Health Policy Advisory Committee on Technology

Transcription

1 Health Policy Advisory Committee on Technology Technology Brief MRI screening for prostate cancer March 2015

2 State of Queensland (Queensland Department of Health) 2015 This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way. To view a copy of this licence, visit For further information, contact the HealthPACT Secretariat at: HealthPACT Secretariat c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland Level 13, Block 7 Royal Brisbane and Women s Hospital HERSTON QLD 4029 Postal Address: GPO Box 48, Brisbane QLD HealthPACT@health.qld.gov.au Telephone: For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, ip_officer@health.qld.gov.au, phone (07) Electronic copies can be obtained from: DISCLAIMER: This Brief is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Brief is based on a limited literature search and is not a definitive statement on the safety, effectiveness or costeffectiveness of the health technology covered. The State of Queensland acting through Queensland Health ( Queensland Health ) does not guarantee the accuracy, currency or completeness of the information in this Brief. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health. This Brief is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information. This Brief was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Brief was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers Advisory Council (AHMAC), reporting to AHMAC s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding. This brief was prepared by Robbie James from The Centre for Applied Health Economics, Griffith University and Linda Mundy from the HealthPACT Secretariat.

3 Technology, Company and Licensing Register ID Technology name Patient indication WP203 Magnetic Resonance Imaging (MRI) screening for prostate cancer MRI-based pathway for screening of men suspected of prostate cancer and the active surveillance (AS) of men diagnosed with low-risk prostate cancer Description of the technology MRI uses a combination of radio-waves and powerful magnet to produce detailed images of soft tissues within the human body. The advantage of MRI as opposed to other X-ray based radiology scans is the ability of producing the image without the usage of ionising radiation. This makes this technology very attractive to requesting general practitioners and specialists, subject to the contraindications in people with metal and electronic implant devices. A typical MRI scan lasts between 20 minutes and 1.5 hours, depending on the complexity of the scan and the technical capabilities of the scanner, in particular the magnet strength. The length of the scan in conjunction with the closed environment of full body scanner; means claustrophobia may play a part in the patient suitability for a MRI scan of the male pelvis. 1 The closed nature of the MRI scanner is demonstrated in Figure 1 (left side). MRI has spread rapidly through hospitals and private practices due to the superior tissue characterisation capabilities. In recent times, innovative pulse sequences have being developed that overcome sensitivity and specificity limitations of conventional MRI. 2 technique involves combining at least two functional pulse sequences (diffusion-weighted, dynamic contrast enhanced or spectroscopic imaging) that can be analysed together in a multi-parametric framework. An example of the integrated multi-parametric sequences can be seen in the right side of Figure 1. Within this protocol, MRI has improved accuracy to detect and stage prostate cancer. Outside of clinical trial settings, spectroscopy is sometimes omitted from the multi-parametric work-up, due to its high cost in terms of additional time required, expertise and additional software demands to execute the scan effectively. 3 This MRI for prostate cancer screening: March

4 ERC = endorectal coil; MRI = magnetic resonance imaging; TRUS = transrectal ultrasound; US = ultrasound Figure 1 Flow of patient from multi-parametric enabled MRI scanner to biopsy (MRI/US fusion) 2 (copyright obtained) If a lesion is detected with multi-parametric MRI, further classification and grading with biopsy is required. Pathologists grade prostate cancers according to the Gleason system. The Gleason sum score helps determine the future prognosis for men and to decide suitable treatments. A higher score indicates less differentiation or ability to recognise normal prostate glands, representing more aggressive tumour and worse prognosis. The most common scores reported on biopsy are Gleason 6-8, with Gleason 6 or lower considered low risk, 7 intermediate risk and 8 and above high risk. Patient management and treatment will be determined largely by this biopsy outcome. A tumour of Gleason 6 can be managed initially with, Gleason 7 and Gleason 8+ tumours require active treatment. 4 There are currently three techniques available for pathologists using MRI-based biopsies: 1. Magnetic resonance-guided biopsy: the only technique utilising a direct, in-bore approach. This results in the greatest reproducibility with the most expensive cost. Given that this procedure is performed within the live magnet, the approach will be restricted to an interventional radiologist; 2. MRI/Ultrasound fusion-guided biopsy: involves software fusion of MRI images with ultrasound images (Figure 2) to spatially coordinate biopsy location using a floor or table mounted grid apparatus. The biopsy approach is either performed transrectal or transperineal to the preference of urologist; and 3. MRI/Ultrasound cognitive- informed biopsy: the simplest technique involving visual correlation of MRI image and ultrasound image to manually direct biopsy. MRI for prostate cancer screening: March

5 Figure 2 MR/ultrasound fusion combines MR images of the prostate (bottom left, red line) with real-time ultrasound images of the prostate (top left, red line) to assist in targeted biopsy of a previously identified lesion (green line). The location of the biopsy can be recorded (yellow line), and a reconstructed 3-dimensional map of the prostate can be generated at the conclusion of the biopsy (right). Standard biopsy cores and targeted biopsy cores are highlighted here for comparison 5, 6 Recent systematic reviews have suggested that MRI and MR-based biopsy can reliably detect prostate tumours, providing critical information on tumour location, volume, grade and stage. 7, 8 As such there is likely to be an increasing role of imaging the prostate using MRI in the areas of: Early detection and screening for prostate cancer; Guiding patient selection for biopsy: shift to image-based approach; Selecting men for repeat biopsy; and Active surveillance: of identified low risk prostate cancer that would otherwise receive radical surgery and/or radiotherapy. Company or developer The Australian Register of Therapeutic Goods (ARTG) lists five manufacturers of full-body MRI systems that may be suitable for MRI-based pathway for prostate cancer imaging: Emergo Asia Pacific Pty Ltd, GE Healthcare Australia Pty Ltd, Philips Electronics Australia Ltd, Siemens Ltd and Toshiba Australia Pty Ltd. Reason for assessment More than 20,000 Australian men are diagnosed with prostate cancer every year. However, there is controversy about the reliability and validity of MRI and associated biopsy MRI for prostate cancer screening: March

6 techniques, which comes at a substantially increased cost to the public and private health systems regarding the ability to improve patient management. Stage of development in Australia Yet to emerge Experimental Investigational Nearly established Established Established but changed indication or modification of technique Should be taken out of use Licensing, reimbursement and other approval Australian Therapeutic Goods Administration approval Table 1 contains information regarding the ARTG numbers for full-body MRI systems that may be used to image the prostate. Table 1 MRI full-body scanners listed on the Australian Register of Therapeutic Goods (ARTG) Company Emergo Asia Pacific Pty Ltd GE Healthcare Australia Pty Ltd Philips Electronics Australia Ltd Siemens Ltd Toshiba Australia Pty Ltd ARTG Number and Class , IIa , IIb, , IIa, , IIa, , IIa 98887, IIb, , IIa 98319, IIb, 98485, IIa, , IIa, , IIa , IIa Technology type Technology use Device Diagnostic Patient Indication and Setting Disease description and associated mortality and morbidity Prostate cancer is a disease in which cells in the prostate gland become abnormal and grow uncontrollably, forming tumours. Prostate cancer is a major health concern in Australia, causing the second highest number of cancer deaths in men (after lung cancer) and the fifth leading cause of death in Australian men. 9 Of the more than 20,000 Australian men diagnosed with prostate cancer each year, almost 3,300 Australian men die from prostate cancer each year accounting for 4.3 per cent of all male deaths. 10 Prostate cancer is rare in men less than 45 years of age, with more than half of those diagnosed over 65 years. 11 Detection of prostate cancer before symptom onset offers a 5 - year survival rate greater than 90 per cent. Symptoms of prostate cancer are varied but typically relate to urinary disturbances. An enlarged malfunctioning prostate can cause several disruptions to the urinary system including difficulty starting urine flow, interrupted and slow flow, increased frequency, MRI for prostate cancer screening: March

7 haematuria and pain during micturition. Problematically, the urinary system also deteriorates with natural ageing and these symptoms can arise in all men. This heterogeneity of symptoms can be attributed to the wide variability in the aggressiveness of prostate tumours. These range from the more common slow-growing tumours ( clinically insignificant disease ) to those more serious ( clinically significant disease ), which if left untreated, can lead to death. The ability to discriminate between lifethreatening and insignificant cancer is paramount, especially since over 40 per cent of men over 50 years of age are estimated to have the low risk prostate cancer. 8 This form of cancer means they have a low likelihood of suffering significant harm from the disease and are more likely to die from other causes of death, resulting in wide variability and treatment decision uncertainty. 12 The severity of prostate cancer also informs subsequent management of the disease, with patients with low risk cancer potentially avoiding highcost surgery and common adverse effects on quality of life (e.g., urinary complications and sexual difficulties). A diagnosis of prostate cancer will significantly impact quality-of-life. There is currently no consensus on the best treatment for localised prostate cancer. Initial therapeutic choices may include surgery or radiation (brachytherapy or external beam radiation), both of which are associated with significant morbidity, or conservative management such as active surveillance. 13 It has been estimated that approximately 90 per cent of men with localised prostate cancer will undergo a radical prostatectomy or radiation therapy, however up to 60 per cent of these men may have undergone unnecessary treatment. 14 Other post-diagnosis options include active surveillance or watchful waiting. Active surveillance of patients involves monitoring those patients deemed to be low risk (PSA level 10g/L, stage T2a, Gleason score 3 +3) usually by serial PSA testing, DRE and biopsies, with curative treatment options being offered if disease progression is detected. Watchful waiting involves observation of patients without monitoring of disease and is usually offered to older men with comorbidities who are expected to die with, but not of, prostate cancer. 14 The draft clinical practice guidelines developed by the Prostate Cancer Foundation of Australia have made the following recommendations regarding active surveillance: Active surveillance should be offered to men with prostate cancer who meet all the following criteria: PSA 20 ng/ml; clinical stage T1-2; and Gleason score 6 (evidencebased recommendation, Grade C); Consider offering active surveillance to men with PSA 10 ng/ml, clinical stage T1-2a prostate cancer and Gleason score (3+4=7) if pattern 4 component is < 10% after pathological review. For patients with PSA ng/ml or T2B or C disease, consider definitive treatment or repeat biopsy if active surveillance is strongly preferred by the patient (consensus recommendation); MRI for prostate cancer screening: March

8 Consider offering active surveillance to younger men (< 60 years of age) with PSA 10 ng/ml, clinical stage T1-2a and Gleason score (3+4=7) if pattern 4 component is < 10%, provided that the patient understands that treatment in these circumstances may be delayed rather than avoided. For younger men (< 60 years of age) with PSA ng/ml or T2B or C disease, consider definitive treatment or repeat biopsy if active surveillance is strongly preferred by the patient (consensus recommendation); For men with prostate cancer managed by an active surveillance protocol, offer monitoring with PSA measurements every 3 months, and a physical examination including digital rectal examination every 6 months (consensus recommendation); Offer a reclassification repeat prostate biopsy within 6 12 months of starting an active surveillance protocol. Offer repeat biopsies every 2 3 years, or earlier as needed to investigate suspected disease progression: offer repeat biopsy and/or multi-parametric MRI (in specialised centres) if PSA doubling time is less than 2 3 years or clinical progression is detected on digital rectal examination (consensus recommendation); and During active surveillance, offer definitive treatment if pathological progression is detected on biopsy, or if the patient prefers to proceed to intervention (consensus recommendation). 15 The draft clinical practice guidelines developed by the Prostate Cancer Foundation of Australia have made the following recommendations regarding watchful waiting: Advise men with potentially curable prostate cancer considering watchful waiting that their risk of developing more advanced prostate cancer and dying from it will be higher with watchful waiting than with immediate definitive treatment but that, in the medium- to long-term, watchful waiting is unlikely to diminish their wellbeing and quality of life (evidence-based recommendation, Grade C); and Offer watchful waiting to men diagnosed with potentially curable prostate cancer who for reasons other than prostate cancer are unlikely to live for more than another 7 years or choose not to accept potentially curative therapy when it is offered to them (consensus recommendation). 15 MRI has been proposed as an active surveillance tool to manage patients identified as having low risk prostate cancer who would otherwise receive radical surgery and radiotherapy. Number of patients The age-standardised incidence of prostate cancer has increased dramatically over time, from 79 per 100,000 males in 1982 to 194 per 100,000 in This is expected to increase to 25,000 new cases per 100,000 in 2020, due to increased diffusion of screening tests, changes in diagnostic practices and the ageing of the population. 9 Most recent annual MRI for prostate cancer screening: March

9 Medicare Benefits Schedule (MBS) historical utilisation statistics show for Australia wide, July 2013 to June 2014: Initial prostate specific antigen (PSA) test (MBS Item 66655) = 705,906; Follow up PSA test (MBS Item 66656) = 790,057; and Ultrasound-guided biopsy MBS Item = 22,616. In , the National Hospital Morbidity Database website (AIHW) recorded 6,421 open prostatectomies and 5,507 closed radical prostatectomies. The screening population could be estimated at the 705,906 people that received an initial PSA test within a 12 month period. The size of the active surveillance subgroup is more difficult to estimate, due to the many treatment options available, and varied treatment decisions for patients with low risk cancer. 12 It is estimated that 40 per cent of men above 50 years of age have low risk cancer 8, and thus an approximate estimate could be 282,362 men (40% of screened population). Speciality Technology setting Oncology and Radiotherapy, Urology Specialist hospital Impact Alternative and/or complementary technology (additive and substitution) MRI and MR-based biopsy is likely to be used in combination with the current standard care (PSA test, digital rectal examination and transrectal ultrasound-guided biopsy) and in some cases as a substitute. This will depend on the identified risk level for prostate cancer and subsequent treatment decisions planned by the specialist urologist. Current technology Population screening for well men The results from one large randomised clinical trial (European Randomised Study of Screening for Prostate Cancer) indicated there was a reduced risk of prostate cancer death with introduction of PSA testing and treatment in the year age group. 16 However, this approach is not efficient as it was estimated that with eleven years follow up, 1,410 men needed to be screened and 48 men need to be treated for prostate cancer to save one life. Despite the subsequent over-detection concerns, the desired reduced mortality rates led the Urological Society of Australia and New Zealand to recommend PSA tests and digitalrectal examinations be offered to men aged years, after providing information about benefits and risks of PSA testing. 4 The problem with frontline screening with PSA and digital rectal examination is that both tests have poor sensitivity and specificity. Unfortunately, abnormal findings may not mean presence of prostate cancer, so the next step is for the urologist to request an invasive MRI for prostate cancer screening: March

10 biopsy. This biopsy can be performed with either transrectal or trans-perineal approach, which allows validation of initial screening results. The PSA and digital-rectal examination frontline screening tests only assess the risk of having prostate cancer, and are not able to differentiate and diagnose low risk from harmful prostate cancer. Routine screening for early detection is not recommended in Australia 11, however PSA testing is subsidised through the MBS. Second line screening: Biopsy The current gold standard of prostate cancer diagnosis is a combination of ultrasoundguided biopsy with PSA and digital rectal examinations (DRE). The biopsy is combined with ultrasound to aid the procedure. The poor imaging capability of ultrasound of the prostate may not allow a direct approach to the diseased area. In the absence of an image-based approach, multiple random sampling (based on equal disease location probability) is performed on accessible regions of the prostate. Standard practice is for the urologist to collect tissue cores 17 in a systematic fashion (from the medial and lateral aspects of base, mid-zone, and apex of each side of prostate gland). The systematic approach attempts to improve detection rates with increased sampling. Despite this rigorous approach, undersampling of the apex and anterior section of the prostate gland can occur due to the physical limitation of a posterior approach. This may result in undetected tumours, both significant and insignificant. 18 Other disadvantages to the patient include discomfort, bleeding and heightened risk of infections. There is growing recognition amongst urologists for transperineal ultrasound-guided biopsy to replace transrectal ultrasound-guided biopsy due to the superior ability of the former to sample the whole prostate. 19 Infection risks are reduced with a transperineal approach due to the avoidance of the mucous membrane of the rectum. 20 This method involves taking more biopsy cores, longer procedural time and has higher surgical and pathology costs. 21 This technology brief will compare MRI and MR-based biopsy to both transrectal and transperineal ultrasound guided biopsy techniques from two Australian clinical trials 22, 23 for men suspected of having prostate cancer. Active surveillance Active surveillance (AS) is a management technique for men identified with low risk prostate that are likely to benefit from monitoring the cancer and offering treatment only if and when the cancer worsens to a level necessary of radical intervention (typically Gleason score 8). As low-risk prostate cancer is the most common type and may mean low likelihood of future progression, a non-invasive technique that can identify men for safe monitoring is needed, in order to reduce over-treatment of indolent disease and the potential harmful side-effects of treatment. Patients are selected for AS based on widely accepted criteria: MRI for prostate cancer screening: March

11 ..low risk consisting of a Gleason score of 6 on biopsy, no more than two positive cores, no involvement of more than 50% of a core and PSA<10 (p. 1). 24 After initial stratification, current AS programs involve regular clinical examination, PSA measurements and repeat biopsies. 4 The Urological Society of Australia and New Zealand guidelines recommend repeat intervals of 3 to 6 months. The current protocol for AS combines clinical T stage, PSA, PSA density, Gleason score from biopsy, number of positive prostate biopsies and/or malignant tissue per core to decide safety for classification of lowrisk AS patients. 25 If repeat assessments suggest the risk of progression, men are offered radical treatment of curative intent with radical surgery (prostatectomy) and/or radiotherapy. However, even with the introduction of stringent AS criteria, a systematic review estimated that 30 to 50 per cent of men classified appropriate for AS after initial biopsy were reclassified at a higher disease level. 23 Misclassification of severity of tumours and subsequent inadequate patient management may have delayed surgery that could potentially extend their survival. Radical prostatectomy is an effective treatment in eradicating prostate cancer but the common harmful treatment side effects include significant urinary dysfunction (1.1% increasing to 12.3% at 3 years post-surgery), erectile dysfunction (21.5% increasing to 77.4% at 3 years post-surgery), bowel dysfunction (4.4% to 3.5% at 3 years post-surgery), loss of fertility and anxiety. 26 International utilisation Country Level of Use Trials underway or completed Limited use Widely diffused Australia United States United Kingdom Europe Diffusion of technology in Australia MRI scanners are available through both public and private radiology providers in Australia. However, not all MRI scanners can perform advanced multi-parametric sequences. Generally, these specialised protocols are performed in specialist settings, where access to highly skilled radiologists and urologists is more readily available. Biopsy with MRI is likely restricted to hospital settings in light of the complexity and invasiveness of the procedure. Standard ultrasound-guided biopsy techniques can be performed in hospital and outpatient urologist clinics. The increased diffusion of 1.5 Tesla and, the more preferred, 3.0 Tesla magnets throughout Australia offers the potential to improve imaging pathways associated MRI for prostate cancer screening: March

12 with early detection of men suspected of developing prostate cancer and for active surveillance in men with low-risk prostate cancer. Cost infrastructure and economic consequences There are two types of MRI devices; the 1.5 and 3.0 Tesla (T) machines, which are expensive to purchase, operate and maintain. The 3.0 Tesla machines can cost in the magnitude of $3-4 million while the 1.5-Tesla machines cost approximately $1-2 million. Currently, there are more 1.5T than 3.0 T MRIs in Australia. Multi-parametric MRI can be conducted using both types of machines for both screening and active surveillance. To date, no study has shown an advantage of 3.0 T over 1.5 T for prostate cancer detection. 23 The 3.0 T MRI does afford greater productivity to the radiology provider due to the quicker scan times as a result of improved inherent signal, compared with the 1.5 T MRI. A 1.5 T MRI may also need an expensive and invasive endorectal coil to maintain image quality, at a higher cost to the provider. A substitute for this coil could be a higher channel phased-array pelvic coil that is clinically and patient preferred due to the non-invasive technique. These latter two coils would not be provided with the standard MRI model and would need to be negotiated with the supplier, thereby increasing costs. The preferred method for biopsy after MRI imaging may also add substantial costs to the radiology provider due to additional expenses such as: Site preparation for installation; Ongoing service contracts (estimated at 6-10% of sale price per year); Staff costs and training; Additional software requirements to enable multi-parametric sequences; Radiologist reporting and interventional fees if performing MR-guided biopsy; Contrast media (gadolinium-based products); Additional medications (i.e. anti-spasmodics given to reduce bowel motion artefact); Consumables (e.g. linen, cleaning equipment, ear plugs etc.); and Overhead costs (e.g. high power demand, helium and chiller ongoing costs to allow the magnet to maintain the unique superconducting environment.). MRI is a sophisticated technology and since its introduction on the MBS and has been carefully managed through requestor, provider and item level restrictions. In 2012, under the Diagnostic Imaging Review Reform Package, General Practitioners (GP) access to Medicare-eligible MRIs was improved. MRI units for adults and paediatrics were increased to 341 Australian-wide funded sites, which included the provision of 30 full Medicareeligible MRI units in regional locations. 27 Partial Medicare-eligible means redcued access to MBS covered items (only new GP coverage items) and fully Medicare-eligible means complete access to all MBS items. Currently, MRI for examination of the prostate is not listed on the MBS. The MBS has two different MRI schedule fees to incentivise improved quality of diagnostic imaging (capital sensitivity rule): MRI for prostate cancer screening: March

13 K items (100% scheduled MBS fee): available only for newer MRI scanners; and NK items (~50% scheduled MBS fee): available to all aged MRI scanners A recent study found the costs of prostate cancer to the MBS and PBS for the first 12 months was, on average, $11,293 per patient. 12 Out-of-pocket costs varied across men, but the majority (75%) faced ~$6,000 for first year. Estimated total government costs for prostate cancer treatment in Australia is $25,000 to $30,000 per case. A summary of key cost estimates are provided in Table 2. Table 2 Summary of key resource costs at Medicare Benefit (75% of fee) Item Cost per unit Number required Cost per patient MRI-based pathway Scan time MRI + MRGB 30 min (MRI) + 45min (MRGB) 1 1hr 15min MRI private fee Australia 28 $ $ MRI contrast (MBS #63491) $ $33.60 MRGB 29 $1, $1, MRI staff costs 30 $ $ Total MRI - - $2, $2, c Standard Care (TRUSGB) Scan time TRUSGB 15min 1 15min TRUSGB (urologist fee for biopsy) $ $ $ Total TRUSGB $3,000 1 $3,000 d Shared Costs b GP consult # $ $37.05 Urologist costs #00104 $ $64.20 Anaesthetics costs #17610, 20910, $ $ Pathologists costs #65070, $ $ PSA test # $ a $32.25-$129 Radical Prostatectomy #37211 $ $ Radical Prostatectomy 29 $23, $23, MRI: Magnetic Resonance Imaging; MRGB: Magnetic Resonance-guided biopsies; TRUSGB: transrectal ultrasound-guided biopsies; GP: general practitioner; PSA: prostate specific antigen. a dependant on if screening (1 only) or AS (2-4 per year); b estimates of key estimated MBS items only. These costs will vary significantly as prostate cancer treatment and detection varies; c likely to be underestimated due to other costs not possible to include, overheads, staff costs, etc; d De Rooij et al 2013 estimated similar costs between MRI pathway and TRUSGB pathway, with this estimate approximately in line with their data. Ethical, cultural or religious considerations No other specific cultural or religious considerations were identified. MRI for prostate cancer screening: March

14 Evidence and Policy Effectiveness The following section is divided into two parts: 1. Screening of patients with MRI/MR based biopsy versus standard ultrasound-guided biopsy for men suspected of having prostate cancer. Clinical evidence is derived from two prospective Australian clinical trials looking at MR-guided biopsy efficacy and MRI pre-biopsy efficacy; and 2. Active surveillance of men diagnosed with low risk prostate cancer: systematic active surveillance review, 1 prospective and 1 retrospective trial. 1. Screening/Early Detection with MRI for patient selection for biopsy: patients suspected of prostate cancer at baseline (MRI as triage test) Both studies (Pokorny et al 2014 and Thompson et al 2014) recruited participants with high or concerning PSA levels referred to a urologist. In Pokorny et al. (2014), all participants had a baseline MRI scan, without endorectal coil, and standard care with the comparatortransrectal ultrasound-guided biopsy. 22 Patients with an equivocal or suspicious lesion received MR-guided biopsy. This allowed comparisons to be made between MRI versus transrectal ultrasound-guided biopsy (low-risk patients only) and MRI/MR-guided biopsy versus transrectal ultrasound-guided biopsy (moderate and high risk patients). In Thompson et al. (2014), patients received baseline MRI, without endorectal coil, and transperineal ultrasound-guided biopsy as the comparator. 23 Table 3 summarises the key study details. MRI for prostate cancer screening: March

15 Table 3 Study description of included studies for analysis Study Design Pokorny et al (2014) 22 Thompson et al (2014) 23 Level of evidence Single-centre, single arm, prospective investigator blinded trial a (Level III-1) Single-centre, single-arm, prospective investigator blinded trial a (Level III-1) Country / Area Australia Australia Intervention vs Comparator MRI and coil used (channels provided where possible) mp-mri (± targeted MRGB) b vs systematic TRUSGB mp-mri vs systematic TPUSGB + targeted MR/US post MRI 3T, pelvic coil only 1.5T (47%) and 3T (53%) alternate allocation, pelvic coil only Number of patients N = 223 with 142 MRGB vs 223 TRUSGB N = 150 scanned and biopsied Discontinuation/Loss to Follow up Patient population Biopsy strategy 2 refused mp-mri, 1 PSA normalised and not suitable. 2 refused TRUSGB of low risk cohort Biopsy naïve men any age with abnormal PSA or DRE. Excluded if prior prostate treatments (alpha reductase inhibitors) MRGB after MRI TRUSGB after MRGB 15 patients insufficient data Men above 40 years with abnormal PSA or DRE and no previous multi-parametric MRI Template TPUSGB prior MRI + targeted MR/US fusion post MRI Primary Outcomes Detection of PCa Detection of PCa c Secondary Outcomes Histologic details of biopsies, identified tumours, MRI reader performance and histology of radical prostatectomy and adverse events Histological details of biopsies, identified tumours, Radiologist accuracy, histology of radical prostatectomy and adverse events Radiologist 3 radiologists reported 2 radiologists double reported and blinded PI-RADs system used PI-RADs system used mp-mri: multi-parametric-magnetic Resonance Imaging; MRGB: Magnetic Resonance-guided biopsies; TRUSGB: transrectal ultrasound-guided biopsies; TPUSGB: transperineal ultrasound-guided biopsies; PI-RADs = Prostate Imaging-Reporting and Data System ; PI-RADs score clinically significant is: 1 = highly unlikely; 2 = unlikely; 3 = equivocal; 4 = likely; 5 = highly likely; a all patients received mp-mri and both biopsy techniques if high risk for disease as per PI-RADs score; b patients receive both intervention and biopsy if moderate to high risk, low risk only receive TRUSGB; c Definition of significant cancer at biopsy: 1 = more strict grade only; 2 = less strict grade only; 3 = more strict grade + vol; 4 = less strict grade + vol (used for most analysis). The key baseline characteristics of the studies are provided in Table 3. The patient populations and levels of risk (similar DRE, prostate volume and suspicion levels of baseline MRI) were comparable. The ages of all populations are typical of men living with prostate cancer in Australia, and expected to require screening diagnostics on the MBS. Table 4 Baseline Characteristics of all included studies Study Design Pokorny et al (2014) 22 Thompson et al (2014) 23 N Age in years, median (IQR) 63 (57 to 68) 62 (55 to 66) PSA (ng/ml), median (IQR) 5.3 (4.1 to 6.6) 5.6 (4.5 to 7.5) DRE: abnormal % 18% 29% Prostate Volume, median (IQR) 41 (30 to 59) ml 40 (30 to 57) cm 3 mpmri score: suspected of Cli Sig PCa PI-RADs 3-5 or mod/high risk 64% 66% mpmri score: not suspected of Cli. Sig PCa PI-RADs 1-2 or low risk 36% 34% IQR: inter-quartile range; PSA: Prostate Specific Antigen; DRE: Digital Rectal Examination; mp-mri: multi parametric-magnetic Resonance Imaging; PI- RADs: Prostate Imaging-Reporting and Data System; cli. Sig.: clinically significant, PCa: Prostate Cancer MRI for prostate cancer screening: March

16 The summary results for key primary and secondary outcomes are provided in Table 5. Given the nature of single-arm trials where patients receive the intervention and comparator (acting as their own control), randomisation of the order may be relevant. Selection bias is identified by the authors as an issue, due to the visualisation of bleeding from the first biopsy that may impact the latter performed biopsy technique. This potential bias may compromise the applicability of findings. Table 5 Results for Primary, Secondary and Sub-group analysis Main Outcomes Pokorny et al (2014) 22 Thompson et al (2014) 23 Total PCa detected n (%) 99/142 (69.7%) mpmri/ MRGB TRUSGB Combined Multi-parametric MRI only versus TPUSGB + post MRI/US targeted biopsy d Both 126/223 (56.5%) 142/223 (63.7%) 61.3% +ve PCa biopsy Histology: Low Risk n (%) 6 a (6.1%) 47 (37.3%) 34/223 (15.2%) Low Risk = 27.3% Histology Mod/High Risk n (%) Biopsies taken n, % positive for PCa 93 (93.9%) 79 (62.7%) 108/223 b (48.4%) 235/417 cores (56.4%) % significant PCa missed 10 missed, 5 misclassified Correlation with Radical Prostatectomy findings 4 insig, 11 sig missed. 60 correct (80%) 401/2672 cores (15%) 16 missed, 13 misclassified 4 insig, 18 sig missed 53 correct (70.1%) MRGB reduced biopsy need by 51% Moderate Risk = 24.3% High Risk = 9.7% 30 (26-33) systematic + 2 targeted post MRI outside template (1 MR/US fusion, 1 MR/US cognitive) - NR 75 men underwent RP. 48 men underwent RP. PI-RADs 1 = 0 (100% correct) PI-RADs 2 = 4 RP, 2 sig (50% correct) PI-RADs 3 = 14 RP, 11 sig (79% correct) PI-RADs4 = 23 RP, 23 sig (96% correct) PI-RADs 5 = 7 RP, 7 sig (100% correct) Insig = insignificant; MRGB: MRI-guided biopsy; MRI-US: MRI-ultrasound guided biopsy; RP: Radical Prostatectomy; Sig: significant; TPUSGB: Transperineal ultrasound-guided biopsy; TRUSGB: Trans-rectal ultrasound-guided biopsy; PI-RADs: Prostate Imaging-Reporting and Data System; PI-RADs score clinically significant is: 1= highly unlikely; 2 = unlikely; 3 = equivocal; 4 = likely; 5 = highly likely. a patients in PI-RADs 1-2 category did not have biopsy MRGB, only TRUSGB; b 7 significant PCa (10.9%) in MRGB were misclassified by TRUSGB, PCa: Prostate Cancer Prostate Cancer Detection Rates: MRI at biopsy (Pokorny et al 2014) 22 The results of the two trials support patient benefit with the introduction of MRI imaging and biopsy pathway. The summary findings are: Combining standard care with MRI-guided biopsy resulted in higher detection rates for prostate cancer (69.7% vs 56.5%); MRI-guided biopsy techniques significantly reduced the number of cores taken (51% fewer) whilst maintaining superior efficiency for likelihood of a positive sample (56.4% vs 15%). This highlights the efficiency of a targeted biopsy strategy as opposed to standard care of a random and systematic approach; Correlation with an alternative reference case, radical prostatectomy, supported MRI-guided biopsy to be more accurate than transrectal ultrasound-guided biopsy (80% correct vs 70%, with crucially fewer significant cancers missed (11% vs 18%) in the subset of higher risk patients; MRI for prostate cancer screening: March

17 MRI-guided biopsy performed better in terms of identifying fewer clinically significant prostate cancers (10 vs 16) and fewer misclassifications (5 vs 13); and A comparison of Pokorny et al. (2014) to a similar European prospective trial comparing MRI/ MR-guided biopsy with transrectal ultrasound-guided biospy, 31 demonstrated greater detection in the Australian trial (69.7% vs 53%). This is partly explained by the differing biopsy strategies, the European trial only sampled suspected lesions seen on baseline multi-parametric MRI, compared with the Australian that targeted the three most suspected lesions, irrespective of the patient risk. Both trials demonstrated improved detection for MRI based pathways, validating MRI detection at multicentre locations and improving generalisability. Prostate cancer detection rates: pre-biopsy (Thompson et al. 2014) 23 The performance of MRI, using the validated Prostate Imaging-Reporting and Data System (PIRDS) mean score, compared pre-biopsy to transperineal ultrasound-guided biopsy as standard care. A subgroup analysis of higher risk disease cohort (patients who underwent radical prostatectomy) found similar results between, confirming the suitability of template transperineal ultrasound-guided biopsy. Like other studies investigating MRI before biopsy, 32 the performance of MRI excelled at higher levels of disease (96-100% correct), and lower levels of disease (100% correct). At intermediate levels MRI findings did not correlate as well with comparators (PIRDS mean score 2-3 = 50% to 79%). The correlation between MRI scores and significant cancers was highly significant (p< 0.001). Logistic regression found magnet strength and family history did not correlate with significant cancer (p>0.8). Adding PIRDS mean score to the base case model of PSA and DRE increased the area under the curve for predicting significant cancer from 0.81 to This suggests adding MRI with PSA and DRE to guide biopsy decisions will result in higher accuracy. Internal and external validation above 0.90 would be required before routine clinical use. 23 Table 6 provides the summary statistical results for clinical effectiveness. Table 6 Summary statistical results for included studies Final Measure Pokorny et al (2014) Thompson et al (2014) MRGB TRUSGB MRI at biopsy MRI pre-biopsy High Risk (n=97) MRI pre-biopsy Low Risk (n=53) Sensitivity 92%, 95%CI [88,95] 70%,95%CI [64,76] 96%, 95%CI [93-96%] - - Specificity 97%, 95% CI [93,99] 94%, 95% CI [89,96] 50%, 95%CI [47%-53%] - - PPV 92%, 95% CI [88,95] 93%,95% CI [89,96] 50%, 95%CI [43%-57%] 71% 28% NPV 97%, 95% CI [93,99] 72%, 95% CI [65,78] 96%, 95%CI [92%-96%] 100% 96% CI: Confidence Interval; MRI: Magnetic Resonance Imaging, MRGB: Magnetic Resonance-guided biopsy; TRUSGB: transrectal Ultrasound-guided biopsy; NPV: negative predictive value; PPV: positive predictive value: a 4 Definitions for PCa from grade 1 (most strict) to grade 4 (less strict). Grade 4 is equivalent to ESUR guidelines. This is the first external validation recommended by international working group START 33. MRI for prostate cancer screening: March

18 The results demonstrate that multi-parametric MRI has: high sensitivity and negative predictive value (NPV); moderate specificity and positive predictive value (PPV); improved PPV and NPV for patient at higher disease risk- highlighting the challenges facing active surveillance programs of more difficult low-risk prostate cancers. The results demonstrated that MR-guided biopsy displayed: high sensitivity, specificity, NPVs and PPVs (> 90%); and similar specificity and PPVs when compared to transrectal ultrasound-guided biopsy; When comparing MRI with and without biopsy to tranrectal ultrasound-guided biopsy, MRI reported a higher sensitivity 1 and NPV. A screening test that is more highly sensitive may result in benefits to the health care system by avoiding overtreatment with costly biopsies and radical surgery that may not be warranted. However, the inclusion of biopsy with current standard of care still appears important in regard to the higher specificity of the test. A high specificity means that men without prostate cancer will be classified correctly as negative. MRI without biopsy may miss prostate cancer and this would significantly affect patient quality-of-life, despite the invasiveness of the procedure. The inclusion of biopsy is imperative in the diagnosis pathway, and a targeted biopsy approach with MRI may offer significant benefits to current systematic ultrasound-guided biopsy techniques. Active surveillance: patients with diagnosed low risk cancer at baseline Two recent large clinical trials investigated patients with identified low risk prostate cancer under active surveillance programs following multi-parametric MRI (Table 7). Siddiqui et al. (2013) 2, was a prospective trial comparing MRI/ultrasound fusion-guided biopsies with standard care of systematic 12-core transrectal ultrasound-guided biopsy. The five year study period included 89 patients with repeated biopsies on active surveillance. Vargas et al. (2013) 34 enrolled 388 men with identified low risk prostate cancer to compare MRI with confirmatory biopsy. 1 A high sensitivity indicates that those patients with prostate cancer are likely to test positive and a high negative predictive value indicates that those patients who test negative can be reassured that they are likely to be disease-free MRI for prostate cancer screening: March

19 Table 7 Study description of included studies for analysis (active surveillance) Study Design Siddiqui et al (2013) 2 Vargas et al (2013) 34 Level of evidence Prospective observational study Level III-1 Retrospective observational study Level III-3 Country / Area United States United States Intervention vs comparator MRI and coil used (channels provided where possible) MRI/US fusion guided prostate biopsy versus 12-core TRUS biopsy 3.0T; 16-channel cardiac surface coil; endorectal coil Endorectal MRI versus confirmatory biopsy 1.5T or 3.0T; body coil; pelvic phased array coil; endorectal coil Number of patients Discontinuation/Loss to Follow up NR Not relevant Patient population Men with MRI visible lesions Men with clinically low risk (Gleason 6 or less) prostate cancer on biopsy Previous MRI performed Biopsy strategy MRI/US-fusion-guided biopsy Transrectal prostate biopsy Primary Outcomes Prostate cancer detections Likelihood of tumour on 1-5 scale Secondary Outcomes PCa Gleason score Biopsies per patient Radiologist Two radiologists independently reviewed and assigned PCa score AS: active surveillance; PCa: Prostate Cancer suspicion score; NR: not reported. Three radiologists independently interpreted the MRI Siddiqui et al. (2013) 2 reported that targeted MRI biopsy showed higher ability to detect significant tumours (67% upgraded at repeat biopsy with 36% insignificant missed). Transrectal ultrasound-guided biopsy in repeat biopsy only detected 26 per cent over targeted MRI cases alone with a smaller proportion (8%) constituting significant cancer. MRI and targeted biopsy protocol has preferential detection compared to standard transrectal ultrasound-guided biopsy and a greater ability to detect significant cancer whilst reducing detection of insignificant cancer. Since this HealthPACT assessment was finalised Siddiqui et al published further results of their ongoing study, reporting on a cohort of 1,003 men undergoing both targeted MR/ultrasound (US) fusion biopsy and standard biopsy concurrently. 6 The characteristics of this study are as described in Table 7, with images fused using the FDA approved UroNAV Fusion Biopsy System (Invivo Corporation, USA). A total of 1,215 men with either an elevated PSA or abnormal DRE were recruited prospectively and assessed for eligibility by undergoing an MP-MRI. Of these, 181 were excluded from the study due to a lack of lesions being visualised on the MP-MRI, resulting in 1,034 men undergoing a biopsy. Of these, 31 were excluded due to having received prior treatment for prostate cancer, leaving a total of 1,003 men (mean age 62.1 ± 7.5 years) included for analysis. The pathology outcomes of targeted versus standard biopsy are summarised in Table 8. Of the 1,003 men, 690 (69%) had an exact agreement between targeted and standard biopsy MRI for prostate cancer screening: March

20 pathologic risk categories. Both techniques diagnosed a similar number of cancer cases with targeted biopsy diagnosing 461 patients and standard biopsy 469. However, the difference between the two techniques is that targeted biopsy diagnosed significantly more high-risk cancers compared to standard biopsy (173 vs 122 cases, p <0.001) and significantly fewer low-risk cancers (213 vs 258 cases, p =0.002). Using targeted biopsy, 167 cases (17%, orange shading) were at an elevated risk of prostate cancer. Of these, 112 (67%, dark orange) were upgraded to intermediate- or high-risk pathology. Using standard biopsy, 146 cases (15%, blue shading) were in an elevated risk category, of which only 60 (41%, dark blue) were upgraded to intermediate- or high-risk pathology. Adding standard biopsy to targeted biopsy an additional 103 cases (22%) of prostate cancer were diagnosed, most of which were low-risk (83% low risk, 12% intermediate risk, and 5% high risk). To diagnose one additional high-risk cancer, 200 men would need to undergo standard biopsy in addition to targeted biopsy. In addition, for every extra case of high-risk cancer diagnosed, 17 additional cases of low-risk cancer would be diagnosed. Using targeted biopsy in addition to standard biopsy led to no change in Gleason score risk stratification in 857 cases (85%) (data not shown). Of those patients with a change in risk category, 86 (9%) increased from no cancer to low-risk cancer, while only 19 (2%) increased from no cancer or low- or intermediate-risk disease to high-risk prostate cancer. Of interest is the small subset of patients who underwent a radical prostatectomy (n=170), allowing for the comparison of the diagnostic accuracy of targeted and standard biopsy compared to the pathology results following whole gland prostatectomy (Table 9). In this group of men with whole-gland pathology, targeted biopsy had a greater predictive ability for differentiating low-risk from intermediate- and high-risk disease when compared to standard biopsy or the two combined approaches (area under the curve, 0.73, 0.59, and 0.67, respectively, p <0.05 for all comparisons). Although these results are promising, with targeted MR/US biopsy resulting in the increased detection of high-risk prostate cancer, long-term follow-up of these patients is required to assess the impact of these improvements on clinically meaningful outcomes including prostate cancer specific mortality or overall mortality. MRI for prostate cancer screening: March

21 Table 8 Comparison of pathology from standard extended-sextant biopsy and targeted MR/US fusion biopsy for prostate cancer 6 Standard extended-sextant biopsy results Low-risk cancer Intermediate-risk cancer High-risk cancer Targeted MR/US fusion biopsy results No cancer Gleason 6 Gleason 3+4 Low volume Gleason 3+4 High volume Gleason 4+3 Totals No cancer Gleason Low-risk cancer Gleason 3+4 Low volume Intermediate-risk cancer Gleason 3+4 High volume High-risk cancer Gleason Totals MRI for prostate cancer screening: March

22 Table 9 Comparison of standard and targeted MR/US fusion biopsy results to whole gland prostatectomy pathology 6 Targeted MR/US fusion biopsy Standard biopsy Combined biopsy Sensitivity, % [95% CI] 77 [67, 84] 53 [43, 63] 85 [76, 91] Specificity, % [95% CI] 68 [57, 78] 66 [54, 76] 49 [37, 60] NPV, % [95% CI] 70 [58, 80] 53 [43, 63] 73 [58, 84] PPV, % [95% CI] 75 [65, 83] 66 [54, 76] 67 [58, 75] Accuracy, % [95% CI] 73 [70, 76] 59 [55, 63] 69 [65, 72] AUC [95% CI] 0.73 [0.66, 0.79] 0.59 [0.52, 0.67] 0.67 [0.60, 0.74] Comparison with targeted MR/US p=0.005 p=0.04 US = ultrasound, MR = magnetic resonance, CI = confidence interval, NPV = negative predictive value, PPV = positive predictive value, AUC = area under the curve The retrospective study by Vargas et al. (2013) 34 included a cohort of 388 men identified with low risk cancer on initial biopsy who underwent MRI followed by surveillance biopsy within 12 month period. MRI again showed high specificity and negative predictive value (98%) for ruling out Gleason upgrading at low and high risk disease (93% sensitive for Gleason upgrading). The study estimated that 20 per cent of the low-risk cohort was classified to higher level disease at later stage. The main reason for the estimated 20 to 30 per cent significant prostate cancers that are missed under active surveillance programs is the functional limitation of under-sampling of the anterior prostate, due to the inherent posterior approach of TRUSGB. 35 MRI may significantly reduce this underestimation by implication of a targeted biopsy technique. This may ensure a better patient selection process for active surveillance. Multi-parametric MRI could also be used to defer the need for biopsy for men still shown to be at low-risk. Diffusion-weighted sequences (a vital component of multi-parametric framework) are proven to be independent reliable indicators of disease progression. Clinical evidence correlated apparent diffusion coefficient scores with raised Gleason scores on biopsy, implying the ability for MRI to upstage disease if possible, permitting a reduction in biopsies for patients maintaining disease level at entry of active surveillance program. 31 A recent systematic review that included 14 trials concluded that multi-parametric MRI may better select patients for active surveillance, as opposed to transrectal ultrasound-guided biopsy. Incorporation of MRI into active surveillance selection criteria for patients with lowrisk prostate cancer may reduce the number of patients reclassified at repeat biopsies, because of better initial prognosis evaluation. 25 MRI for prostate cancer screening: March