage III PCa and NA ADT was used in all cases.

Results: The mean age at diagnosis was 63 (from 55 to 75) years. Different types of NA ADT were used, including orchidectomy in 7 (30,43%) cases, antiandrogens (mostly cyprotherone acetate) in 4 (17,39%), both orchidectomy and antiandrogens in 8 (34,78%), LHRH agonists in 1 (4,35%) and LHRH agonists with antiandrogens in 2 (8,70%) patients. In 1 (4,35%) patient antiandrogen therapy for 22 months was followed by radiotherapy (RT) (40 Hy) and then by RPE.

RPE was performed after a median of 4 months after the beginning of ADT (mostly after 2 – 5 months (69,57%), less than 2 months in 1 (4,35%), from 6 to 12 months in 3 (13,04%) patients). In 3 (13,04%) cases NA ADT lasted for more than a year (up to 29 months) for different reasons.

No other treatment after RPE was used in 15 (65,22%) cases, in 3 (13,04%) patients ADT continued postoperatively and external beam RT was used in 2 (8,70%) cases. Both ADT and RT were used in 1 (4,35%) case.

The mean follow-up was 26 months. During this time most patients (n=19, 82,61%) stayed disease-free, progression was diagnosed in 4 (17,39%) cases. 3 (13,04%) patients died because of the PCa progression.

Conclusions: So, NA ADT is beginning to be used before RPE for stage III PCa patients in our country, and it helps to obtain rather good results for the treatment of this category of patients.

41Early rebiopsy is not necessary for patients with prior detected atypical small acinar proliferation (ASAP) at 12 core TRUS guided prostate biopsy and candidate for active surveillance

Soydan Hasan, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyYesildal Cumhur, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyOkcelik Sezgin, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyDursun Furkan, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyYilmaz Omer, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyAtes Ferhat, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeySenkul Temucin, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, TurkeyKarademir Kenan, Urology, Gulhane Military Medical Academy Haydarpasa Teaching Hospital, Istanbul, Turkey

Introduction & Objectives: To review rebiopsy and long-term follow-up results of patients prior detected atypical small acinar proliferation (ASAP) and investigate whether these patients are candidate for active surveillance.

Material & Methods: We retrospectively reviewed the TRUS guided at least 12 core prostate biopsy results. We examined age, serum PSA level, digital rectal examination (DRE), rebiopsy and follow up results and treatments of patients who detected ASAP and investigated whether there is any difference between the patients with tumor and no tumor at rebiopsy.

Results: Between 2007-2012 926 patiens underwent prostate biopsy in our clinic. ASAP was detected in 20 (%2,2) of these patients. The average age of patients was 62 (67-79) years. The mean PSA level is 6.67 ng/ ml (1.5 to 23). 3 patients had DRE abnormality, while 17 patients had no abnormality. 18 patients were detected with ASAP at their first biopsies. In one patient ASAP was detected after one benign biopsy. In another patient ASAP was detected after two benign biopsies. The following 18 core control biopsy results were reported benign for these two patients. Considering the patients with ASAP detected at their first biopsy, 15 of them underwent second biopsy. Among the 15 patients, 9 of them reported as benign, 6 of them reported as prostate adenocarcinoma: 4 one core Gleason score 3+3, 1 two core positive Gleason score 3+3, 1one core positive Gleason score 4+3.

58ABSTRACTS

The mean PSA level of the patients with tumor is 5.43ng/ ml (3.7 to 7.41). Except one all patients with tumor had no DRE abnormality. 4 patients with prostate cancer has chosen active surveillance. They are followed for an average of three years. On the control biopsies, except for one patient had no tumor. The biopsy results of the patient who has detected tumor on the control biopsy was similar to his first biopsy. Radical prostatectomy is applied to 1 patient and his pathologic result was pT2, Gleason score 3 +3, tumor volume was less than 1% of the of prostate. We proposed radical prostatectomy to the patient whose biopsy result was reported as gleason 4+3 prostate adenocarsinoma

Conclusions: Although we have limited number of patients, applying late biopsy instead of early does not effect the oncologic outcomes adversly in patients detected ASAP in their first biopsies appropriate for active surveillance.

42Age stratified outcomes after primary HIFU for organ localized prostate cancer in a series of 5206 patients

Baco Eduard, Urology, Oslo University Hospital, Aker, Oslo, NorwayBlana Andreas, Urology, Fuerth Hospital, Fuerth, GermanyBerge Viktor, Urology, Oslo Univeristy Hospital, Aker, Oslo, NorwayChaussy Christian, Urology, University of Regensburg, Krankenhaus St Josef, Regensburg, GermanyGanzer Roman, University of Regensburg, Krankenhaus St Josef, Krankenhaus St Josef, Regensburg, GermanyCrouzet Sèbastian, Urology, Edouard Herriot Hospital, Lyon, FrancePasticier Gilles, Urology, Pellegrin Hospital, Bordeaux, FrancePaulesu Antonello, Urology, Ospedale S�Anna, Como, ItalyRobertson Carry, Urology, Duke University, Durham, United StatesThueroff Stefan, Urology, Harlaching Hospital, Munich, GermanyWard John, Urology, MD Anderson Center, Huston, United StatesSanchez-Salas Raul, Urology, Institut Mutualist Montsouris, Paris, FranceGelet Albert, Urology, Edouard Herriot Hospital, Lyon, France

Introduction & Objectives: High intensity focused ultrasound (HIFU) performed by Ablatherm® has been used as primary treatment of localized prostate cancer since 1993. In the last years, HIFU has been recognized as a therapeutic option in patients over 70 years old with 10 years life expectancy. The objective of this study is to report the biochemical and biopsy outcomes, stratified by age, in patients who have undergone HIFU.

Material & Methods: 5206 consecutive patients with cT1-T3 prostate cancer treated by HIFU Ablatherm® (EDAP-TMS, Lyon, France), 16 European HIFU centers were included. Treatment results, and post treatment morbidity as the bladder outlet obstruction (BOO) or urethra stenosis have been registered in the online Ablatherm® HIFU database, @-Registry. This is a secured on-line database collecting relevant de-identified clinical and technical information for patients treated by HIFU. Patients were stratified by age into two groups: below 70 years (n=2291) and above 70 years (n=2915) and according to D’Amico’s 2003 risk group classification. Kaplan-Meier analyses were performed to determine biochemical survival with failure defined according to the 2006 Phoenix definition (nadir+2). Univariable and multivariable Cox analyses were performed to adjust for possible confounding variables (clinical stage, Gleason score, PSA, prostate volume).

Results: Follow-up time was 3.4 ± 2.9 years. The median PSA nadir: 0.15 ng/ ml was reached 14.0 ± 11.5 weeks after HIFU. The negative biopsy rates (<70 yrs/ >70yrs) were 70%/ 73%, actuarial biochemical disease free survival (BDFS) at 5 years: 84%/ 73% low risk, 74%/ 65% intermediate risk, 69%/ 63% high risk patients. Urinary incontinence rates (GII and GIII) were 4%/ 7%. BOO or urethra stenosis rates were 18%/ 19 %.

Conclusions: HIFU presents positive oncological and functional outcome in patients both below and above 70 years. HIFU treatment appears therefore as a valuable therapeutic option for prostate cancer control independent of age.

59 ABSTRACTS

43Anticipating metabolic changes: magnetic resonance spectroscopy as a diagnostic tool for early detection of prostate cancer

Voskanyan Georgy, Urology, I�M� Sechenov First Moscow Medical Unviversity Urological Clinic, Moscow, Russian FederationGlybochko Pyotr, Urology, I�M� Sechenov First Moscow Medical Unviversity; Research Institute for Uronephrology and Reproductive Health, Moscow, Moscow, Russian FederationVinarov Andrey, Urology, I�M� Sechenov First Moscow Medical Unviversity; Research Institute for Uronephrology and Reproductive Health, Moscow, Russian FederationKorobkin Artem, Radiology, Cardiology Research Center, Moscow, Russian FederationShariya Merab, Radiology, Cardiology Research Center, Moscow, Russian FederationTernovoy Sergey, Radiology, Cardiology Research Center, Moscow, Russian Federation

Introduction & Objectives: The objective of our study was to evaluate the diagnostic capabilities of magnetic resonance spectroscopy (MRS) as a novel imaging technique for early detection and localization of organ-confined prostate cancer (PCa).

Material & Methods: The study enrolled 36 males aged between 49 and 81 years with suspected PCa based on solely elevated PSA levels (4.52 to 53.4 ng/ ml, mean 7.82±9.01 ng/ ml) and no signs of disease on DRE, TRUS, and negative bone scan when PSA>20 ng/ ml. MRS was a part of multiparametric MRI protocol, the procedure being performed with “Philips Achieva 3T TX” MR scanner. The spectroscopic scanning was carried out after the native stage of MRI and was followed by diffusion MRI and DCE imaging. MRS was carried out in multiple fixed size 7x7x7 mm voxels with water/ fat noise suppression. The spectrum interpretation was based on the single parameter--ratio of choline, creatine and citrate peaks: (Cho+Cr)/ Cit ≥.48±.11, considered cancer-positive if exceeded the median norm by more than 2 standard deviatioins. All patients subsequently underwent transrectal 12-core needle prostate biopsy for pathologic examination of prostate tissue. We estimated the correlation between T2 MRI vs. MRS sings of PCa and pathologic reports, MRS sensivity, specificity and diagnostic accuracy as well as capacity to differentially diagnose between high grade PIN and PCa, and MRS precision in localizing organ-confined prostatic lesions.

Results: 13 (36%) and 23 (63%) of 36 enrolled patients demonstrated symptoms of PCa on native MRI T2 images and MRS respectively. PCa was verified by pathology in 20 of 36 patients (56%), Gleason score ranging from 4 to 9 pts. The concordance of MRS data and pathologic report was observed in 17 (85%) of 20 verified patients. False positive and false negative results accounted for 6 of 23 MRS-positive patients and 3 of 20 histologically proven cancers respectively. High grade PIN was reported in all false positive cases which may reaffirm that metabolic changes anticipated by MRS are early signs of PCa. The precise localization of lesion was observed in 14 (82%) of 17 MRS positive histologically proved tumors; the rest of which demonstrated a high-grade PIN in pathologic spectrum voxels. The assessed spectroscopic ratio significantly (p<.01) differed between groups of patients with histologically verified PCa vs. patients without any tumorous lesion, whilst a less evident difference could be observed among patients with histologically verified high-grade PIN vs. without any tumor lesion and within cancers with different Gleason patterns.

Conclusions: Our current results suggest MRS as a diagnostic tool for PCa to be 85% sensitive and 63% specific; diagnostic accuracy of the technique was limited to 75%. We were unable to discover reliable capability of MRS to distinctively diagnose between high grade PIN and PCa. The sensitivity of MRS was higher than that of native T2 MRI. The MRS specificity was lower as compared to native MRI which may have been due to masking effect of high-grade PIN and usage of a single spectroscopic parameter. This also may confirm that metabolic changes in prostate tumors precede structural ones detected by MRI. We are looking forward to further investigation of the potential role of MRS in early diagnosis of PCa, optimization of its protocol and increasing the reliability of the results.

60ABSTRACTS

44Development of a sheath for an ultrasound probe used to monitor coagulation during prostate cancer treatment

Alam Adeel, Institute of Biomaterials and Biomedical Engineering, University Health Network, Toronto, CanadaWilson Brian, Medical Biophysics, University Health Network, Toronto, Ontario, CanadaWeersink Robert, Medical Biophysics, University Health Network, Toronto, Ontario, Canada

Prostate cancer is one of the leading causes of death by cancer for men. Several methods are available to treat low risk prostate cancer; however each method causes a significant reduction in the quality of life. Focal therapy is being tested to target only the cancer portion in the prostate. However, due to the need to ensure that the laser is targeting only the cancer and not surrounding tissues, a real-time treatment monitoring system is required.

A combined optical-ultrasound monitoring system is in development at Princess Margaret Hospital based on different optical properties for coagulated versus normal tissue. Using this property light will scatter and adsorb differently with coagulated tissue.

In this project, we are developing the sheath, housing the fiber-optic cables used for light delivery to and from the prostate that will be placed on top of the existing ultrasound probe. Computer-aided design was used to design and visualize the prototype. Specific consideration was given towards placement and holding of the optical fibers, conformation of its shape to the ultrasound probe and biocompatibility with the rectum. After a material is chosen, based on toxicity and sterilization considerations, the prototype will be fabricated. Simulated, controlled testing will take place to observe the feasibility of the prototype. Once that is complete, clinical testing will take place. Once approved, we believe it the device will aid in making laser thermal therapy a successful treatment for localized low risk prostate cancer patients.

45Efficacy of early duloxetine therapy in urinary incontinence occurred after radical prostatectomy

Eren Ali Erhan, Department of Urology, Canakkale Onsekiz Mart University Medical Faculty, Canakkale, TurkeyBaştürk Gökhan, Department of Urology, Canakkale Onsekiz Mart University Medical Faculty, Canakkale, TurkeyAlan Cabir, Department of Urology, Canakkale Onsekiz Mart University Medical Faculty, Çanakkale, Turkey

Introduction & Objectives: To evaluate the efficacy of early duloxetine therapy in stress urinary incontinence occurred after radical prostatectomy.

Material & Methods: Fifty-eight patients with an age range 55-65, who had body mass index range 28-30, were selected between 112 patients operated due to prostate cancer between 2010 and 2013. The patients had radical prostatectomy were randomized into 2 groups following the removeling of urinary catheter; group1(n:28): in which the patients had pelvic outlet exercise (POE) and duloksetin therapy, group 2 (n:30): in which the patients had POE alone. ICIQ-IU-SF and IEF questionnaires were used to evaluate the continence of the patients at the beginning and during the follow-up. Number of pad used and 1-hour pad test were used in determining the degree of urinary incontinence. The treatment lasted for 10 months and called for the control in the first month with 3-month intervals. The treatment was assessed with the tests mentioned above in each controls.

Results: Mean age of the patients mean follow-up were 60.2 (55-62) and 7.8 months (2-13), respectively. 27 of the patients (96.4%) in group 1 were completely dry at the end of first year. 5 of them were dry in first 3 months. On the other hand 17and 3 of rest of the patients in group 1 had dryness in 6th and 10th months and gave up pad usage, respectively. Only 1 patient in group 1 could not get dryness and had urethral stricture at the end of first year. 26 of the patients (86.7%) in group 2 were completely dry at the and of first year. None of these patients had dryness in the first 3 months. 12 patients of group 2 were dry in 6th months, hovewer, 6 and 8 patients in this group had dryness in 9th and 12th months in follow-up and gave up pad usage. 4 patient in group 2 could not get dryness and 1 of them had urethral stricture at the end of first year. There was a significant difference for the time to reach continence in group 1 (p:0.008). There were significant differences in number of pad usage and weight of pad in 7th months between 2 groups. However, there was no significant difference in IEF questionnaire. None of the patients did give up the drug due to side effects and medication was ended with dose reduction after 1 month of the obtainment of continence.

Conclusions: According to our results, early duloxetine therapy in stress urinary incontinence occurred after radical prostatectomy has efficacy to provide continence.

61 ABSTRACTS

46Efficacy outcomes by baseline prostate-specific antigen (PSA): results from the phase 3 AFFIRM trial

Saad Fred, Department of Surgery, University of Montreal Hospital Center, Montreal, Canadade Bono Johann S�, Drug Development Unit, Institute of Cancer Research, London, United KingdomShore Neal D�, Urology, Carolina Urologic Research Center, Myrtle Beach, South Carolina, United StatesFizazi Karim, Department of Cancer Medicine, University of Paris Sud, Villejuif, FranceHirmand Mohammad, Clinical Development, Medivation, Inc, San Francisco, California, United StatesForer David, Clinical Development, Medivation, Inc, San Francisco, California, United StatesScher Howard I�, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Introduction: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway. The Phase 3 AFFIRM trial demonstrated that ENZA vs placebo (PBO) increased median overall survival (OS) by 4.8 months (P <0.001, HR 0.63), radiographic progression-free survival (rPFS) by 5.4 months (P <0.001, HR 0.40), and time to PSA progression (TTPP) by 5.3 months (P <0.001, HR 0.25) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC) patients (Scher et al, NEJM 2012; 367:1187).

Methods: The AFFIRM trial was a Phase 3 multinational, randomized, double-blind, PBO-controlled study in 1,199 post-docetaxel mCRPC patients. Randomization was stratified by baseline ECOG performance status and mean pain score. Results are presented by baseline PSA quartile for efficacy outcomes of OS, rPFS, and TTPP.

Results: Consistent benefit in outcomes with ENZA treatment were observed in all subsets (Table).

Conclusions: A consistent relative benefit in time to event outcomes was observed with ENZA treatment in patients enrolled in the Phase 3 AFFIRM trial regardless of baseline PSA.

Baseline PSA (ng/ mL)

<40.2 (n=299)

40.2 to <111.2 (n=300)

111.2 to <406.2 (n=300)

≥406.2 (n=300)

Median OS, months (95% CI)

ENZA NM* (NM, NM)

18.8 (17.0, NM)

15.4 (13.0, NM)

14.7 (12.3, 17.4)

PBO 19.2 (15.8, NM)

16.2 (10.4, NM)

10.9 (9.5, 14.4)

9.5 (6.8, 11.3)

HR** (95% CI)

0.55 (0.36, 0.85)

0.69 (0.47, 1.02)

0.73 (0.53, 1.01)

0.53 (0.39, 0.73)

Median rPFS, months (95% CI)

ENZA 10.9 (8.3, 13.5)

8.3 (8.0, 10.1)

8.2 (5.6, 9.0)

8.1 (5.9, 10.6)

PBO 3.8 (2.8, 5.5)

3.2 (2.8, 5.5)

2.8 (2.8, 3.0)

2.8 (2.8, 4.0)

HR (95% CI)

0.38 (0.28, 0.52)

0.39 (0.28, 0.52)

0.40 (0.30, 0.53)

0.41 (0.31, 0.55)

Median TTPP, months (95% CI)

ENZA 11.1 (8.3, 14.0)

8.3 (5.6, 8.4)

8.2 (5.6, 8.3)

5.8 (5.6, 8.2)

PBO 2.9 (2.8, 3.0)

3.1 (2.8, 3.7)

2.9 (2.8, 3.7)

3.7 (3.0, 4.6)

HR (95% CI)

0.20 (0.14, 0.30)

0.25 (0.17, 0.38)

0.23 (0.15, 0.34)

0.31 (0.20, 0.48)

*NM = not met**HR = hazard ratio as assessed by Cox regression with treatment as covariate. HR <1 favors ENZA over PBO

62ABSTRACTS

47Outcomes in patients with liver or lung metastatic castration-resistant prostate cancer (mCRPC) treated with the androgen receptor inhibitor enzalutamide: results from the phase 3 AFFIRM trial

Loriot Yohann, Medical Oncology, Institute Gustave Roussy, Villejuif, FranceFizazi Karim, Department of Cancer Medicine, University of Paris Sud, Villejuif, Francede Bono Johann S�, Drug Development Unit, Institute of Cancer Research, London, United KingdomForer David, Clinical Development, Medivation, Inc, San Francisco, California, United StatesHirmand Mohammad, Clinical Development, Medivation, Inc, San Francisco, California, United StatesScher Howard I�, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States

Introduction & Objectives: Enzalutamide (ENZA) inhibits multiple steps in the androgen receptor signaling pathway (Tran et al, Science. 2009;324:787). The Phase 3 AFFIRM trial demonstrated that ENZA increased median overall survival (OS) by 4.8 months (P <0.001, HR 0.63) vs placebo (PBO) in post-docetaxel mCRPC patients (pts) (Scher et al, NEJM 2012; 367:1187). Here we assess the effect of ENZA on outcomes in pts with liver or lung metastases in the AFFIRM trial.

Methods: The AFFIRM trial was a Phase 3 multinational, randomized, double-blind study in post-docetaxel mCRPC pts. Randomization was 2:1 to ENZA 160 mg/ day or PBO, stratified by baseline ECOG and mean pain score. The primary endpoint was overall survival (OS). Radiographic progression-free survival (rPFS) was a key secondary endpoint. PSA response defined as a decline of ≥50% compared to baseline, and soft tissue objective response per RECIST 1.1 were also assessed and reported here.

Results: Pts with liver mCRPC comprised 11.5% (92/ 800) of ENZA pts and 8.5% (34/ 399) of PBO pts. Pts with lung mCRPC comprised 15.3% (122/ 800) of ENZA pts and 14.8% (59/ 399) of PBO pts. The median OS for patients with liver and/ or lung mCRPC in the AFFIRM trial was 11.4 months (ENZA: 13.4 months; PBO: 9.5 months). Improved outcomes with ENZA treatment were observed in both liver and lung mCRPC pts.

Conclusions: In the Phase 3 AFFIRM trial, pts with lung mCRPC had higher median OS than pts with liver mCRPC. Consistent with the overall results from AFFIRM, in these post-hoc analyses, OS and rPFS were generally improved in both pt groups treated with ENZA. ENZA also resulted in higher response rates in both liver and lung mCRPC pts.

Liver mCRPC Lung mCRPC

ENZA

(n=92)

PBO

(n=34)

ENZA

(n=122)

PBO

(n=59)

OS (months)

(95% CI)

9.0

(6.4‒10.7)

5.7

(4.2‒9.5)

16.5

(12.5‒NM)

10.4

(8.1‒NM)

HR=0.697

(0.436‒1.114)

HR=0.760

(0.493‒1.172)

rPFS (months)

(95% CI)

2.9

(2.8‒4.9)

2.8

(2.7‒3.2)

5.6

(5.3‒8.2)

2.8

(2.7‒2.9)

HR=0.645

(0.413‒1.008)

HR=0.427

(0.298‒0.612)

Confirmed PSA

response (%)

(95% CI)

35.1

(24.4‒47.1)

4.8

(0.1‒23.8)

52.8

(42.9‒62.5)

4.3

(0.5‒14.5)

Objective

response (%)

(95% CI)

14.9

(8.2‒24.2)

3.3

(0.1‒17.2)

29.3

(20.6‒39.3)

4.9

(0.6‒16.5)

CI=confidence interval; ENZA=enzalutamide; HR=hazard ratio; NM=not

met; OS=overall survival; PBO=placebo; rPFS=radiographic progression-free

survival; PSA=prostate-specific antigen

63 ABSTRACTS

48Correlation between basal PCA3 level and biopsy-driven disease reclassification in active surveillance

Marenghi Cristina, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyRancati Tiziana, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyRavagnani Fernando, Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyLombardo Claudia, Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyTaverna Francesca, Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyMagnani Tiziana, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyAlviisi Maria Francesca, Prostate Cancer Program, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyColecchia Maurizio, Anatomopathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyVilla Sergio, Radiation Oncology 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyNicolai Nicola, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalySalvioni Roberto, Urology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, ItalyValdagni Riccardo, Prostate Cancer Program and Radiation Oncoloty 1, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Introduction & Objectives: One of the open issues in Active Surveillance (AS) for prostate cancer (PCa) is related to research of new biomarkers that could more clearly discriminate PCa aggressiveness. Urinary PCA3 levels has been significantly associated with Gleason Score (GPS) and PCa volume in prostatectomy series, suggesting that this marker may be useful in the selection of pts for AS. The goal of the present study was to evaluate the relationship between PCA3 and biopsy-driven disease reclassification in an AS cohort.

Patients & Methods: Starting in 2005, we are proposing AS in very low-risk Pca within an institutional protocol (SAINT). In November 2007 we activated the international PRIAS protocol. Until February 2013 a total of 454 pts were enrolled in AS. Pts are monitored through PSA kinetics, with DRE and re-biopsy. Beginning in 2008, pts were proposed to provide urine samples for PCA3 measurement at AS enrollment (no specific selection criteria were applied). Biopsy-driven active treatment free survival (ATFS) was assessed using Kaplan-Meier (KM) survival analysis and the log-rank (LR) test was used to assess correlation between PCA3 score and ATFS. 3 separate endpoints were considered: reclassification due to upgrading OR upsizing, reclassifications due to upgrading and upsizing separately.

Results: 78pts had PCA3 (75/ 78 had at least one re-biopsy). A PCA3 score>80 was correlated with increased disease reclassification rate due to upgrading+upsizing (LR p=0.005, HR=3.7) and to upgrading (LR p=0.04, HR=4.4). KM curves are presented in figure.

Conclusions: In this preliminary analysis, in a cohort of pts with very-low risk PCa who were selected for AS, a PCA3 score>80 was significantly associated with disease re-classification at re-biopsy. Specifically, it was correlated to enhanced rates of upgrading. Further analysis is necessary to assess the usefulness of PCA3 in AS management.

64ABSTRACTS

49The value of PSA testing in men presenting with haematuria

Dhanasekaran Ananda Kumar, Urology, Wrightington Wigan & Leigh NHS Foundation Trust, Wigan, United KingdomHassouna Hussam, Urology, Wrightington Wigan & Leigh NHS Foundation Trust, Wigan, United KingdomManikandan Ramaswamy, Urology, Wrightington Wigan & Leigh NHS Foundation Trust, Wigan, United Kingdom

Introduction & Objectives: To look at the clinical usefulness of estimating PSA in patients presenting with both visible and non-visible haematuria. No international guidelines available regarding the usefulness of PSA screening in men presenting to haematuria clinic.

Methods: We analysed the records of 1332 consecutive men presenting to a protocol driven haematuria clinic. As part of the work up all men were duly counselled about the implication of PSA testing and had PSA estimation. We then analysed the outcomes of these patients following PSA estimation.

Results: 1223 agreed to have their PSA estimated. The average age was 69.9 years (Range is 52 to 74). Of these 68 (5.5%) had a PSA above the age specific range. 62 underwent a transrectal ultrasound guided biopsy of the prostate. Six patients did not have a TRUS biopsy due to their advanced age. Nine had a positive biopsy (0.73% of the total tested or 14.5% of those biopsied).

Conclusions: Incidence of CaP in our study population is only 0.73%. This is much lower than the incidence of CaP in screening studies like ERSPC (8.2%) and PLCO (1.16%). Men presenting with hematuria are not having higher incidence of CaP when compared to the general population. Before offering PSA tests to patients presenting for hematuria clinic, proper counselling is necessary.

50Focal prostate cancer therapy - capabilities, limitations, prospects

Schostak Martin, Urology, Universitätsklinikum Magdeburg, Magdeburg, GermanyBaumunk Daniel, Urology, Universitätsklinikum Magdeburg, Magdeburg, Sachsen-Anhalt, GermanyBlana Andreas, Urology, Klinikum Fürth, Fürth, Bayern, GermanyGanzer Roman, Urology, Uniklinikum Regensburg, Regensburg, Bayern, GermanyHenkel Thomas, Urology, Praxis, Berlin, Berlin, GermanyKöllermann Jens, Pathology, Dr� Horst Schmidt Kliniken, Wiesbaden, Hessen, GermanyRoosen Alexander, Urology, Klinikum der Universität München, Campus Großhadern, München, Bayern, GermanySalomon Georg, Urology, Martini-Klinikum, Hamburg, Hamburg, GermanySentker Ludger, Urology, Praxis, Sinsheim, Baden-Württemberg, GermanyWitzsch Ulrich, Urology, Krankenhaus Nordwest, Frankfurt/ Main, Hessen, GermanyKöhrmann Kai-Uwe, Urology, Theresienkrankenhaus, Mannheim, Baden-Württemberg, Germany

Introduction: Patients with low-risk prostate cancer (PCa) face the difficult decision between a potential overtreatment by one of the standard therapies and active surveillance (AS) with the potential insecurities regarding cancer control. A ´focal therapy´ (FT) implies a treatment of the tumour within the prostate only.

Methods: This paper evaluates the current literature and expert opinion of different therapies suited for FT as well as concepts for prostate imaging, biopsy and the histopathological evaluation.

Results: Currently there is a lack of multicenter, randomized, prospective data on the effectiveness of FT. Nonetheless the published data indicates a sufficient tumor control with a favourable side effect profile. There are still flaws in the diagnostics in regard to tumor detection and histological evaluation. Multicenter studies are currently recruiting worldwide. These studies will provide new data with a higher level of evidence. This Paper presents the applied techniques.

Conclusions: At present, the effectiveness of FT should not be compared directly to standard radical therapies. FT should only be performed within studies. In case of cancer progression after FT, a salvage treatment should stay executable.

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51Intensity-modulated radiotherapy for prostate cancer: 8-years follow-up at a single centre

De Meerleer Gert, Radiation Oncology, Gent University Hospital, Gent, BelgiumOst Piet, Radiation Oncology, Gent University Hospital, Gent, BelgiumVilleirs Geert, Radiology, Gent University Hospital, Gent, BelgiumLumen Nicolaas, Radiation Oncology, Gent University Hospital, Gent, BelgiumSadeghi Simin, Radiation Oncology, Gent University Hospital, Gent, BelgiumDecaestecker Karel, Urology, Gent University Hospital, Gent, BelgiumDhaenens Peter, Radiation Oncology, Gent University Hospital, Gent, BelgiumFonteyne Valérie, Radiation Oncology, Gent University Hospital, Gent, Belgium

Objective: To report on long-term oncological results of IMRT for prostate cancer.

Material & Methods: 140 patients were treated with IMRT to 2 dose levels: 74 Gy (n=55) and 76 Gy (n=85). Maximal rectal dose was set at 72 Gy and 74 Gy respectively.

Patients were divided into 3 prognostic groups:

• Good prognosis: no androgen deprivation therapy (ADT).

• Intermediate prognosis: ADT for 6 months.

• Poor prognosis: ADT for 36 months.

Biochemical relapse free-survival (bRFS), clinical relapse free-survival (cRFS), cause specific survival (CSS) and overall survival (OS) were calculated using Kaplan-Meier statistics.

Results: Distribution in risk groups was as follows: low risk: n=26; intermediate risk: n=75; high risk: n=39. Median follow-up was 96 months. The 8-year bRFS was 81%. The low- and intermediate risk group had a significantly better 8-year bRFS when compared to the high-risk group (94% vs. 84% vs. 68%; p<0.01). The 8-year cRFS was 86%, with the best result observed in the low risk group (100% vs. 88% vs. 75%; p=0.03). CSS and OS at 8 years were 86% and 78% respectively. The actuarial probability of being free of grade 3 GI and GU toxicity at 8 years was 99 (± 1%) and 92 (± 3%), respectively.

Conclusions: IMRT for prostate cancer results in excellent 8-years bRFS, cRFS and CSS. Severe toxicity rates are low. This study represents the longest follow-up of IMRT for prostate cancer in Europe

52The RADICALS trial, is adjuvant therapy needed for the majority of cases?

Robinson Simon, Urology, Wexham Park, Windsor And Slough, United KingdomMotiwala Hanif, Urology, Wexham Park, Windsor, United KingdomKarim Omar, Urology, Wexham Park, Windsor, United KingdomLaniado Marc, Urology, Wexham Park, Windsor, United KingdomRao Amrith, Urology, Wexham Park, Windsor, United Kingdom

Radicals trial: Radiotherapy and androgen deprivation in combination after local surgery.

Criteria for adjuvant treatment

• Post op PSA >0.2ng/ ml

• pT3/ 4 stage

• Gleason score >6 (biopsy or surgery)

• Pre op PSA >10ng/ ml

• Positive surgical margins

Methods: 549 patients underwent radical prostatectomy and were analysed for biochemical recurrence according to stage and use of adjuvant treatment.

Results: see Kaplan Meier curve graphs enclosed.

Conclusions: We see that biochemical relapse for all T3a patients, whether they received adjuvant treatment or not fare as well as T2 patients with over 90% free of PSA progression at 8 years.

High grade disease includes a majority of Gleason 3+4 (82%) which shows less BCR than 4+3.

A total of 113 of 549 patients received adjuvant treatment.

37 T3a patients and 50 T2 patients, 87/ 113 (77%) do not appear to need this additional treatment with its comorbidities.

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38% low grade

62% high grade

Stage n

T1 2

T2a 47

T2b 56

T2c 284

T3a 107

T3b 44

T4 9

Stage n dxt % dxt

T1 2 0 0

T2a 47 1 2

T2b 56 7 13

T2c 284 28 10

T3a 107 22 21

T3b 44 17 39

T4 9 2 22

T2 no adjuvant 87

T2 adjuvant 13

T3a no adjuvant 65

T3a adjuvant 35

T3b/ 4 no adjuvant 49

T3b/ 4 adjuvant 51

Stage nMean post op PSA ng/ ml

T2 258 0.08337

T3a 77 0.08878

T3b 33 0.24479

T4 9 0.1344

53Combined point mutations in codon 12 and 13 of KRAS oncogene in prostate carcinomas

Baştürk Gökhan, Urology, Canakkale Onsekiz Mart University, Çanakkale, TurkeyAlan Cabir, Urology, Canakkale Onsekiz Mart University, Çanakkale, TurkeyEren Ali Erhan, Urology, Canakkale Onsekiz Mart University, Çanakkale, TurkeyÖzdemir Öztürk, Medical Genetics, Canakkale Onsekiz Mart University, Çanakkale, Turkey

Introduction & Objectives: To investigate the prevalence and predictive significance of KRAS mutations in patients with prostate carcinomas.

Material & Methods:Fresh tumoural prostate tissue samples from 30 patients that underwent radical prostatectomy or TUR(P) patients, who were diagnosed prostate cancer before, no treatment given, not suitable for radical prostatectomy or not accepted this operation, but had severe lower urinary tract problem or urinary retension, in the Department of Urology were used for KRAS mutation analysis in the current results. Fresh tumoural tissue specimens that enriched in neoplastic cells were used for total genomic DNA isolation and KRAS point mutation analysis in the current descriptive study. Solid tumoural tissues were also examined and diagnosed histopathologically. Approximately, 5–10 mg of the fresh tumoural specimens were used for genomic DNA isolation and in vitro gene amplification. Total genomic DNA was isolated by the nucleospin kit extraction technique (Invitrogene, Germany) with some modifications. In vitro amplification of DNA fragments encompassing codons 12 and 13 of the KRAS oncogene was performed from blood and tumoral tissue biopsy. Twelve common muation regions of KRAS oncogene were simultaneously in vitro amplified and biotin-labelled in a multiplex amplification reaction. PCR was performed in a Perkin Elmer 9600 and the profile consisted of an initial melting step of 2 min at 94_C; followed by 35 cycles of 30 s at 94_C, 30 s at 61_C, and 30 s at 72_C; and a final elongation step of 7 min at 72_C. The KRAS genotyping was performed by StripAssay technique (Vienna Lab, StripAssay GmbH, Austria) which is based on the reverse-hybridization principle automatically.

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Results: KRAS mutations were characterized in 30 prostate carcinomas by enhanced multiplex PCR based StripAssay reverse hybridisation method. The target proto-oncogene KRAS genotyped for codon 12 and 13 in the current results. The identified KRAS mutations were then analyzed with respect to reoperative serum PSA levels, Gleason scores and tumour stages. Twenty-nine (96.6%) were diagnosed as prostate adenocarcinoma and one (3.33%) was diagnosed small cell prostate carcinoma. Gleason scores (GS) of these patients were divided into two groups as five (17.3%) low grade (GS ≤ 6), twenty- four (82.7%) were high grade (GS ≥ 8–10) The point mutations in the KRAS proto-oncogene were detected in 40% (12 of 30 patients) of current PC patients. One patient with codon 12 Val (3.44%), two patients with codon 13 Asp(6.8%) and nine patients with combined mutations in both codons (31%) respectively. Prostate carcinomas with a combined codon 12 and 13 mutations for KRAS were tended to show higher preoperative serum PSA levels, Gleason scores and advance tumor stages. No mutation was detected in 18 (60%) current PC patients with low grade and PSA levels. Prostate adenocarcinomas with combined point mutations showed clinicopathologic features that differed from those of prostate adenocarcinoma without KRAS mutation. Twelve mutated patients were detected (40%) in the second group with a Gleason score ≥ 8 (high grade).

Conclusions: Our results confirm the importance of combined point mutations in KRAS codon 12 and 13 in the molecular pathogenesis of high grade prostate adenocarcinomas in human. The current findings also pointed out the tumoural tissue specific idendification extremely need for the alternative therapeutic strategies and patient’s survival. The complexity of etiological parameters in PC development showed us; case specific tumour identification and treatment extremely need for each affected subject in the future.

54PCA3 and TMPRSS2:ERG urine tests stratify prostate cancer risk in men recommended for initial prostate biopsy

Groskopf Jack, Director, Oncology Research & Development, Hologic Gen-Probe, San Diego, United StatesDay John, Hologic Gen-Probe, San Diego, CA, United StatesKella Naveen, Urology & Prostate Institute, San Antonio, TX, United StatesJones LeRoy, Urology San Antonio Research, San Antonio, TX, United StatesMeyer Sarah, Hologic Gen-Probe, San Diego, CA, United StatesHodge Petrea, Hologic Gen-Probe, San Diego, CA, United StatesAussie Jacqueline, Hologic Gen-Probe, San Diego, CA, United StatesSaltzstein Daniel, Urology San Antonio Research, San Antonio, TX, United States

Introduction & Objectives: There is an unmet need for new tests that can be used in conjunction with current methods to guide initial prostate biopsy decisions. PROGENSA®PCA3 and TMPRSS2:ERG (T2:ERG) gene fusion urine tests can improve accuracy for predicting prostate biopsy outcome, and may also help discriminate between indolent and significant cancers. The purpose of this study was to examine the utility of PCA3 and T2:ERG in a large cohort of men undergoing initial prostate biopsy.

Material & Methods: Patients enrolled in the study were referred for an initial prostate biopsy based on elevated serum PSA, abnormal DRE, or other clinical suspicion. Post-DRE first-catch urine was collected prior to 12-core prostate biopsy. PCA3 and T2:ERG RNA copies were quantified using transcription-mediated amplification assays and normalized to PSA mRNA copies. PCA3 and T2:ERG results were used to divide the subject population into risk groups. For each risk group, the percent of subjects with cancer, significant cancer (Epstein criteria) or high-grade cancer (Gleason Score >6) at biopsy was determined.

Results: A total of 638 subjects were enrolled in the study: 66% white, 27% Hispanic, and 6% black. 99.8% (637/ 638) of specimens yielded sufficient RNA for analysis and the proportion of men who had a positive biopsy was 43% (272/ 637). For predicting cancer at biopsy, areas under the receiver operating characteristics curve for PCA3, T2:ERG and serum PSA were 0.73, 0.69, and 0.59, respectively. Positive biopsy rates in the lowest and highest PCA3 + T2:ERG Score risk groups were 14% vs. 84% (any cancer), 5% vs. 80% (significant cancer) and 2% vs. 44% (high-grade cancer).

Conclusions: In men recommended for initial prostate biopsy, urinary PCA3 and T2:ERG Scores can be combined into a simple matrix to stratify risk of detecting cancer, significant cancer and high-grade cancer at biopsy.

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55Predictive factors associated with biochemical recurrence after radical prostatectomy with negative surgical margins for organ-confined disease

Henriet Benjamin, Urology, Erasme-ULB hospital, Brussels, BelgiumTombal Bertrand, Urology, Cliniques Universitaires St Luc, Brussels, BelgiumVan Velthoven Roland, Urology, Bordet Institute, Brussels, BelgiumRoumeguère Thierry, Urology, Erasme-ULB Hospital, Brussels, Belgium

Introduction & Objectives: Despite excellent surgical cancer control, some patients with organ-confined disease experience biochemical recurrence. Positive surgical margins have been clearly demonstrated to be one of the main predictive factors for biochemical failure. The goal of this study was to identify potential factors associated with biochemical recurrence in patients with organ-confined prostate cancer and negative surgical margins after radical prostatectomy.

Material & Methods: 910 patient’s data from 3 university centres were evaluated after radical prostatectomy performed between 1990 and 2006 for a localised prostate cancer with negative surgical margins. Several parameters were evaluated: age, body mass index, smoking status, testosterone values before and after surgery, PSA, PSA density, pathological stage Gleason score, perineural invasion, capsular invasion and apical invasion.

Results: Median follow-up was 108 months. 11.76% of the patients presented with a biochemical recurrence. Univariate analysis showed that smoking status (p=0.003), PSA value (IC95% 6.9-9.3, p=0.002), PSA density (p=0,009), Gleason score ≥7 (p<0.01) and perineural invasion (p=0,005) were associated with biochemical recurrence. Multivariate analysis showed that Gleason score (RR 2.48, IC95% 1.36-4.53, p=0.003) and perineural invasion (RR 2.08 (IC95% 1.13-3.83, p=0.018) were independent prognostic factors of recurrence, respectively.

Conclusions: Gleason Score and perineural invasion status are associated with worse prognosis in terms of recurrence free survival after radical prostatectomy for organ-confined disease with negative surgical margins. Smoking status could have a potential impact on the recurrence risk. These data could help physicians for a personalized patient counselling.

56Urethrovesical anastomosis with single knot running suture in open retropubic radical prostatectomy. Experience with 536 cases

Filipensky Petr, Urology, St�Ann´s University Hospital Brno, Brno, Czech RepublicPacik Dalibor, Urology, University Hospital Brno, Brno, Czech RepublicRehorek Petr, Urology, St�Ann´s University Hospital Brno, Brno, Czech RepublicHrabec Roman, Urology, St�Ann´s University Hospital Brno, Brno, Czech RepublicCermak Ales, Urology, University Hospital Brno, Brno, Czech RepublicVarga Gabriel, Urology, University Hospital Brno, Brno, Czech Republic

Introduction & Objectives: The authors describe results of 536 consecutive nerve sparing open radical retropubic prostatectomies (RRP) performed by 3 surgeons, where the anastomosis was created with running suture. This technique described by Van Velthoven is commonly used in laparoscopic radical prostatectomy. In our center this method is performed also for open retropubic radical prostatectomy since September 2005.

Methods: Between September 2005 and December 2012 536 RRP with „single knot running suture“ in urethrovesical anastomosis were performed. Two polyglycolic acid 2-0 sutures are used and tied together at their tail ends. A running suture is completed from the 5:00-o clock position to the 12:00-o’clock position counter clockwise by first part and then clockwise to the 12:00-o’clock position by the second part of the suture, where they are tied together. The catheter is placed before completing the anterior row of sutures. Number of turns varies from 6 to 10 for one half of the suture. The water-tightness of anastomosis is tested by irrigation of 300ml saline solution. With regards to the evaluation of the benefits of this approach the following factors were followed up: operative time (skin to skin), time for anastomosis, water-tightness of anastomosis, duration of permanent catheterization, acute urinary retention occurrence after catheter removal, continence rate and development of anastomotic stricture.

Results: The average time for surgery (skin to skin) was 77 minutes (range 42 to 153). The average time for the anastomosis was 9 minutes (range 7 to 20). In 5 cases (<1%) symptomatic postoperative urinary leaks have occurred, when the anastomosis could not be performed precisely. The catheter was left in place for 5 to 16 days, mean time 6,2 days. 12 weeks after RRP with running suture 78% patients were continent using 0 or 1 pad (security pad)/ 24hours. There were 3 clinically evident bladder neck contractures observed in our set – follow up time varies from 4-88 months. Bladder neck strictures were solved by ureterotomy with TUR of bladder neck.

Conclusions: Single knot running suture during open retropubic radical prostatectomy is considered a feasible alternative technique for anastomosis creation associated with the following major advantages: reduced time to catheter removal in open technique (primarily), water-tightness of anastomosis and elimination of urethrovesical strictures. These improvements can have impact on satisfactory continence recovery.

69 ABSTRACTS

57Active surveillance in prostate cancer: 8 year experience

Marenghi Cristina, Prostate Cancer Program, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyRancati Tiziana, Prostate Cancer Program, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyAvuzzi Barbara, Radiation Oncology 1, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyNicolai Nicola, Surgery Department Urology Unit, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyMagnani Tiziana, Prostate Cancer Program, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyAlvisi Maria Francesca, Prostate Cancer Program, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyBellardita Lara, Prostate Cancer Program, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalySalvioni Roberto, Surgery Department Urology Unit, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, ItalyValdagni Riccardo, Radiation Oncology 1, Fondazione IRCCS istituto Nazionale dei Tumori, Milan, Italy

Introduction & Objectives: To avoid overtreatment, in March 2005 we started to offer Active Surveillance (AS) to selected low risk prostate cancer (PCa) patients (pts), in a multidisciplinary setting. Active Treatment-Free Survival (ATFS) was evaluated as primary end-point.

Patients & Methods: The mono-institutional SAINT protocol started in March 2005. In November 2007 we joined the PRIAS study. Common inclusion criteria: initial PSA≤10ng/ ml, DRE≤T2 and GPS≤3+3. Differences: PSA density (PSAd)<0.2 ng/ ml/ cc required by PRIAS and number of positive cores ≤ 2 in PRIAS, ≤ 25% with ≤ 50% core involvement in SAINT.

First repeated biopsy was at 12 mos and subsequently every 2 yrs in SAINT, every 3 yrs in PRIAS. PSA doubling time (DT) in the range 3-10 yrs advised extra biopsy. Patients are switched to active treatment when PSADT turns < 3yrs, cT>2, number of positive cores > 2 (or 25%) or GPS>3+3.

ATFS was assessed using Kaplan-Meier survival analysis and correlations were analysed through log-rank test and Cox analysis.

Results: 454 pts were enrolled in AS (Feb 2013): 167 in SAINT and 287 in PRIAS. 266/ 454 (58.6%) pts are still on AS (median f-up of 37.2 mos, range 2.3-107.7). 136 (29.9%) pts dropped out: 22 due to PSADT, 114 to upgrading and/ or upsizing at re-biopsy (64 at first re-biopsy). 10 pts dropped out due to comorbidities, 7 due to anxiety, 34 due to off-protocol reasons and 1 due to non-PCa death. Actuarial ATFS is 76% and 58% at 18 (after the first rebiopsy) and 36 months, respectively (Fig. 1). To date only 1 pt experienced a biochemical failure after radical prostatectomy. Biopsy-related ATFS correlates with age <66 yrs (p=0.06, HR=1.6), with PSAd<0.12 ng/ ml/ cc (p=0.03, HR=1.8) and prostate volume <52cc (p=0.004, HR=2.2).

Conclusions: AS is feasible in selected men with low risk PCa. Half drop out from AS occurred after 1yr re-biopsy, due to histology re-classification. Age>66yrs, PSAd>0.12 ng/ ml/ cc and prostate volume >52cc correlate with 1-year ATFS due to biopsy reclassification.

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58Development of prostate cryoablation program in Russia

Govorov Alexander, Urology, Moscow State University of Medicine and Dentistry, Moscow, Russian FederationVasyliev Alexander, Urology, Moscow State University of Medicine and Dentistry, Moscow, Russian FederationIvanov Vladimir, Urology, City Hospital 50, Moscow, Russian FederationPushkar Dmitry, Urology, Moscow State University of Medicine and Dentistry, Moscow, Russian Federation

Introduction & Objectives: The first cryoablation for prostate cancer (PCa) using the modern equipment was performed in Russia in March 2010 at the Department of Urology of MSMSU. The aim of our study was to prospectively collect and analyze the results of prostate cryoablation in Russian patients.

Material & Methods: From March 2010 through March 2013 89 PCa patients were treated with third generation cryotherapy device SeedNet (Galil Medical, Israel). Primary treatment was performed in 81 (91%) men and salvage treatment – in 8 (9%) patients (4 after EBRT, 2 after brachytherapy and 2 after primary cryoablation). According to D’Amico classification 33 (37.1%), 40 (44.9%) and 16 (18%) patients were from the low, intermediate and high-risk groups respectively. Mean patient’s age was 72.6 (60-81) years, median PSA 10.6 (1.3-65) ng/ ml and prostate volume 46.2 (14-110) cc. The cT1c, cT2 and cT3 stages were diagnosed in 45 (50.6%), 30 (33.7%) and 14 (15.7%) patients respectively. Gleason score (GS) of 6, 7(3+4), 7(4+3) and 8 (4+3) was diagnosed in 38 (42.7%), 24 (27%), 21 (23.6%) and 6 (6.7%) of cases. The median Qmax was 11.5 (4.2-36) ml/ s and IPSS 9 (0-27). The median IIEF score was 2.4 (1-8) in patients scheduled for total prostate cryoablation. In the past 3 men underwent TURP and 5 – open prostatectomy due to BPH.

Results: We have performed 85 total and 4 focal prostate cryoablation procedures. General anesthesia was used in 1 case; all other operations were performed under epidural/ spinal anesthesia. “IceRod” needles were used in 63 (70.8%) and “IceSeed” needles – in 26 (29.2%) patients. Intra-op cystostomy was done only in 1 case and Foley catheter was inserted in 88 men for a median of 7 (4-9) days. The median operation time was 105 (72-168) min. The only 1 intraoperative complication consisted of malfunction of urethral warming catheter which has resulted later in urethral sloughing: subsequently transurethral removal of necrotic tissue was performed. The follow-up regimen included total PSA test every 3 months and transrectal prostate biopsy in 1 year (independently of PSA level). At 3, 6 and 12 months IPSS and Qmax were also checked. The median follow-up was 20 months. 55 patients had full evaluation data at 1 year: the median total PSA was 0.28 (0.001-12.8) ng/ ml, IPSS score 12 (2-18) and Qmax 10.4 (4.4-32) ml/ s. The 1-year biopsy detected 4 adenocarcinomas out of 55 cases. One salvage patient had severe urinary incontinence, 3 men suffered from urgent incontinence 3-7 times per week. One patient underwent bilateral orchidectomy due to orchoepididymitis 3 months after cryo.

Conclusions: We consider the development of the first and largest prostate cryoablation program in Russia successful. After a short-term follow-up few patients have showed PSA progression and even fewer had histologically proven adenocarcinoma of the prostate at 1 year. The small number of serious complications (e.g. no cases of urethra-rectal fistula) during the learning curve may encourage other centers to adopt cryoablation of the prostate in their PCa treatment armamentarium. We continue to evaluate the oncological and functional results of both total and focal prostate cryoablation.

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59Applicability of radical radiotherapy for prostate cancer after renal transplantation: a case report

Alessandro Marina, Oncology Department, Ospedale Città di Castello, Città di Castello, ItalyCorazzi Francesca, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyFerranti Francesca, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyMinciarelli Marco, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyPentiricci Andrea, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyRossi Giampaolo, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyAngelini Massimo, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyBiagini Francesco, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, ItalyCheccaglini Franco, Oncology Department, Ospedale Città di Castello, Città di Castello, Perugia, Italy

Introduction & Objectives: In renal transplant recipients (RTR), the incidence of malignances appears to be 3-4 times higher than the general population. Over the past 30 years, the survival of these patients has greatly improved, so the incidence of prostate cancer, even if similar to that of the general population, it is still important; because prostate cancer is one of the most frequent cancers in males. Radiotherapy remains one of the principle treatment option for patients with localized or locally advanced prostate cancer but the anatomical position of renal allograft in the pelvis can creates serious difficulties for the treatment planning. We report the case of a 69-years-old man with prostate cancer and renal allograft, who received radical radiotherapy, at the Città di Castello Hospital.

Patients & Methods: In October 2012 we treated with radical radiotherapy the patient with bilateral prostatic adenocarcinoma Gleason score 3+3, cT2cN0M0, PSA of value 9.1 ng/ ml, with relevant co-morbidities morbidities that indicated against the intervention.For the treatment planning, computer tomographic images were obtained in supine position, the bladder full and the rectum empty. Three dimensional radiotherapy planning was used, the CTV included the prostate and the seminal vesicles for a total dose of 60 Gy in 30 fractions, the prostate receiving 78 Gy. The planning target volume (PTV) was obtained expanding the CTV with 7 mm wide margin in all directions and 5 mm posteriorly to reduce the dose to the rectal wall. Both to obtain an optimal coverage of the PTV and to reduce the dose to the OAR, in particular to the bladder, femoral heads and especially to the graft some options have been evaluated and we used a 4 fields technique for the first 30 fractions and a 6 fields technique for the last 9. The mean dose delivered to the graft was 0.61 Gy, the femoral heads received a mean dose of 22 Gy and 20 Gy and the bladder of 33 Gy.

Results: During radiotherapy, the patient evaluated each week with a clinical visit did not complain of urinary and gastrointestinal toxicity, except for mild cystitis (G1). Moreover, he performed regular evaluations of the renal function with monitoring of creatinine clearance. The patient was enrolled in our protocol of follow-up, consisting of a clinical evaluation, PSA dosage and renal function evaluation 1 month after the end of the treatment and every 3 months thereafter. At the last follow–up, the patient was well without signs of recurrence.

Conclusions: Radiotherapy is part of the standard treatment for many cases of prostate cancer. In the literature few cases of RTR treated with radiotherapy for prostate cancer are reported. Improving techniques of radiotherapy, the 3D planning techniques allow higher doses of radiation to be administered safely reducing the risk of acute and cronic toxicities. According to the few series reported in the literature and also to our experience, radiation therapy is feasible also in RTR with accurate treatment planning.

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60Stereotactic body radiation therapy with real-time tracking for localized prostate cancer

Beltramo Giancarlo, Cyberknife, Centro Diagnostico Italiano, Milan, ItalyBergantin Achille, Cyberknife Unit, Centro Diagnostico Italiano, Milan, ItalyMartinotti Anna Stefania, Cyberknife Unit, Centro Diagnostico Italiano, Milan, ItalyVite Cristina, Cyberknife Unit, Centro Diagnostico Italiano, Milan, ItalyRia Francesco, Cyberknife Unit, Centro Diagnostico Italiano, Milan, ItalyInvernizzi Marta, Cyberknife Unit, Centro Diagnostico Italiano, Milan, ItalyBianchi Livia Corinna, Cyberknife Unit, Centro Diagnostico Italiano, Milan, Italy

Introduction & Objectives: To evaluate the clinical outcome of a cohort of localized prostate cancer patients treated with Stereotactic Body Radiation Therapy

Material & Methods: A retrospective analysis was carried out on 125 consecutive patients with a median age of 75 (range 60 – 86) years and clinically localized prostate cancer who underwent Cyberknife stereotactic radiosurgery at our Institution. The majority of patients 68 (54%) were low risk, 35 pts (28%) were intermediate risk and 22 pts (18%) were high risk patients using the NCCN criteria. Pre-treatment PSAs ranged from 1.75 to 23.88 ng.ml (median 7.4 ng.ml). Among the entire study cohort 11 of 22 high risks patients received androgen deprivation therapy (ADT), ADT was not administered to any low – intermediate risk patients. A prescribed dose of 38 Gy in four fraction was delivered to the PTV, which was defined as the prostate (plus seminal vesicles in High risk patients). Real-time intrafractional motion tracking was used.

Results: Acute urinary symptoms (frequency, disurya, urgency, hesitancy and nicturia) were common with 53% of patients experiencing grade I-II RTOG toxicity. Only 3 patients (2%) experienced RTOG grade 3 acute and late urinary toxicity following repeated urological instrumentation, including cistoscopy and urethral dilatation. No RTOG grade 3 acute and late rectal toxicity was observed. Four patients, one with prior Turp, experienced incontinence, One 9 months after treatment, two 12 months after treatment, one 27 months later. One patient experienced rectal incontinence 12 months after treatment. The actuarial median follow up is 34 months (range 12 – 66 months). The Five years actuarial psa relapse free survival rate is 94% (CI: 89.0%-99..2%) with 98.1% for low risk-patients, 93.2% for intermediate –risk patients and 82.2% for high risk-patients. To date 6 patients failed biochemically. One low risk patient revealed local relapse 30 months after Cyberknife treatment. One high and one intermediate risk patients developed bone metastases, in 2 intermediate and in 1 high risk patient we observed nodal metastases. All patients are alive except four died of unrelated causes.

Conclusions: Cyberknife SBRT produces excellent biochemical control rates at up to 4 years with mild toxicity and minimal impact on quality of life. Median PSA levels compare favourably with other radiation modalities and strongly suggest durability of our results.

61Hydrodissection technique of neurovascular bundles preservation during robotic radical prostatectomy

Kolontarev Konstantin, Urology, MSMSU, Moscow, Russian FederationPushkar Dmitry, Urology, MSMSU, Moscow, Russian Federation

Introduction & Objectives: Preservation of the neurovascular bundle during radical prostatectomy is extremely important for postoperative erectile function. We determined whether hydrodissection of the neurovascular bundle during da Vinci radical prostatectomy would result in improved erectile function postoperatively.

Material & Methods: Sixty-three patients (mean age 64.4 years) who underwent nerve sparing radical prostatectomy were randomly assigned to a standard neurovascular bundles dissection (n=30) or hydrodissection of the neurovascular bundles using ErbeJet 2 equipment (n=33). All procedures were done by a single high volume surgeon. In all men erectile function was evaluated by the International Index of Erectile Function (IIEF-6) score preoperatively, and 6 weeks and 3 months postoperatively.

Results: There was no significant difference in IIEF-6 score preoperatively in both groups. In men with bilateral neurovascular bundle preservation mean International Index of Erectile Function scores in the hydrodissection group were higher than in the standard dissection group by 1.8 at 6 weeks and by 2.8 at 3 months (p <0.05). In men with unilateral partial neurovascular bundle resection there was also significant improvement between the hydrodissection and standard dissection groups at 6 weeks and 3 months (p <0.05).

Conclusions: Hydrodissection of the neurovascular bundle during da Vinci radical prostatectomy improves postoperative International Index of Erectile Function scores. Longer follow-up needed to evaluate direct impact of hydrodissection on erectile function in patients after da Vinci prostatectomy.

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62Barbed bidirectional suture in robot-assisted radical prostatectomy: first Russian randomized trial

Pushkar Dmitry, Urology, MSMSU, Mocow, Russian FederationKolontarev Konstantin, Urology, MSMSU, Moscow, Russian FederationDyakov Vladimir, Urology, MSMSU, Moscow, Russian FederationRasner Pavel, Urology, MSMSU, Moscow, Russian Federation

Introduction & Objectives: The urethrovesical anastomosis (UVA) is one of the most challenging steps of robot-assisted radical prostatectomy (RARP). Failure to achieve a watertight anastomosis is associated with postoperative urinary leak and its consequences. In a previous pilot study of 40 consecutive patients who underwent this self-sinching anastomotic technique using a Quill absorbable barbed suture during RARP for clinically localized prostate cancer, barbed suture for UVA was associated with shorter time for UVA compared to monofilament suture.

Material & Methods: This was a prospective randomized controlled trial which was conducted in 100 consecutive RARP cases by a single surgeon. All patients were randomized in two groups according to UVA technique. Standard UVA was performed using two 3-0 monofilament sutures (Monocryl; Ethicon Endosurgery, Cincinnati, OH, USA) in one group (50 cases). In the other group (40 pts) UVA was performed using a Quill absorbable barbed suture. Time to complete anastomosis and need to adjust suture tension were recorded. Suture-related complications and validated-questionnaire continence were also examined.

Results: All cases were finished successfully without major complications or conversion to open surgery. Compared with the conventional reconstruction technique, there was a significant reduction in mean reconstruction time (13.1 vs. 20.2 min; P < 0.01) for the barbed suture technique. The need to readjust suture tension for watertight closure was greater in the standard monofilament group than in the barbed suture group (20% vs. 7%; P < 0.01). With a median follow-up of 9.1 months no delayed anastomotic leak or bladder neck contracture was observed in either group. Pad-free continence rates for the monofilament suture vs. the barbed suture groups at 1, 3 and 6 months were similar.

Conclusions: Our experience with a barbed bidirectional Quill suture has shown that this novel technique is feasible, shortens anastomotic time, provides for a faster anastomotic recovery and is as safe as monofilament suture. Use of the barbed suture technique prevents slippage, precluding the need for assistance, knot-tying and constant reassessment of anastomosis integrity. Further follow-up will determine any benefits of this technique on anastomotic urinary leak rates, continence, and catheter removal times.

63Anterior prostate cancer: Gleason score based on MRI/ TRUS elastic image fusion guided prostate biopsy vs prostatectomy

Baco Eduard, Division of Surgery and Cancer Medicine, Department of Urology, Oslo University Hospital, Aker, Oslo, NorwayRud Erik, Division of Diagnostic and Intervention, Department of Radiology and Nuclear Medicine, Oslo University Hospital, Aker, Oslo, NorwayVlatkovic Ljiljana, Division of Diagnostic and Intervention, Department of Pathology, Oslo University Hospital, Radiumhospitalet, Oslo, NorwaySvindland Aud, Division of Diagnostic and Intervention, Department of Pathology, Oslo University Hospital, Radiumhospitalet, Oslo, NorwayEggesbø Heidi, Division of Diagnostic and Intervention, Department of Radiology and Nuclear Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway

Introduction & Objectives: Gleason score (GS) based on needle prostate biopsy PBx is one of the most important factors in decision making for appropriate treatment of prostate cancer (PCa). The literature reports on 40-80% agreement of GS from prostatectomy and PBx. Anterior prostate cancers (APC) are commonly under-estimated by PBx.

Magnetic resonance imaging (MRI) can localize clinically important PCa. Further, low apparent diffusion coefficient (ADC) values) can indicate the aggressiveness of PCa.

The aim of this study was to evaluate the agreement of GS performed using MRI/ TRUS elastic image fusion guided prostate biopsy versus GS after prostatectomy in patients with APC.

Material & Methods: Forty-eight patients with elevated prostate specific antigen (PSA) and suspicious APC on MRI were prospectively included in this quality control study conducted from January 2010 to February 2013. All patients underwent robot assisted laparoscopic prostatectomy (RALP) after MRI/ TRUS guided PBx that confirmed APC.

Mean (range) of age, PSA and MRI-prostate volume were: 63 years (45-73 years), 19 ng/ ml (4-44 ng/ ml) and 45 ml (22-98 ml). MRI was performed using 1.5T Avanto (Siemens®, Erlangen, Germany). The sequences were: axial 3D T2 weighted (T2w), axial diffusion weighted imaging (DWI) with apparent diffusion coefficient (ADC) map calculated from b50 and b1000. In addition, an axial DWI using b2000 was obtained. A suspicious APC were highlighted on axial T2 images as a circle in the areas with the lowest ADC signal. Targeted biopsies (TBs) were performed using 3D TRUS Accuvix V10 (Medison®, Korea) and elastic MRI/ TRUS fusion and navigation system Urostation (Koelis®, La Tronche, France). Biopsy groups were: initial biopsy in 3, and 1st -11th re-biopsies in 45 patients. Mean previous negative biopsy procedures was 3.1 (range 2-11). Of these, re-biopsy due to active surveillance was performed in 9/ 48 (19%) patients. Mean number of TB from each MRI target was 2.4 (range 1-5). Both prostate biopsy material and prostatectomy specimen were evaluated by the same group of uropathologists. Kappa (κ) statistics were used for measurement of agreement on GS.

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Results: GSs in the 48 patients with prostatectomy were GS6 n=17, GS7 n=27, and GS8 n=4. GS agreement on biopsy versus prostatectomy was found in 43/ 48 (90%), (κ 0.81).

GS over- and under-grading of biopsy were in 4/ 48 (8%) and 1/ 48 (2%). Upgrading to high risk cancer from biopsy GS 7b to prostatectomy GS 8 was found only in one patient.

Conclusions: MRI/ TRUS guided prostate biopsies of MRI suspected APC offer a high agreement between Gleason score biopsy and prostatectomy.

A few biopsy cores are needed to achieve the diagnosis.

64A phase III randomised, open-label, multicenter trial to evaluate the benefit of leuprorelin acetate for 24 months after radical prostatectomy in patients with high risk of recurrence (AFU-GETUG 20/ 0310)

Rozet Francois, Urology, IMM, Paris, FranceHabibian Muriel, Unicancer, Paris, FranceSalomon Laurent, Urology, CHU Mondor, Creteil, FranceSoulié Michel, Urology, CHU Toulouse, Toulouse, FranceCuline Stephane, Medical Oncology, Saint Louis, Paris, France

Introduction & Objectives: Post radical prostatectomy patients (RP) with extra prostatic extension or high Gleason grade are considered to have a high risk of treatment failure. Actual role of LH-RH agonists after RP in patients with high risk of recurrence remains unclear, except for the patients with positive lymph nodes. For pN0 patients, randomized studies with flutamide or bicalutamide showed no improvement in overall survival. No randomized prospective study has been published with LH-RH agonists in the PSA era. Recent SWOG 9921 study shows a favorable disease-free and 5-year overall survival of 96% for high-risk patients treated with 24 months of ADT after surgery. However, this study does not define the optimal protocol of adjuvant ADT, and does not demonstrate the superiority of immediate vs delayed treatment. The objective of the AFU-GETUG 20 study is to evaluate the benefit of leuprorelin acetate for 24 months after RP in patients with high risk of recurrence.

Methods: Academic phase III randomised, open-label, multicenter trial starting in late 2011. Inclusion criteria: R0, N0-Nx M0 patients after RP in the 3 months preceding inclusion and with postoperative Gleason score > 7, or ≥ 7 with the presence of 5 grade Gleason patterns or, or pT3b tumor, and with postoperative PSA < 0.1 ng/ mL. Exclusion criteria: previous/ current therapy for PCa. Primary endpoint is the evaluation of metastatic progression free survival. Secondary endpoints include overall survival, disease-specific survival, PSA evolution, evaluation of testosterone level, and quality of life.

Results: A total of 700 patients (350 in each arm) and 250 events are required to have 80% ability to detect a difference with a bilateral Logrank test with α= 0.05 and β= 0.20. Decision rules will be determined by the O’ Brien-Fleming sequential boundaries at the time of the analysis. Interim analysis is planned at the 125th event (50% of events) for 6.5 years after the start of the trial. Final analysis is planned for 12 years after the inclusion of the first patient.

Conclusions: The AFU-GETUG 20 study is a pioneering French multicenter trial aiming to evaluate the actual role and place of ADT after RP for patients with high-risk prostate cancer.

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65A pathology verified, innovative method to predict nodal (N) status using an artificial intelligence (AI) approach in prostate cancer (PC) patients (pts): beyond the Roach formula?

De Bari Berardino, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyVallati Mauro, University of Huddersfield, School of Computing and Engineering, Huddersfield, United KingdomGatta Roberto, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyBuglione Michela, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyPasinetti Nadia, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyGirelli Giuseppe, Radiation Oncology, Ivrea Hospital, Ivrea, ItalyMunoz Fernando, Radiation Oncology, Turin University, Turin, ItalyMeattini Icro, Radiation Oncology, Florence University, Florence, ItalyBellarita Rita, Radiation Oncology, Perugia Hospital, Perugia, ItalyKrengli Marco, Radiation Oncology, Piemonte Orientale University, Novara, ItalyCagna Emanuela, Radiation Oncology, Como Hospital, Como, ItalyGuarnieri Alessia, Radiation Oncology, Turin University, Turin, ItalyBunkheila Feisal, Radiation Oncology, Policlinico S�Orsola-Malpighi, Bologna, ItalyRicardi Umberto, Radiation Oncology, Turin University, Turin, ItalySignor Marco, Radiation Oncology, Udine Hospital, Udine, ItalyMangoni Monica, Radiation Oncology, Florence University, Florence, ItalyBorghesi Simona, Radiation Oncology, Arezzo Hospital, Arezzo, ItalyGabriele Pietro, Radiation Oncology, Fondazione Piemontese per la Ricerca sul Cancro, Candiolo, ItalyBonetta Alberto, Radiation Oncology, Cremona Hospital, Cremona, ItalyStefanacci Marco, Radiation Oncology, Pistoia Hospital, Pistoia, ItalyDi Marco Adriano, Radiation Oncology, Mantova Hospital, Mantova, ItalyBertoni Filippo, Radiation Oncology, Modena Hospital, Modena, ItalyPegurri Ludovica, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyCaraffini Bruno, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyCiccarelli Stefano, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, ItalyMagrini Stefano, Istituto del Radio “O� Alberti”, AO Spedali Civili di Brescia - Brescia University, Brescia, Italy

Introduction & Objectives: We present an innovative AI-based, pathologically verified method, to predict N status in PC, integrating several pre-treatment variables (Gleason Score/ sum, age, initial PSA, neoadjuvant hormonal therapy vs no hormonal therapy - HT).

Material & Methods: 1804 pts from a National Italian multicentre database with a known cN0-1 status were analyzed. Cases (N=55) with node-positive pelvic MRI and/ or CT scan and/ or showing a nodal only relapse after RT (none received pelvic RT), were considered N+. The performances of the Roach formula (cut-offs: >15%, >10% and >5%) and of 3 AI methods, based on decision trees (J48, Random Tree and Random Forest) combined with 3 techniques of manipulation of imbalanced samples (oversampling, undersampling and combined under/ oversampling) were tested on an independent population of 204 operated Brescia patients classified as cN0 preoperatively, with a known pN status (187 pN0 and 17 pN1 pts).

Results: The AI methods perform better than the Roach formula. The classic approach showed an accuracy rate (i.e. true positives + true negatives/ whole population) ranging, depending on the cut-off, between 19% and 42% in the test sample of 204 pts and between 34% and 52% in the whole series of 1804 pts. The accuracy of the 3 AI methods ranged between 19% and 86% in the test sample of 204 pts and between 56% and 98% in the whole series of 1804 pts. Concerning the specificity, the Roach Formula showed rates ranging, depending on the cut-off, between 12% and 38% in the test sample of 204 pts and between 72% and 81% in the whole series of 1804 pts. The specificity of the 3 AI methods ranged between 13% and 91% in the test sample of 204 pts and between 53% and 100% in the whole series of 1804 pts. Concerning the sensitivity, the Roach Formula showed rates ranging, depending on the cut-off, between 88% and 94% in the test sample of 204 pts and between 32% and 51% in the whole series of 1804 pts. The sensitivity of the 3 AI methods ranged between 17% and 88% in the test sample of 204 pts and between 57% and 96% in the whole series of 1804 pts. It should be noticed that HT was always considered in the decisional trees obtained with the AI-based methods (when considered amongst the input variables). When the HT is not considered as input variable, the performances of the AI-based methods worsened.

Conclusions: Non-linear relationships with more than two variables influence the N status of the patients and the Roach formula has suboptimal predictive performances. New approaches considering more variables could possibly improve these performances. Considering their intrinsic algorithms, the AI techniques could be interestingly and usefully used to perform analysis on large numbers of variables in order to find relationships between the considered variables and to establish the weight of each variable in the considered clinical context. These results should be prospectively confirmed in larger databases.

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66High AMACR expression in multifocal PIN patients makes it possible to anticipate the diagnosis of prostate cancer in consecutive biopsy

Zakharava Viktoryia, Pathology, Belarusian State Medical University, Minsk, BelarusLiatkouskaya Tatsiana, Pathology, Belarusian State Medical University, Minsk, BelarusCherstvoy Eugeniy, Pathology, Belarusian State Medical University, Minsk, BelarusIvanovskaya Margarita, Belarusian Medical Academy of Postgraduate Education, Minsk, BelarusMasansky Igar, Oncosurgery, Minsk Municipal Center for Clinical Oncology, Minsk, BelarusSagalchik Lidia, Oncosurgery, Minsk Municipal Center for Clinical Oncology, Minsk, BelarusPuchinskaya Marina, Pathology, Belarusian State Medical University, Minsk, BelarusDedik Sergey, Belarusian State Medical University, Minsk, Belarus

Introduction & Objectives: Multiple research data demonstrate the importance of detecting high grade prostatic intraepitelial neoplasia (HGPIN) in needle biopsy material as it is associated with higher probability of finding prostate cancer (PCa) in consecutive biopsies, however frequency of occurrence of cancer differs depending whether the HGPIN process is unifocal or multifocal and whether or not it is associated with atypical small acinar proliferation (ASAP). The aim of the study was assessment of the frequency of detection of PCa in patients with multifocal HGPIN in relation to the degree of expression of AMACR in the material of the initial prostate biopsy.

Material & Methods: A prospective study comprising 72 patients who were submitted to repeated prostate biopsy during the period from 2005 to 2012 after they had been diagnosed with multifocal HGPIN (not associated with ASAP or small cancer foci) based on the material of their first prostate biopsy with 6 to 18 random cores. All patients were re-biopsied with the mean period of 11.8 months. All the cases were examined using immunohistochemistry with triple-antibody cocktail (34βE12+p63+AMACR) staining in single paraffin sections. AMACR expression was scored semi-quantitatively as 0 (no expression), 1+ (partial and/ or weak expression), or 2+ (strong circumferential expression).

Results: In initial prostate biopsy 2+AMACR expressions was observed in 48 cases (66.7%), 1+AMACR – in 18 cases (25%) and 0+AMACR expression – in 6 cases (8.3%). The first re-biopsy revealed PCa in 45 cases (62.5%), at that in 40 cases PCa were detected in patients with 2+AMACR expressions in initial prostate biopsy, in 4 cases – in patients with 1+AMACR expression and in 1 case – in a patient with 0+AMACR. Cancer detection rate in repeated biopsy in patients with 2+AMACR HGPIN in the initial biopsy was 88.9% which differed significantly from that in patients with 1+AMACR HGPIN (22.2%, p<0.01) and 0+AMACR HGPIN (16.7%, p=0.024) in the initial biopsy. The difference between the 1+AMACR and 0+AMACR groups was not statistically significant (p=1.0). Calculation of Kaplan-Meier survival probability showed prognostic significance of strong AMACR expression in multifocal HGPIN in the initial biopsy in relation to frequency of PCa detection in consecutive biopsies.

Conclusions: Patients with multifocal HGPIN with high AMACR expression run high risk of PCa being found in their consecutive biopsies even without ASAP-associated HGPIN in their initial biopsy.

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67Functional and early oncological results of radical perineal prostatectomy for the management of clinically locally advanced prostate cancer. Experience of a single institute

Bolomitis Stefanos, Urology, 401 General Military Hospital of Athens, Athens, GreeceAndritsos Konstantinos, Urology, 401 General Military Hospital of Athens, Athens, GreeceTsavdaris Dimitrios, Urology, 401 General Military Hospital of Athens, Athens, GreeceIoannidis Konstantinos, Urology, 401 General Military Hospital of Athens, Athens, GreeceTzelepis Vasileios, Urology, 401 General Military Hospital of Athens, Athens, GreeceArchontakis Athanasios, Urology, 401 General Military Hospital of Athens, Athens, Greece

Introduction & Objectives: According to current literature, radical prostatectomy is the best choice for the management of organ confined prostate cancer. There is increased evidence that surgical approach has an important role to play as a therapeutic approach for clinically locally advanced prostate cancer. The aim of our study is to evaluate the oncological and functional results of radical perineal prostatectomy for the management of patients with clinically advanced prostate cancer.

Patients & Methods: Between 1993 and 2012 627 patients underwent radical perineal prostatectomy for histologically confirmed prostate cancer. 83 out of 627 patients had clinically advanced disease. Perioperative morbidity, functional results and early oncological outcomes were examined and compared between the organ confined and clinical advanced subgroups.

Results: The mean follow-up was 37 (8-62) months. There was no statistically significant difference in the operative time, the intraoperative blood loss, the hospital stay and the duration of catheterization between the 2 groups. The rate of complications was also similar, with the exception of two rectal injuries at the locally advanced subgroup, which were repaired successfully at the same time. 17.3% of the clinically advanced patients resulted to be organ-confined (pT2). 99,8% were continent and 36,7% were potent at the locally advanced subgroup compared to 100% and 62,5% respectively at the organ confined subgroup. One patient of the first subgroup, with infiltration of the apex, had postoperative urinary incontinence, which was managed with the placement of an artificial sphincter. The cancer-specific survival rates were not significantly different between the 2 groups.

Conclusions: In cases of locally-advanced prostate cancer, the removal of the tumor -combined with adjuvant therapy, when necessary- may possibly change the natural course of the disease. In addition, through the application of RPP it is possible that the number of cases with positive surgical margins may be further reduced. At the same time, there are good functional results for the patients, without complications and local symptoms, providing overall a satisfactory quality of life.

68 SOCS3-protein expression as marker of prostate cancer aggressiveness

Calarco Alessandro, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyPinto Francesco, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyRecupero Salvatore Marco, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyTotaro Angelo, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyPalermo Giuseppe, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyMiglioranza Eugenio, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyD’Agostino Daniele, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyPierconti Francesco, Pathology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, ItalyBassi Pierfrancesco, Urology, Catholic University School of Medicine “A� Gemelli” Hospital, Roma, Italy

Introduction: Chronic inflammation might play a key role in prostate carcinogenesis. Interleukin-6 (IL-6) by the interaction with its specific receptor or the inhibitory effect of several regulators, such as the suppressor cytokine signaling (SOCS1-8 and CIS) family proteins or the protein inhibitor of activated STAT (PIAS) instaurates and maintains chronic inflammation. SOCS3 was identified as a inhibitor of FGF-2 signalling and, in prostate cancer cells, antagonises the effect of the growth factor by interfering with the activation of the p44/ p42 MAPK pathway. Hypermethylation of SOCS-3 with downregulation of protein expression identifies a subgroup of prostate cancer with a more aggressive behavior.

Methods: We analyzed SOCS3 protein expression by immunohistochemistry in 85 patients (pt) who underwent prostate biopsy and radical prostatectomy (RP) from January 2006 to March 2011. Both prostate biopsy and surgical specimens were analized. Follow-up was on 69/ 85 pt (median 4 years, max 7 min 2). Slides were incubated with monoclonal antibody SOCS3 (1E4, 1.5 µg/ ml; Abnova,Taiwan). SOCS3 staining intensity was evaluated in three different ways: positive (+), negative (-) and weak (+/ -).

Results:Gleason score (Gs) was: <7 in 17 pt, 7 in 48 pt (3+4 pattern in 39 pt, 4+3 pattern in 9 pt), >7 in 4 pt. All GS <7 pt were ≤ pT2 and none of them had any biochemical recurrence. 15/ 17 (88,2%) pt with Gs <7 and 12/ 48 (25%) with Gs 7 were SOCS (+). 11/ 48 (22,9%) pt with Gs 7 and 2/ 4 (50%) pt with Gs > 7 were SOCS3 (-). In 2/ 17 (11,7%) pt Gs <7, 25/ 48 (52%) pt Gs 7 and 2/ 4 (50%) pts GS > 7 were classified as SOCS3 (+/ -). None GS >7 pt were SOCS (+).

78ABSTRACTS

GS 7(3+4) pt who underwent RP who were SOCS3 (+) had an organ confined disease (≤ pT2) in 8/ 9 (88,8%) and 1/ 9 (11,1%) had a biochemical recurrence; otherwise GS 7(3+4) pt with SOCS3 (+/ -) had an organ confined disease in 13/ 23 (56,5%) and 10/ 23 (43,4%) had a biochemical recurrence. The last group of GS 7(3+4) pt with the SOCS3 (-) had an organ confined disease (≤ pT2) in just 2/ 7 (28,5%) and 5/ 7 (71%) had a biochemical recurrence.

Conclusions: The suppression of the SOCS3 protein seems to identify PC with more aggressive behavior. SOCS3 (-) pts turned out to have a more aggressive disease compared with SOCS3 (+) ones. Also SOCS3 (+/ -) tumors seemed to have an aggressive behavior like the negative ones. This is more evident in the GS 7(3+4) pt who represent the most challenging category.

69Significantly less voiding symptoms after robot-assisted radical prostatectomy compared to retropubic radical prostatectomy – results of a propensity score matched analysis

Musch Michael, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyKunz Inga, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyRoggenbuck Ulla, Institute for Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, GermanyJanowski Maxim, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyLoewen Heinrich, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyKlevecka Virgilijus, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyKroepfl Darko, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, Germany

Introduction & Objectives: We present a propensity score matched analysis on the comparison of continence and voiding symptoms three months after robot-assisted [RALP] and retropubic radical prostatectomy [RRP].

Material & Methods: Between 03/ 04 and 04/ 12 228 underwent RALP and 293 RRP performed by two surgeons. Following propensity score matching for age, BMI, ASA, prostate weight, surgeon, nerve-sparing, pT stage, and the preoperative domains of the ICSmale short form questionnaire (ICSmale incontinence symptom score [ICSmaleISS], ICSmale voiding symptom score [ICSmaleVSS] and ICSmale quality of life question [ICSmaleQol]) 187 RALP and 187 RRP patients formed the final study population. Both groups were compared three months postoperatively according to their ICSmaleISS, ICSmaleVSS and ICSmaleQol.

Results: RALP and RRP patients were comparable according to the variables of the propensity score matching, and additionally to PSA, cT stage, pN stage and surgical margin status (all p>0.3). However, RALP patients showed higher biopsy and prostatectomy Gleason scores, longer operation time, lower blood loss and shorter catheterization duration (all p<0.001). Three months after RALP and RRP, respectively, the ICSmaleISS was not significantly different (mean 5.11±4.40 and 4.32±3.72; p=0.1421), but the ICSmaleVSS was significantly lower in RALP patients (mean 2.90±2.92 and 3.93±3.51; p=0.0038). At the same time, the answers to the ICSmaleQol reflected comparable interference of quality of life due to urinary symptoms (p=0.8740).

Conclusions: Three months postopertively RALP patients experienced significantly less voiding symptoms compared to RRP patients. At the same time, similar good continence and quality of life due to urinary symptoms was reported.

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70Initial results of transrectal ultrasonography/ multiparametric magnetic resonance imaging fused stereotactic prostate biopsy

Hohenhorst Lukas, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyMusch Michael, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyTaskiran Baris, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyHerholz Roman, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, GermanyKoch Jens-Albrecht, Diagnostic and Interventional Radiology, Kliniken Essen-Mitte, Essen, GermanyKroepfl Darko, Urology, Pediatric Urology and Urologic Oncology, Kliniken Essen-Mitte, Essen, Germany

Introduction & Objectives: Recently multiparametric MRI [mpMRI] targeted prostate biopsy [PBx] demonstrated improved prostate cancer [PCA] detection. We evaluated our initial experience with TRUS/ mpMRI fused stereotactic PBx in patients with or without prior PBx.

Material & Methods: Between 05/ 12 and 09/ 12 23 patients with prior negative PBx and 13 patients without prior PBx underwent TRUS/ mpMRI fused stereotactic perineal PBx. Based on mpMRI (i.e. T2-weighted [T2], diffusion weighted [DWI], dynamic contrast enhanced [DCE] and MR spectroscopic [MRSI] imaging) each lesion was assigned a PI-RADS [Prostate Imaging-Reporting and Data System] score. Beside the mpMRI targeted PBx systematic PBx were also taken to cover all regions of the prostate. We analyzed the PCA detection rate of the mpMRI targeted and systematic PBx. In addition, the predictive value of the PI-RADS score was assessed.

Results: The 36 patients had a median age of 69 years, a median PSA of 9.2 ng/ ml and a median prostate volume of 71.5 ml. A median of 26 PBx was taken. PCA was detected in 15 (42%) patients – in 6 of 13 (46%) patients without prior PBx and in 9 of 23 (39%) with prior PBx. 12 of the 15 (80%) PCA would have been diagnosed through mpMRI targeted PBx alone. Accordingly, mpMRI targeted and systematic PBx contained tumor in 15% and 3% of cases, respectively (p<0.0001). The mpMRI targeted PBx were taken from a total of 76 mpMRI determined lesions of which 18 (24%) were tumor-bearing. Considering the PI-RADS score 10 of 63 (16%) lesions with a score <15 and 8 of 18 (44%) lesions with a score ≥15 contained tumor (p=0.0208). The rate of PCA with a Gleason scores ≥7 was 22% in lesions with a PI-RADS score <15 and 50% in lesions with a score ≥15 (p=0.3348). In univariate analysis higher PI-RADS scores were associated with PCA detection (p=0.038). From its underlying parameters only T2 imaging was a significant predictor (p=0.004) while DWI (p=0.279), DCE (p=0.668) and MRSI (p=0.607) imaging were not. In addition, lower PSA (p=0.024) and higher lesion volume (p=0.023) also proved to be significant predictors of PCA. In multivariate analysis accounting for all variables only T2 imaging remained an independent predictor for PCA detection (p=0.006).

Conclusions: TRUS/ mpMRI fused stereotactic PBx obtained high PCA detection rates in patients with and without prior PBx. In addition, higher PI-RADS scores were predictive for PCA.

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Authorlist

A

Abbasfard Adnan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Acar Ömer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Akpek Sergin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Alam Adeel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Alan Cabir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60, 66

Al-Batran Salah-Eddin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Alberts Arnout . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Alekseev Boris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Alessandro Marina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Alviisi Maria Francesca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Alvisi Maria Francesca . . . . . . . . . . . . . . . . . . . . . . . 36, 69

Andrianov Andrey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Andritsos Konstantinos . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Angelini Massimo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Antonov Alexander . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Aoyagi Teiichiro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Archontakis Athanasios . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Aspeslagh Barbel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Ates Ferhat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Atoria Coral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Aufderklamm Stefan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Aussie Jacqueline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Avuzzi Barbara . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36, 69

B

Baco Eduard . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58, 73

Baiocchi Cristina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Bassi Pierfrancesco. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Baştürk Gökhan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60, 66

Baumunk Daniel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Bazille Celine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48, 49

Bedini Nice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Bellardita Lara . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35, 36, 69

Bellarita Rita. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Beltramo Giancarlo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Bensadoun Henri . . . . . . . . . . . . . . . . . . . . . . . . . .48, 49, 56

Bergantin Achille . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Berge Viktor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Bertoni Filippo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Biagini Francesco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Bianchi Livia Corinna . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Biasoni Davide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Biegmohamadlo Hossein . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Blana Andreas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58, 64

Blumenstock Gunnar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Bolomitis Stefanos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Bolzicco Giampaolo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Bonetta Alberto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Borghesi Simona . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Bottomley David . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Bott Simon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Boucher Nigel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Brawer Michael . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Briganti Alberto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Buglione Michela. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Bunkheila Feisal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

C

Cagna Emanuela . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Calarco Alessandro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Callewaert Nico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Caraffini Bruno . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Carlsson Sigrid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Carroll Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Castillo Elisabeth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Center Finn . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Cermak Ales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Cezayirli Fatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Chaussy Christian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Checcaglini Franco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Cherstvoy Eugeniy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 76

Chiche Laurence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Chun Felix K.H. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Ciccarelli Stefano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Colecchia Maurizio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Collette Eelco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42, 43

Comoz François . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48, 49

Cooperberg Matthew . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Corazzi Francesca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Cortvriend Jim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Crouzet Sèbastian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Culine Stephane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Cuzick Jack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

D

D’Agostino Daniele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Day John . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Debacker Tibaut. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

De Bari Berardino . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

de Bono Johann S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61, 62

De Bruyne Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Decaestecker Karel . . . . . . . . . . . . . . . . . . . . . . .50, 51, 65

Dedik Sergey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Delanghe Joris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

De Meerleer Gert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50, 65

Deng Feng-Ming . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

De Smet Jens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Desmonts Alexis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48, 49

Dhaenens Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Dhanasekaran Ananda Kumar . . . . . . . . . . . . . . . 64

D’Hont Christiaan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Di Marco Adriano . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Doerfler Arnaud . . . . . . . . . . . . . . . . . . . . . . . . . . . .48, 49, 56

Dosta Nikolay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Dursun Furkan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Dyakov Vladimir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

E

Eastham James . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Eggesbø Heidi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Ehdaie Behfar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Elkin Elena . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Eren Ali Erhan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60, 66

Esen Tarık . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Evseev Alexey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

F

Fang Fang . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Favretto Maria Silvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Ferranti Francesca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Filipensky Petr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Fisher 44

Fizazi Karim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61, 62

81 ABSTRACTS

Fonteyne Valérie . . . . . . . . . . . . . . . . . . . . . . . . . . .50, 51, 65

Forer David . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61, 62

Fossion Laurent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Freedland Stephen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

G

Gabriele Pietro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Ganzer Roman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58, 64

Garcia-Vargas Jose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Gatta Roberto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Gelet Albert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Girelli Giuseppe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Glybochko Pyotr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Gontero Paolo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Gordeev Vasily. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Govorov Alexander . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Graefen Markus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Groskopf Jack . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Guarnieri Alessia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Guleryuz Kerem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Gutin Alexander . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

H

Habibian Muriel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Hakim Lukman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Hammerer Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Hassouna Hussam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Henkel Thomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Hennenlotter Jörg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Henriet Benjamin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Herholz Roman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Hermans Tom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Herrera Bernardo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Hirmand Mohammad . . . . . . . . . . . . . . . . . . . . . . . . .61, 62

Hodge Petrea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Hoebeke Piet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .41, 50

Hofheinz Ralf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Hohenhorst Lukas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Hoskin Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Hrabec Roman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Hsu Chao Yu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Hurault de Ligny Bruno . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

Hussain Muddassar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

I

Invernizzi Marta . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Ioannidis Konstantinos . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Ivanovskaya Margarita . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Ivanov Vladimir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Iyer Subrmanian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

J

Jacobs Rens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

James Nicola . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Janowski Maxim . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Jones LeRoy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Joniau Steven . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

K

Kairemo Kalevi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Kaprin Andrey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Karademir Kenan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Karim Omar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Karnes R Jeffrey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Kella Naveen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Kienitz Carsten . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

King Gary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Klaver Sjoerd . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42, 43

Klevecka Virgilijus. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Kloß Susanne . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Koch Jens-Albrecht . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Köhrmann Kai-Uwe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Köllermann Jens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Kolontarev Konstantin . . . . . . . . . . . . . . . . . . . . . . 72, 73

Korobkin Artem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Krasheninnikov Alexey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Krengli Marco. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Kroepfl Darko . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78, 79

Kunz Inga . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Kuroda Isao . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

L

Lanchbury Jerry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Lange Carsten. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Laniado Marc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Leer Jan Willem. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Le Gal Sophie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48, 49

Liatkouskaya Tatsiana . . . . . . . . . . . . . . . . 54, 57, 76

Loewen Heinrich . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Logue John . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Lombardo Claudia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Loriot Yohann . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62

Lumen Nicolaas . . . . . . . . . . . . . . 41, 47, 50, 51, 65

M

Machuca Francisco Javier . . . . . . . . . . . . . . . . . . . . . . . . . 31

Magnani Tiziana . . . . . . . . . . . . . . . . . . . 35, 36, 63, 69

Magrini Stefano. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Mangoni Monica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Manikandan Ramaswamy . . . . . . . . . . . . . . . . . . . . . . . . 64

Marenghi Cristina . . . . . . . . . . . . . . . . . . . . . . . .36, 63, 69

Marliere François . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Martinotti Anna Stefania . . . . . . . . . . . . . . . . . . . . . . . . . 72

Masaltseva Natalia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Masansky Igar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 76

Masansky Ihar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Meattini Icro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Melamed Jonathan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Meyer Sarah . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Miglioranza Eugenio. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Mikheev Artem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Minciarelli Marco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Mortier Margarete . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Motiwala Hanif . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Munoz Fernando . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Musch Michael . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78, 79

N

Naghizade Mohammad . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Nicolai Nicola. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36, 63, 69

Nilsson Sten . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Nitkin Dmitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Nobes Kate. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Nyushko Kirill . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

82ABSTRACTS

O

Okcelik Sezgin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Oosterlinck Willem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47, 51

Orczyk Clement . . . . . . . . . . . . . . . . . . . . .46, 48, 49, 56

Ost Piet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50, 65

Ouzzane Adil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Özdemir Öztürk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

P

Pacik Dalibor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Palermo Giuseppe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Parker Christopher . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Pasinetti Nadia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Pasticier Gilles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Paulesu Antonello . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Pawar Vivek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Pegurri Ludovica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Pentiricci Andrea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Pereira Nicola . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Pierconti Francesco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Pinto Francesco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Puchinskaya Marina . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57, 76

Pushkar Dmitry . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70, 72, 73

R

Rai Hem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Rancati Tiziana . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .36, 63, 69

Rao Amrith . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Rasner Pavel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Ravagnani Fernando . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Recupero Salvatore Marco . . . . . . . . . . . . . . . . . . . . . . . . 77

Rehorek Petr . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Reid Julia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Reuning-Scherer Jonathan . . . . . . . . . . . . . . . . . . . . . . 29

Ria Francesco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Ricardi Umberto . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Robertson Carry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Robinson Simon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Roggenbuck Ulla . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78

Roosen Alexander . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Rosario Derek . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Rosenkrantz Andrew . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Rossi Giampaolo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Rottey Sylvie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Roumeguère Thierry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Rozet Francois . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Rud Erik . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Rusinek Henry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

S

Saad Fred . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Sadeghi Simin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Saez Felipe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Sagalchik Lidia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76

Salomon Georg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Salomon Laurent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Saltzstein Daniel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Salvioni Roberto . . . . . . . . . . . . . . . . . . . . . . . . . . . .36, 63, 69

Sanchez-Salas Raul . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Satariano Ninfa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Scher Howard I. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .61, 62

Schostak Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Schwentner Christian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Scremin Enrico . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Secco Michael . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48, 49

Senkul Temucin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Sentker Ludger . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Shabbooie Zohre. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Shariya Merab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Shimodaira Kenji . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Shore Neal D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Signor Marco. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Sorber Marc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Soulié Michel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74

Soydan Hasan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Spahn Martin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Stagni Silvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Stalmeier Peep . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Staudacher Karin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Stefanacci Marco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Stenzl Arnulf . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Stone Steven . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Stonier Thomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Svindland Aud . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Swanson Greg . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

T

Taneja Samir . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Tasca Andrea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

Taskiran Baris . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Taverna Francesca . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Ternovoy Sergey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Thueroff Stefan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Tillou Xavier. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .48, 49, 56

Todenhöfer Tilman. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

Tombal Bertrand . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Tosco Lorenzo. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Totaro Angelo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Toussaint Nele . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Tsavdaris Dimitrios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

Tzelepis Vasileios . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77

U

Upsdell Stephen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

V

Valdagni Riccardo . . . . . . . . . . . . . . . . . 35, 36, 63, 69

Vallati Mauro . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Van Belle Simon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Vandecasteele Katrien . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

Van den Ouden Dies. . . . . . . . . . . . . . . . . . . . . . . . . . . . 42, 43

Vanderschaeghe Dieter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Van Erps Peter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

van Lin Emile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

van Oort Inge. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Van Poppel Hein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Van Praet Charles. . . . . . . . . . . . . . . . . . .41, 47, 50, 51

van Tol-Geerdink Julia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Van Velthoven Roland . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Varga Gabriel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Vasyliev Alexander . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70

Venugopal Suresh. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Verbaeys Anthony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Verbaeys Antony . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Vergunst Henk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Vermassen Tijl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

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Villa Sergio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35, 36, 63

Villa Silvia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35, 36

Villeirs Geert . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50, 65

Villers Arnauld . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Vinarov Andrey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Vite Cristina . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

Vlatkovic Ljiljana . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Vorobyev Nikolay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Voskanyan Georgy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59

Vural Metin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

W

Wall Joshua . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Ward John . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

Weersink Robert. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Wijburg Carl . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Wilson Brian . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

Witjes Fred . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

Witzsch Ulrich . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

Y

Yañez Ana . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Yesildal Cumhur . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Yilmaz Omer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Z

Zakharava Viktoriya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Zakharava Viktoryia. . . . . . . . . . . . . . . . . . . . . . . . . . . .54, 76

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Immunotherapy for prostate cancer: concepts and practice

Jacques Banchereau Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

Bertrand Tombal Service d’Urologie, Cliniques universitaires Saint-Luc, Brussels, Belgium

Karim Fizazi Department of Cancer Medicine, Institut Gustave Roussy, University of Paris Sud, Villejuif, France

DisclosuresDr Banchereau has acted as a consultant for Dendreon; Prof Tombal has been an advisor for Dendreon; Dr Fizazi has participated in advisory boards and as a speaker for Dendreon and Bristol Meyers Squibb.

Introduction

Recent developments are elucidating the central role of the immune system in controlling the proliferation of cancer cells. This has resulted in the development of a plethora of immune‑mediated anticancer therapies, some of which are now established components within the oncology armamentarium. In 2010, the US Food and Drug Administration (FDA) approved sipuleucel-T, the first immunotherapy for the treatment of advanced prostate cancer (also currently under review by the European Medicines Agency [EMA]). A number of other immunotherapeutics for prostate cancer are under development. This article summarizes current knowledge of antitumor immune responses, data on current and emerging immunotherapies in prostate cancer, and considerations for their use.

The role of the immune system in cancer protection

It is now recognized that the immune system is key in controlling cancer, and can play both host‑protective and tumor‑promoting roles [1,2]. Immune responses can suppress tumor growth by destroying or inhibiting cancer cells, and the presence of immune cells within tumors can be

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associated with better outcomes (Figure 1) [3,4]. In fact, evasion of immune destruction has become recognized as a hallmark of cancer pathogenesis [5]. This concept is supported by the increased incidence of malignant tumors in immunocompromised individuals. In transplant patients, this increased risk versus the general population ranges from a 2‑fold higher incidence of lung and colon cancer to a 20‑fold or more increased incidence of non‑melanoma skin cancer, non‑Hodgkin’s lymphoma and Kaposi’s sarcoma [6]. Similarly, in patients with acquired immunodeficiency syndrome (AIDS), the risk of Kaposi’s sarcoma and non-Hodgkin’s lymphoma increases with increasing levels of immunosuppression [7]. However, immune cells may also promote tumor progression [4], either by applying ‘selective pressure’ that encourages the growth of more pathogenic tumor cells or by establishing conditions within the tumor micro‑environment that facilitate cell proliferation [1,2].

The generation of an immune response is a dynamic process that requires several sequential steps, starting with the engagement of antigen‑presenting cells (APCs). APCs process and present tumor antigens and, once activated themselves, can activate tumor antigen-specific T cells to proliferate and target tumor tissue [8]. The fundamental characteristics of an antitumor immune response are: specificity (targets tumor tissue, spares healthy tissue), adaptability (adapts to emergence of new tumor variants), focus (locates effect at tumor site), effectiveness (demonstrates antitumor cytotoxicity), and potential durability (immune memory maintains antitumor activity beyond initial challenge). Engagement of the immune system with immunotherapies offers the potential for the ideal anticancer therapy, combining many desirable therapeutic attributes into a single modality.

Current and emerging immunotherapies in prostate cancer

Immunotherapy is defined as treatment to boost or restore the ability of the immune system to fight cancer, infections, and other diseases [9]. Cancer immunotherapy is an established treatment strategy and examples of available immunotherapies include monoclonal antibodies against various targets (e.g. cluster of differentiation [CD] 20 [ibritumomab tiuxetan, ofatumumab, rituximab,

Figure 1. Kaplan-Meier curve for overall survival (OS) in advanced ovarian cancer according to the presence or absence of T cells within tumors (adapted from [3]).

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tositumomab], CD52 [alemtuzumab], and cytotoxic T-lymphocyte antigen 4 [CTLA-4; ipilimumab]), cytokines (e.g. interleukin [IL]-2, interferon [IFN]-α), and active cellular immunotherapies (e.g. sipuleucel-T) [10,11].

Immunotherapies present several features that typically distinguish them from more traditional therapies, including a distinct mechanism of action, delayed kinetics, and the potential for increased long-term efficacy and durability. For example, unlike standard treatments, therapeutic cancer vaccines prime T cells to seek out and destroy target cancer cells [12]. Although immunotherapies can increase OS [10,13,14] the clinical effect shows delayed kinetics, therefore traditional measures may show subtle or absent objective responses. A significant effect on progression-free survival (PFS) may be absent, and Response Evaluation Criteria in Solid Tumors (RECIST) response criteria [15] may not be appropriate. As such, groups including the Association for Cancer Immunotherapy (CIMT) and the Cancer Immunotherapy Consortium (CIC) are involved in efforts to better report immunological outcomes through the Minimal Information About T cell Assays (MIATA) project. Since the clinical effect takes time to develop, early use should be considered when the patient is healthier and the disease burden is lower. The patient’s immune system may also be more intact and functional in earlier‑stage disease [16]. Finally, the beneficial effects of immunotherapies are potentially durable and may interact favorably with subsequent therapies once appropriate sequential and/or combination strategies have been developed. There are several current and emerging immunotherapies in prostate cancer, including PSA‑tricom (PROSTVAC®, Bavarian Nordic), sipuleucel-T (PROVENGE®, Dendreon Corporation), and ipilimumab (YERVOY®, Bristol‑Myers Squibb) (Table 1).

PSA‑tricom, an active viral vaccine‑based approach (Table 1), has demonstrated promise in metastatic castrate‑resistant prostate cancer (mCRPC). In a phase II study, patients with asymptomatic or minimally symptomatic mCRPC were randomized to receive PSA-tricom plus GM-CSF (N = 84) or placebo (N = 41) and were followed until disease progression [13]. There was an 8.5 month survival benefit with PSA-tricom versus placebo and a significant reduction in the risk of death (hazard ratio [HR]: 0.56; P = 0.0061), which was not accompanied by a PFS benefit (primary endpoint; Figure 2a). Phase III trials are ongoing in mCRPC.

Table 1. Current and emerging immunotherapies in prostate cancer [13,14,17].

Agent Description Mechanism of action

PSA-tricom [13] (emerging in PCa)

Viral-based vaccine Immunization with a vaccinia co-expressing PSA and immunostimulatory molecules. Boosted with a fowlpox expressing the same

Ipilimumab [17]* (emerging in PCa)

Monoclonal antibody that binds and blocks CTLA-4

Non-specifically inhibits immune suppression, augmenting ongoing immune responses

Sipuleucel-T [14]† (approved [USA] PCa)

Active cellular immunotherapy

Recombinant PAP-GM-CSF activates the patients immune cells ex vivo. Cells are then re-infused and stimulate PAP-specific immune response in vivo

*Approved in the EU & USA for the treatment of advanced melanoma in adults†Approved in the USA for treatment of asymptomatic or minimally symptomatic patients with mCRPC

EU: European Union; GM-CSF: granulocyte-macrophage colony-stimulating factor; PAP: prostatic acid phosphatase; PCa: prostate cancer;

PSA: prostate-specific antigen; USA: United States of America

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Ipilimumab potentiates the antitumor immune response by non‑specific inhibition of immune regulation via blockade of CTLA-4, which itself reduces immune responses. Ipilimumab is approved (EU and USA) for the treatment of malignant melanoma. In a phase III study of ipilimumab in patients with unresectable stage III or IV melanoma, participants were randomized to receive ipilimumab plus a melanocyte peptide-derived vaccine against gp100 (N = 403), ipilimumab alone (N = 137), or vaccine alone (N = 136) [17]. A significant OS benefit (primary endpoint) was seen with ipilimumab versus vaccine (3.6 month survival benefit; HR: 0.66; P < 0.001; Figure 2c). This was not accompanied by a benefit in median time to PFS, but did show a significant reduction in the risk of progression (19%; HR: 0.81; P < 0.05; Figure 2d). Ipilimumab is currently undergoing phase III trials in prostate cancer.

Sipuleucel‑T is an active cellular immunotherapy approved (by the FDA) for the treatment of asymptomatic or minimally symptomatic mCRPC. During treatment, the body’s own cells are primed to generate antitumor immune responses (Figure 3). First, the patient’s peripheral blood mononuclear cells (PBMCs) are isolated using leukapheresis, purified, and cultured with PA2024, a fusion protein of PAP and the APC-stimulator GM-CSF. The PA2024-cultured cells are then re-infused back into the patient. Sipuleucel‑T is designed to generate antitumor immune responses through in‑vivo engagement with T cells following re-infusion. Overall, 3 cycles of leukapheresis and re-infusion are performed at 2‑week intervals. In a pivotal phase III study of sipuleucel‑T, patients with mCRPC (N = 512) were randomized to receive sipuleucel-T or control and were followed until disease progression [14,18]. A 4.1 month survival benefit (primary endpoint) and a significant reduction in

Figure 2. Efficacy of a) PSA-tricom in patients with mCRPC [13], b) sipuleucel-T in patients with mCRPC [14,18], c) and d) ipilimumab in melanoma [17]. CI: confidence interval; gp100: melanocyte peptide-derived vaccine against gp100; ipi: ipilimumab; mo: months; NS: not significant

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risk of death (HR: 0.775; P = 0.032) were observed with sipuleucel-T versus control, but a PFS benefit was not seen (Figure 2b). Following FDA approval, sipuleucel‑T is currently under review by the EMA.

Overall, immunotherapy is an established cancer treatment modality that has been approved for use in several malignant conditions, including prostate cancer. In clinical trials, several different immunotherapies have demonstrated a significant effect on OS without a significant effect on PFS. This highlights the fact that immunotherapies generally demonstrate a time‑lag in clinical response that may mask currently applied secondary measures of clinical outcome. Phase III trials are ongoing to study potential future immunotherapies across several different malignancies [19].

Treatment considerations for the use of immunotherapies in prostate cancer treatment

Data correlating an immune mechanism of action with clinical outcomes

The majority of data on immunological outcomes following immunotherapy for prostate cancer are with sipuleucel‑T, which is the most advanced in terms of clinical development (approved by the FDA in 2010 and currently under review by the EMA). Data for sipuleucel‑T suggest a link between immune responses and clinical outcomes. With sipuleucel‑T, the patient’s own APCs are cultured in vitro with PAP-GM-CSF and form the active component of the sipuleucel-T product (Figure 3, upper part). Key product attributes include the total nucleated cell (TNC) count, the number of cells expressing the APC-specific marker CD54, and the degree of CD54 upregulation by APCs (a measure of APC activation during manufacture). Sipuleucel‑T activates APCs, with greater activation noted at the week 2 and 4 infusions compared with week 0 (i.e. an immunological prime-boost effect). Importantly, correlation between OS and the key sipuleucel‑T product parameters was noted in a

Figure 3. Proposed mechanism of action of sipuleucel-T. The precise mechanism of action is unknown.

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post‑hoc analysis (Figure 4a). Furthermore, in‑vivo immune responses, such as T cell and antibody responses, are generated following sipuleucel‑T treatment (Figure 3, lower part) and correlate with OS (Figure 4b). A trend for enhanced survival in patients with greater T cell responses has also been reported with PSA‑tricom [21].

The durability of T cell responses generated with sipuleucel‑T were investigated in non‑metastatic, androgen‑dependent patients, and these were found to be long lasting [22]. Antigen-specific immune responses could be detected in patients after a median of 2 years (range 2–5 years) following initial treatment with sipuleucel‑T. These durable antitumor responses were subsequently boosted by administration of a further single sipuleucel‑T infusion.

Evidence also suggests that immune responses detected within the blood may translate to local immune activity in the tumor, since T cell infiltration has been noted at the tumor interface following sipuleucel-T neoadjuvant therapy. In this analysis, a 3-fold or more increase in mean T cells was observed at the tumor interface compared with the pretreatment biopsy, internal tumor tissue, or benign prostatic tissue [23].

Figure 4. Post-hoc correlation between OS and a) sipuleucel-T product parameters or b) immune responses against PAP or PA2024 (recombinant PAP-GM-CSF) [20]. These post-hoc analyses are intended for informative purposes only and have not been verified or approved by any regulatory agency as correlates of clinical outcome.

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Why are objective responses difficult to demonstrate with immunotherapies?

Although treatment with sipuleucel-T, PSA-tricom or ipilimumab may achieve an OS benefit for prostate cancer patients, there may not be a significant impact on median PFS or objective disease progression. There are several potential reasons for this. Firstly, objective disease progression can be a difficult endpoint to measure reliably (predominance of bony disease). Secondly, the correlation between OS and time to progression or PFS in mCRPC has not always been consistent, even with traditional therapies [24]. There may also be a time‑lag in the response to immunotherapy (Figure 5), such that short‑term changes in PSA values might not reflect the impact on OS. This model is supported by data in sipuleucel‑T‑treated, non‑metastatic, androgen‑dependent patients, where the earlier disease stage allowed a longer period of observation prior to subsequent therapeutic intervention. In this patient group, sipuleucel-T treatment achieved a 47% increase in PSA doubling time versus control (P = 0.038) [22].

Given the delayed kinetics of response to immunotherapies, traditional measures of objective response, such as the RECIST criteria [15], may occur too rapidly for a treatment difference to be demonstrated. Therefore, other measures of response are needed and new definitions of progression may be required (e.g. immune‑related response criteria) [26]. In addition, response criteria may need to be measured at later time points after treatment than with traditional therapies. For example, overall data on treatment with sipuleucel-T showed no statistically significant impact on time to objective disease progression versus control. Subsequent analysis of time to disease‑related pain, although not statistically significant, demonstrated a pronounced trend in favor of sipuleucel-T versus control. Further analyses on yet more proximal endpoints, such as time to first use of an opioid analgesic and OS, were statistically significant [13,27].

Data informing appropriate patient selection for immunotherapy

Given the time-lag in deriving the greatest benefit from immunotherapy, patients with earlier-stage disease may be optimal candidates for treatment. Sipuleucel‑T therapy has demonstrated a clear association between increased OS and lower versus higher baseline PSA [28]. This is supported by data

Figure 5. A theoretical mathematical model of differential effects of immunotherapy versus chemotherapy (adapted from [25]).

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demonstrating greater APC activation, as measured by CD54 upregulation, in sipuleucel-T-treated patients with early versus late‑stage disease [29]. These data are further corroborated by similar analyses from melanoma patients treated with ipilimumab in which the OS benefit was more pronounced in patients with less advanced melanoma (based on M stage at baseline) versus those with more advanced disease [17].

Conclusions

The immune system plays a critical role in cancer control and protection, which may be augmented by immunotherapy. Immunotherapy is an established cancer treatment modality that is approved for the treatment of several malignant conditions, including prostate cancer. Immunotherapy can combine several anticancer features into a single treatment and may augment existing therapies through combination or appropriate sequencing. Immunotherapies generally demonstrate a time‑lag in clinical response, and therefore appropriate patients are likely those with high performance status, earlier‑stage disease and greater immune responsiveness. In addition, this time‑lag may mask currently applied secondary measures of clinical outcome, which may be absent or delayed. This requires understanding from the healthcare provider, appropriate patient selection, and management of the patient’s expectations.

Acknowledgments

This article is based on a symposium presented at the Global Congress on Prostate Cancer 2013, which was supported by Dendreon. Medical writing assistance was provided by Gardiner-Caldwell Communications and was funded by Dendreon.

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Copyright figures

Figure 1: From N Engl J Med, Zhang L, Conejo-Garcia JR, Katsaros D, et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer, 348, 203–13. Copyright © 2003 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 2: a) Kantoff PW, Schuetz TJ, Blumenstein BA, et al., J Clin Oncol 28(7), 2010:1099–1105. Reprinted with permission. © 2010 American Society of Clinical Oncology. All rights reserved. b) From N Engl J Med, Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, 363, 411–422. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. c) and d) From N Engl J Med, Hodi FS, O’Day SJ, McDermott DF, et al., Improved survival with ipilimumab in patients with metastatic melanoma, 363, 711–723. Copyright © 2010 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 4: Adapted from Sheikh NA, Petrylak D, Kantoff PW, et al. Cancer Immunol Immunother 2013;62:137–47, published under Creative Commons license 2.0 CC-BY.

Figure 5: Republished with permission of The Oncologist, from Therapeutic cancer vaccines in prostate cancer: the paradox of improved survival without changes in time to progression, Madan RA et al., 15(9), 2010; permission conveyed through Copyright Clearance Center, Inc.

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February 2015 – Rome, Italy

http://prosca.org

supported by

http://prosca.org

supported by

3rd edition

GLOBAL ORGANISING COMMITTEE

Alex Mottrie UrologyOLV Clinic, Aalst, Belgium

Maria De Santis Medical OncologyKaiser Franz Josef Hospital - SMZ South, Vienna, Austria

Alberto Bossi Radiation OncologyGustave Roussy Institute, Villejuif, France

The Global Congress on Prostate Cancer aims to bring together top experts and delegates for an in-depth discussion of the different aspects of prostate cancer, with a focus on difficulties and dilemmas of clinical decision making.

LOCAL ORGANISING COMMITTEE

Francesco MontorsiUrologyVita-Salute San Raffaele University, Milan, Italy

Cora SternbergMedical OncologySan Camillo Forlanini Hospital, Rome, Italy

Alberto BossiRadiation OncologyGustave Roussy Institute, Villejuif, France

Published by e-HIMS Duwijckstraat 17, 2500 Lier, Belgium

F: +32 3 491 82 71.This publication is supported by an educational grant of Dendreon.

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