SITE IMAGING MANUAL ACRIN 6698

SITE IMAGING MANUAL ACRIN 6698 Diffusion Weighted MR Imaging Biomarkers for Assessment of Breast Cancer Response to Neoadjuvant Treatment: A sub-study of the I-SPY 2 TRIAL Version: 1.0 Date: May 28, 2012 www.acrin.org

VERSION HISTORY Version Section Summary of Change 1.0 Final Document ACRIN 6698 Site Imaging Manual, Version 1.0 Page 2 of 11

TABLE OF CONTENTS 1.0 Overview of Imaging Requirements.... 4 2.0 Imaging Qualification.... 4 2.1 Imaging Equipment 2.2 DWI Phantom Test 2.3 DWI Test Scans 2.4 DW MRI Learning Module 2.5 Qualification Review and Notification 2.6 Changes to Qualified Scanner(s) and/or Breast Coil 3.0 Standardized Breast MRI.... 6 3.1 Imagine Schedule 3.2 Imaging Procedure 3.2.1 Exam Preparations 3.2.2 DWI Acquisition Protocol 3.2.3 DWI Reproducibility Scan 4.0 Management of Image Data...... 9 4.1 Storage of Image Data 4.2 Submission of Image Data to Core Lab 4.2.1 De identification of Images 4.2.2 Image Transmittal Worksheet (ITW) 5.0 Quality Control. 10 5.1 Study Imaging 5.2 DWI Phantom Tests Standardized I SPY 2 and ACRIN 6698 MRI Acquisition Parameters (Table 4).. 11 Please refer to the ACRIN 6698 web page for the current versions of all study documents, http://www.acrin.org/6698_protocol.aspx. DW MRI Qualification Form DWI Phantom Test Instructions Image Transmittal Worksheet (ITW) Imaging Equipment Update Form ACRIN 6698 Site Imaging Manual, Version 1.0 Page 3 of 11

1.0 OVERVIEW OF IMAGING REQUIREMENTS DWI Qualification MRI/DWI Time Points Reproducibility DWI Standardized QC Submit prior to ACRIN 6698 study enrollment (for each scanner): DWI Qualification Form DWI Phantom QC Testing 2 DWI Test Scans 6698 DW MRI Learning Module Perform per standardized I SPY 2/ACRIN 6698 acquisition protocol MRI 1: Pre treatment (prior to randomization) MRI 2: Early treatment (end of paclitaxel cycle 3, prior to cycle 4) MRI 3: Inter regimen (at least 1 day after paclitaxel, prior to AC) MRI 4: Pre surgery (at least 2 3 weeks after AC, prior to surgery) Perform per standardized ACRIN 6698 acquisition protocol MRI 1: Preferred time point (select sites and patients only) MRI 2: If not performed at MRI 1 DWI Phantom QC Testing performed every 6 months 2.0 IMAGING QUALIFICATION Participation in the I SPY2 trial and ACRIN 6698 sub study requires that all sites adhere to a standardized MR imaging protocol. The use of standard imaging guidelines is an essential component of clinical trials in which imaging plays a central role in the research endpoints. This is of particular importance in multicenter trials where equipment, personnel, and imaging acquisition protocols can vary significantly. Thus, the use of standardized imaging guidelines helps control the inter and intra site variability inherent in multicenter imaging trials. To participate in the ACRIN 6698 sub study, I SPY 2 sites will be required to perform phantom QC testing and submit at least 2 DWI test scans acquired using the multi b value DWI sequence provided below in Section 3. Sites must pass the qualification requirements for at least one scanner prior to accrual to ACRIN 6698. The purpose of the imaging qualification process is to help ensure trial imaging is of high quality and performed per the trial standardized acquisition protocol. Suboptimal image quality and/or imaging not performed per the trial standardized protocol can result in exclusion of the imaging exam(s) and/or the entire case from analysis. Therefore, routine QC and adherence to the I SPY 2 and ACRIN 6698 image acquisition protocol are of great importance. 2.1 Imaging Equipment Consistent with I SPY 2, the required imaging equipment includes: at least one 1.5T or 3T whole body MRI scanner a dedicated breast radiofrequency coil Sites are required to identify at least one 1.5T or 3T MR scanner for imaging of ACRIN 6698 study patients. An ACRIN 6698 DW MRI Qualification Form is required for each ACRIN 6698 Site Imaging Manual, Version 1.0 Page 4 of 11

scanner to be used for study imaging. In choosing which scanner(s) to qualify, please note that it is preferred (best practice) that all study imaging for a given patient be performed on the same scanner. When this is not possible, all imaging for a given patient must be performed using the same scanner configuration (manufacturer, field strength, model, and breast coil model). 2.2 DWI Phantom Test DWI phantom tests are required for each scanner to be used for study imaging. Upon receipt of the ACRIN 6698 Protocol Specific Application (PSA), a pair of DWI phantoms will be delivered to the site for system testing. These ice water based phantoms, by utilizing a medium with a known diffusion coefficient and temperature control, provide a standardized/harmonized method for DWI QC testing. The DWI Phantom Test Instructions, detailing phantom preparation and scan instructions, is available for download from the ACRIN 6698 web site, http://www.acrin.org/6698_protocol.aspx. For image submission instructions, refer to section 4.2 below. 2.3 DWI Test Scans Two clinical DWI test scans are required for each scanner to be used for study imaging. The DWI test scans should be acquired per the 4 b value DWI acquisition protocol provided in Section 3, but only after receiving ACRIN approval of the DWI phantom test. The test scans can be performed on current I SPY 2 patients or volunteers. Refer to Section 4.2 for image submission instructions. 2.4 DWI Learning Module As part of the site qualification process, sites will be asked to identify a lead/research MRI technologist to oversee the study related imaging activities. This technologist is required to complete a study specific DWI learning module. The learning module will provide an overview of the 6698 imaging requirements as well as provide information regarding image quality issues specific to DWI. Though not required, all MRI technologists working with 6698 study participants are urged to complete the learning module. 2.5 Qualification Review and Notification The DWI data from both the QC and clinical test scans will be evaluated for general image quality (e.g. artifacts, distortion, signal to noise) and compliance with the standardized DWI acquisition protocol. Upon approval of the DWI phantom tests, ACRIN will notify sites via email to move forward with the required test scans. If the test scans are approved, ACRIN will email a scanner specific qualification notification/report. If the test scans are not approved, the required technical corrections will be communicated (by email and/or phone) and another test scan, with the required corrections, should be submitted for review. Approval of the test scan(s) is mandatory prior to a site registering a participant onto the ACRIN 6698 trial. 2.6 Changes to Qualified Scanner(s) and/or Breast Coil Changes in the scanner or breast coil used to image I SPY 2 and/or ACRIN 6698 study patients should be reported immediately to the ACRIN Core Lab using the Imaging ACRIN 6698 Site Imaging Manual, Version 1.0 Page 5 of 11

Equipment Update Form (download from http://www.acrin.org/6698_protocol.aspx.). The addition of a new scanner or breast coil for study imaging will require full scanner qualification. Software and/or hardware upgrades to already qualified scanners will be reviewed by the ACRIN Imaging Core Lab to determine whether additional QC testing or test scans will be required. In either case, use of a new scanner/breast coil or software/hardware upgrades, sites should consult ACRIN prior to scanning study patients. 3.0 STANDARDIZED BREAST MRI Because acquisition protocols can vary significantly across institutions both the I SPY 2 and ACRIN 6698 studies make use of a standardized MR acquisition protocol. All breast MRI scans performed on ACRIN 6698 study patients should be performed per the I SPY 2 acquisition protocol with the exception of the DWI scan, which should be performed using the 4 b value DWI acquisition protocol provided below instead of the two b value I SPY 2 DWI acquisition protocol. Contact the ACRIN Imaging Core Laboratory with any questions regarding the imaging protocol. 3.1 Imaging Schedule All I SPY 2 and ACRIN 6698 imaging should be performed at the following time points, as defined in the I SPY 2 protocol. Figure 1. Schema MRI 1 6698 DWI Reproducibility DWI (If patient consented) MRI 2 6698 DWI Reproducibility DWI (If patient consented and not acquired with MRI 1) MRI 3 6698 DWI MRI 4 6698 DWI ACRIN 6698 Site Imaging Manual, Version 1.0 Page 6 of 11

3.2 Imaging Procedure As identified by the I SPY 2 protocol, the standardized MRI protocol includes a bilateral pre contrast T2 weighted sequence, a pre contrast diffusion weighted imaging (DWI) sequence, a pre contrast T1 weighted sequence, and a T1 weighted dynamic contrastenhanced (DCE) sequence. For I SPY 2 patients also enrolled to ACRIN 6698 the DWI sequence will be acquired using a diffusion weighted spin echo echo planar imaging (DW SE EPI) sequence with 4 b values. When setting up this acquisition protocol for the first time (e.g. for the qualification test scans) the protocol should be saved to the scanner s protocol menu under an easily recognizable name, such as ISPY2 or ACRIN 6698; this will help avoid future confusion about which imaging protocol to select. Please note that some facilities limit access to the system s protocol menu so this may require special user permissions. 3.2.1 Exam Preparations All MRI exams of the same patient must be performed on an ACRIN qualified scanner, using the same scanner (best practice) or the same scanner configuration (manufacturer, field strength, model, and breast coil model), and using the same contrast agent brand. Patients should be scanned prone and centered to the table. Place an intravenous catheter in the arm or hand prior to the start of imaging for contrast injection. Sites should adhere to standard clinical guidelines for the safe administration of contrast media (such as pre testing and contrast history). Please use universal MRI safety precautions. 3.2.2 DWI Acquisition Protocol The DWI scan must be acquired prior to the DCE sequence using a diffusionweighted spin echo echo planar imaging (DW SE EPI) sequence. Axial orientation Diffusion gradients in three orthogonal directions to measure isotropic ADC Parallel imaging (reduction factor > 2) Fat suppression utilizing the optimal technique (SPAIR, STIR, etc.) for the MRI scanner being used 4 b values: 0, 100, 600 and 800 s/mm 2 Acquire the maximum number of slices that can be acquired during a single acquisition (typically 24 30 slices). Coverage should be adjusted to keep the scan within a single acquisition to minimize scan time and motion artifacts. Total scan duration for the DWI sequence should be 4 6 minutes; for multi bvalue acquisition, should be on the order of 5 minutes. The required imaging sequences are outlined below in Table 2. Refer to Table 4 (on page 11) for detailed acquisition parameters. ACRIN 6698 Site Imaging Manual, Version 1.0 Page 7 of 11

Table 2. Acquisition Sequences: I SPY 2 / ACRIN 6698 MRI Protocol Localizer/Scout Pre contrast T2 weighted fast spin echo (FSE) or STIR Pre contrast DWI (DW SE EPI) Pre contrast 3D T1 weighted gradient echo (GE) 1 Post contrast dynamic multi phase 3D T1 weighted GE (DCE) 1 1 Pre and post contrast T1 weighted sequences MUST have identical image parameters to allow subtraction/maps. Transmit and receive gain settings should remain constant. Pre contrast T1 images should be checked prior to contrast injection to confirm acceptable fat suppression. 3.2.3 DWI Reproducibility Scan A subset of patients (approximately 60) will undergo a reproducibility DWI scan with MRI 1 (preferred) or MRI 2. For participating patients, two T2 (for DWI planning) and DWI sequences are to be acquired prior to injection of contrast for the DCE sequence. To simulate performance of an entirely distinct DW MRI exam, completely remove the patient from the scan table after the first DWI sequence, re position the patient on the table and re landmark, acquire a new localizer (scout), then acquire a full MRI exam per the standardized I SPY 2/ACRIN 6698 acquisition protocol. DO NOT end the exam session after the first DWI sequence as this will cause multiple exams to be created with the same accession number, which can complicate the image submission process. Rather, all sequences should be acquired within a single exam session. The required imaging sequences are outlined below in Table 3. Refer to Table 4 (on page 11) for detailed acquisition parameters. Table 3. Acquisition Sequences: DWI Reproducibility Sub Study Localizer/Scout Pre contrast T2 weighted fast spin echo (FSE) or STIR Pre contrast DWI (DW SE EPI) Remove patient from MRI scanner but DO NOT exit exam session Reposition patient in MRI scanner and start new series (same exam session) Localizer/Scout Pre contrast T2 weighted fast spin echo (FSE) or STIR Pre contrast DWI (DW SE EPI) Pre contrast 3D T1 weighted gradient echo (GE) 1 Post contrast dynamic multi phase 3D T1 weighted GE (DCE) 1 1 Pre and post contrast T1 weighted sequences MUST have identical image parameters to allow subtraction/maps. Transmit and receive gain settings should remain constant. Pre contrast T1 images should be checked prior to contrast injection to confirm acceptable fat suppression. ACRIN 6698 Site Imaging Manual, Version 1.0 Page 8 of 11

4.0 MANAGEMENT OF IMAGE DATA 4.1 Storage of Image Data Sites are expected to keep all study data, including study imaging, for at least 7 years after the trial closes. 4.2 Submission of Image Data to Core Lab All I SPY 2 and ACRIN 6698 imaging should be submitted to the ACRIN Imaging Core Lab via TRIAD within 48 hours of acquisition. Developed by the American College of Radiology, TRIAD provides a secure, web based method of transferring and managing image data. For questions related to TRIAD contact TRIAD Support by phone at 215 940 8820 or email TRIAD Support@acr.org. Additionally, the TRIAD Installation Guide and TRIAD Users Guide can be found online at https://triad.acr.org/learning.htm. Imaging for patients enrolled to both the I SPY 2 and ACRIN 6698 trials should be submitted via TRIAD under the ACRIN 6698 trial. I SPY 2 patients not enrolled to ACRIN 6698 should continue to be submitted via TRIAD under the I SPY 2 trial. 4.2.1 De identification of Images Sites are urged not to employ the use of other de identification software before uploading the images to TRIAD as these applications are typically not developed for research purposes and may remove data pertinent to the research. TRIAD removes patient information and replaces it with site and study specific identifiers provided by and at the site. The implementation of TRIAD anonymization is based on DICOM Supplement 142: Clinical Trial De Identification Profiles, ftp://medical.nema.org/medical/dicom/final/sup142_ft.pdf. 4.2.2 Image Transmittal Worksheet (ITW) An ACRIN 6698 ITW must be submitted for all imaging at the time of image submission. The ITW should be completed in full and submitted via email to ACRIN CoreLabData@acr.org. All current study documents can be found on the ACRIN 6698 web site, http://www.acrin.org/6698_protocol.aspx.). 5.0 QUALITY CONTROL (QC) 5.1 Study Imaging Sites are expected to acquire the MRI exams per the standardized MR acquisition protocol and review all imaging at the time of acquisition for basic image quality and compliance with the standardized acquisition protocol. MR technologists with any questions/concerns regarding image quality of the study MR, as performed, should consult their study radiologist(s) prior to the patient leaving to determine whether the exam should be repeated. ACRIN 6698 Site Imaging Manual, Version 1.0 Page 9 of 11

Upon receipt of the images at ACRIN, a QC review will be conducted by a qualified ACRIN Imaging Technologist (ACRIN IT). The QC review includes checking for: [a] missing images/sequences, [b] appropriate level of de identification, [c] complete anatomical coverage of the breast parenchyma, [d] absence of image artifacts, [e] scanner compliance (performed on qualified scanner, performed on same scanner or same scanner configuration), and [f] compliance with acquisition parameters. Missing or discrepant image data will be communicated to the site by the ACRIN IT via a Z5 Data Query. Queries will be emailed to the responsible site personnel for resolution. Sites are expected to resolve data queries expeditiously. Queries not resolved within 7 business days will be categorized as overdue data. All study imaging will undergo an additional quality review as part of the central review and image analysis process conducted by the UCSF Breast MRI Research Laboratory. 5.2 DWI Phantom Test For each qualified scanner, sites are required to conduct DWI phantom tests every 6 months using the same phantom and testing procedures used for the qualification testing. The DWI Phantom Test Instructions is available for download from the ACRIN 6698 web site, http://www.acrin.org/6698_protocol.aspx. The purpose of the phantom test is to provide a standardized, quantitative process to confirm ongoing MRI system performance in acquisition of diffusion weighted (DW) images of the breast. ACRIN will identify a testing schedule for each site based on the approval date of the site qualification testing. All phantom imaging should be submitted to the ACRIN core lab via TRIAD under the ACRIN 6698 study (versus I SPY 2). ACRIN 6698 Site Imaging Manual, Version 1.0 Page 10 of 11

Table 4. Standardized I SPY 2 and ACRIN 6698 MRI Acquisition Parameters Parameter T2 weighted DWI T1 weighted Sequence type FSE or STIR DW SE EPI GE 2D or 3D sequence 2D 2D 3D Slice orientation Axial or sagittal Axial Axial Laterality Bilateral Bilateral Bilateral Frequency direction A/P A/P A/P Phase direction R/L (axial) R/L R/L S/I (sagittal) FOV frequency 260 360 mm (axial) 260 360 mm (a) 260 360 mm 180 220 mm (sagittal) FOV phase 300 360 mm (axial) 300 360 mm (a) 300 360 mm 180 220 mm (sagittal) Matrix frequency 256 512 128 192 384 512 (acquired) Matrix phase (acquired) 256 128 192 256 Reconstruction Matrix 512 x 512 256 x 256 512 x 512 In plane resolution 1.4 mm 1.7 2.8 mm 1.4 mm Fat suppression Active fat sat recommended Active fat sat Active fat sat recommended TR 2000 10000 ms > 4,000 ms 4 10 ms TE 70 140 ms (STIR 70 ms) Minimum (50 100ms) Minimum (fat/water in phase preferable) Echo Train Length 16 N/A N/A TI (STIR sequence) 170 ms (1.5T) N/A N/A 230 ms (3.0T) Flip Angle 90 degrees 90 degrees 10 20 degrees Readout Bandwidth N/A N/A Maximum (per pixel) b values N/A 0, 100, 600, 800 s/mm 2 N/A Slice thickness (acquired) 4 mm 4 5 mm 2.5 mm # of slices Variable; complete bilateral coverage Variable; bilateral coverage; adjust to keep 60; complete bilateral coverage w/in single acquisition Slice Gap 1.0 mm No gap No gap Parallel imaging factor 2 >2 2 # of excitations/averages 2 >2 2 k space ordering N/A N/A k to +k standard, non centric Sequence acquisition time 7 minutes 4 6 minutes (multi b seq ~ 5 min) 80 sec scan time 100 sec Total post contrast imaging duration N/A N/A 8 minutes following injection (a) Adjust up to 400 mm to accommodate for large body habitus if necessary. ACRIN 6698 Site Imaging Manual, Version 1.0 Page 11 of 11