1. Volumetric Multimodality Imaging and Planning Data: A Challenge for Cooperative Group Clinical Trials James A. Purdy, Ph.D. Professor and Director Division of Radiation Physics Department of Radiation Oncology Washington University School of Medicine St. Louis, Missouri, USA Evolving Strategies in Radiation Oncology Rome, Italy, June 3-5, 2004

2. What is the Advanced Technology Consortium (ATC)? April 1992 3DQA Center established at WU-St. Louis to provide QA for RTOG 3DCRT trials. May 1993 RTOG & 3DQA Center (ITC) awarded NCI grant for Operation/ Statistical Center for prostate dose escalation study (3DOG, became RTOG 94-06). April 1999 NCI funded two Advanced Technology QA Centers l 3DQA Center (with sub-contracts to RPC, QARC, and RTOG) l Resource Center for Emerging Technology (RCET) at the University of Florida

3. What is the Advanced Technology Consortium (ATC)? In July 2002, NCI funded an Advanced Technology QA Consortium capitalizing on existing infrastructure and strengths of national QA programs l Image-Guided Therapy Center (ITC – Washington University in St. Louis) l Resource Center for Emerging Technologies(RCET – University of Florida in Gainesville) l Radiological Physics Center (RPC – M.D. Anderson Cancer Center) l Radiation Therapy Oncology Group (RTOG) l Quality Assurance Resource Center (QARC)

4. Advanced Technology QA Consortium (ATC) New consolidated approach will help eliminate duplication of developmental effort and facilitate sharing of QA resources among cooperative groups. ATC will help ensure that appropriate and uniform QA procedures and criteria are developed for advanced technology trials across all cooperative groups.

5. ATC ’ s Mission Developmental efforts: ­ electronic data exchange of digital planning data between ATC QA Centers and protocol participating institutions; ­ web-based software tools to facilitate protocol digital data submissions and QA reviews by RTOG, QARC, and RPC; ­ archival treatment planning & QA databases that can be linked with the cooperative group’s clinical outcomes database. Service efforts: - assist in protocol development, manage/facilitate protocol digital data submissions, credentialing, QA review, and data analysis.

6. ATC WEB SITE http://atc.wustl.edu T2 forms (document) QA Guidelines (by protocol) Dry Run Test Guides Facility Questionnaires Data submission checklists Links to RTOG for protocol information

7. Question: What’s different about these type studies? Answer: Digital Data Submission; Remote Review Primary data (patient model, dosimetry) –Patient Volumetric Image (CT) –Structures: GTV, CTV, PTV, OAR –3-D Dose Distribution (including fractionation information) Secondary data (QA of primary data) l Beam/Source Geometry l Dose-Volume Histograms l Digital Simulator and Portal Images Typical Data Set per Patient ~ 100 MB

8. DVHs alone are not sufficient Different dose distributions throughout an organ may lead to different expectations of toxicity for some organs. Loss of Spatial Information in DVHs Why not just collect the DVH data? Need to link treatment planning data to clinical outcomes (Evaluating response statistics and developing dose-response models).

9. Historical Review: RTOG Data Exchange Format Originated with: –AAPM Report #10 Used and/or modifed by: –NCI Particle Beam CWG –NCI External Photon Beam CWG –NCI External Electron Beam CWG –Image-Guided Therapy QA Center

10. ATC Method 1: Digital Data Submissions to ATC (current ITC Method) Fed-Ex, etc. CD-R Participating Institution ITC RTP System RTP System / TPV Database Tape ITC QA Database RRT Web Server Data Submission Workstation FTP Client/ DICOMpiler FTP DICOM Pt 10 files RTOG format RTOG / DICOM FTP Server QA Data- base UI RRT RTOG HQ RRT Study Chair

11. (current ITC Method) ATC Method 1: Remote QA Review (current ITC Method) RTP System / TPV Database ITC QA Database RRT Web Server QA Data- base UI RRT RTOG HQ RRT Study Chair Remote Review Tool (RRT)

12. QA REVIEW Dosimetry QA review - Prescription compliance - Dose heterogeneity - Score 1: 100% of PTV2 receives prescription dose (no variation) - Score 2: At least 95% of PTV2 receives prescription dose (minor variation) - Score 3: Less than 95% of PTV2 receives prescription dose (major variation)

13. 1861 complete digital data sets submitted over past 10 year period 11 commercial RTP systems have implemented export capability 130+ institutions able to submit data

14. ATC Method 1 FTP Server Data Upload Volume

15. Digital Data Exchange Status http://atc.wustl.edu/credentialing/atc_compliant_tps.html Compliant 8/8/2003 Compliant 8/11/2003 Compliant 10/6/2003 Compliant 3/15/2004

16. Data Exchange Technical Workshops For RTP Vendors Mar 10, 1995, St. Louis: Implementation of RTOG Data Exchange standard. Sep 10-11, 1999, St. Louis: Implementation of RTOG Data Exchange standard (prostate brachy). March 16-17, 2001, St. Louis: Implementation of DICOM 3.0 standard. March 16, 2002, St. Louis: Implementation of DICOM 3.0 standard. May 3, 2003, St. Louis: Implementation of DICOM 3.0 standard. April 14, 2004, St. Louis: Implementation of DICOM 3.0 standard. (followed by a WG7 meeting)

17. ATC DICOM Assistance for Vendors Vendors submit DICOM datasets to ITC via FTP or media ITC imports the datasets into pseudo-protocols per vendor Vendors evaluate correctness of data transfer using ITC’s Remote Review Tool (RRT) l CT, Structures, and Dose (Dose Array and DVH) For RT Plan validation, screensnaps are sent to vendor

18. Continuing Challenges Data Exchange - RTP Vendors Group Chairs Site Committee Chairs Study Chairs Physicians, Physicists RTP Vendors Imaging Vendors ATC

19. Other Vendors DICOM Status with ATC DICOM implementations working with ATC, but not yet ATC approved: l Nucletron Plato HDR l Varian BrachyVision l Nomos Corvus l Siemens Dosimetrists Workspace (CT simulator) l Siemens KonRad RTP system l Others

20. ATC Method 2 : Digital Data Submissions to ATC (in development) RCET NetSys/WebSys (IJROBP 57, 1427-1436, 2003) ITC Remote Review Tool

21. ATC Method 2 : Digital Data Submissions to ATC (in development) Participating Institution ITC RTP System RTP System / TPV Database ITC QA Database RRT Web Server RRT / Image viewer RRT / Image viewer Data Submission Workstation WebSys Client RTOG / DICOM WebSys / NetSys Server (Production) RTOG HQ Study Chair Diagnostic, Tx Verif. Imager DICOM WebSys / NetSys Server (Backup/ Developmental) Data Center Web Server (Backup) RCET Data Center Web Server HTTP, SOAP WebSys Client / NetSys Client WebSysNetSys WebSys 1 2 3 4

22. ATC Method 2 Data Import Import of diagnostic and treatment verification images to Image Viewer database Required to build thumbnail images and database entries for Image Viewer Currently accomplished by WebSys download, NetSys upload RCET to develop automated import mechanism Import of treatment planning images and data to Remote Review Tool database Convert submitted CTs, Structures, Doses, DVHs in DICOM or RTOG to local treatment planning system format Data QA / consistency check is important for immature DICOM implementations ITC to integrate RRT with WebSys database 2 3

23. Use NetSys Data Center to review diagnostic CT, MR, PET images and verification images Use RRT to review TV/OAR contours, dosimetry Method 2 (in development): Remote QA Review

24. ATC Digital Data Submission Server Web page (provides links to): ATC Digital Data Submission Server Web page (provides links to): –WebSys – secure upload/download –RRT – image segmentation and dosimetry review –Rapid Image Viewer (diagnostic image display) ATC Method 2 : Digital Data Submissions to ATC (in development)

25. ATC Method 2 Testing / Server Development Method 2 data submission testing has been carried out in conjunction with the deployment of a production ATC Data Submission Server located at ITC. Attempts to upload and download COG test data sets from the ATC server constitute the first full-scale test of the NetSys server software. –These test have been helpful in identifying implementation errors in the NetSys database and DICOM import/export mechanism. –By providing realistic data sets and a meaningful test protocol, the COG test process has greatly accelerated the correction of these errors. –The first apparently successful submission and retrieval of both DICOM RT objects and RTOG data sets between ITC and the RCET server occurred on December 2, 2003. Since that time, additional bugs have been identified and corrected.

26. ITC QA Database Existing Database –Data QA (timeliness, completeness, evaluability) –Organ-at-risk/target-volume QA –Dose-volume analysis Protocol-dependent Automatic import from treatment planning data –Treatment delivery record –Problem/correspondence log Need to scale for many new protocols!

27. Mechanisms for Data Sharing Export of RTOG Data Exchange format data for secondary analysis at M.D. Anderson (Tucker, et al.) Dose-volume analysis data from ITC QA database exported to RTOG statisticians for various outcomes studies. WebSys client provides for controlled, secure download of case data (DICOM or RTOG Data Exchange format). Computational Environment for Radiotherapy Research (CERR, Deasy) can be used to import DICOM or RTOG data, visualize interactively, and save as Matlab data sets.

28. ATC Supported Clinical Trials RTOG 94-06: Phase I/II Prostate 3DCRT (closed, data analysis) RTOG 93-11: Phase I/II Lung 3DCRT (closed, data analysis) RTOG 98-03: Phase I/II GBM 3DCRT RTOG H-0022: Phase I/II Oropharyngeal IMRT RTOG L-0117: Phase I/II Lung 3DCRT RTOG P-0126: Phase III Prostate 3DCRT/IMRT RTOG H-0225: Phase I/II Nasopharyngeal IMRT RTOG P-0232: Phase III Prostate Brachy Seed RTOG 0319: Phase I/II Breast 3DCRT Irradiation Confined to Lumpectomy Cavity

29. ATC Supported Clinical Trials (Pending) l RTOG 0236: Phase II Extracranial Stereotactic Radioablation in Treatment of Patients with Medically Inoperable Stage in NSCLC. l RTOG 0238: A Phase I/II Study of Gross Tumor Volume Definition with or without Pet Fusion for Patients with Non-Small Cell Lung Carcinoma. l RTOG 0245: Phase I/II Highly Conformal Radiation Therapy for Patients with Unresectable Liver Metastases. l RTOG 0321: Phase I/II Prostate: High Dose Brachytherapy and External Beam. l NSABP B39/RTOG 0413: Phase III Study of Whole Breast RT versus Partial Breast Irradiation.

30. How to Participate in an ATC Supported Clinical Trial 3DCRT and IMRT protocols: – Submit completed Facility Questionnaire (only available from ATC website) to the ITC. – Successfully complete protocol specific Dry Run test through ATC – IMRT protocols only: in addition to above two items, successfully complete phantom experiment. Dosimetry data to RPC Digital phantom plan data to ITC

31. FACILITY QUESTIONNAIRE 3DCRT or IMRT Two formats – Microsoft Word, or – Adobe Acrobat (PDF) – Soon to be web-based Identifies key personnel and information on treatment planning and delivery systems and QA procedures Get current version only from ATC web site Physicist will have to assist in completion

32. T2 FORM Documents digital data submitted to ITC Also provides information that can not be attained digitally Form acquired from ATC web site Should not be sent until digital submission has been accomplished Soon to be online web form

33. DRY RUN TEST The Dry Run Test is intended to demonstrate: –Digital patient data exchange capability –Understanding of protocol requirements Tumor/target volumes Critical structures Dose prescription Identical to an actual case for planning and submission excepting verification films and actual treatment.

34. Protocol Design, Credentialing, QA,… Dry Run test serving as an educational resource to the nation’s clinical trial cooperative groups and participating institutions Incorrect Contouring for 0319 –Breast incorrect –PTV incorrect Corrected contouring after feedback from ITC

35. RTOG 0022 Dry-Run 18 institutions have passed the Dry-Run requirement 1 institution achieved no deviation 17 institutions achieved minor deviation Parotid sparing 13 institutions achieved no deviation 5 institutions achieved minor deviation Number of submissions it took to meet credentialing guidelines 1 submission: 6 institutions 2 submissions: 9 institutions 3 submissions: 3 institutions

36. RPC IMRT Phantom Test RPC tests ability of each RTOG institution to deliver IMRT by asking facility to: – Scan RPC phantom (CT, MRI, etc.) – Generate an IMRT plan according to defined protocol – Deliver treatment to phantom – Return phantom and dosimeters to RPC for evaluation. – Submit digital planning data to the ITC for future comparisons TLDs

37. RPC IMRT Phantom Test RPC uses ITC Remote Review Tool to analyze phantom dosimetry data:

38. IMRT H&N Phantom Results TLD and Film results 52 institutions have received phantom 34 institutions have passed criteria (±7%/ ±4mm) 13 institutions still trying to pass 4 first-time institutions under analysis or in mail 1 institution will not re-irradiate 12 failures-TLD dose (±7%); 8 failures-displacement (±4 mm)

40. Institution Approval Letter for RTOG – 0022 & 0225

41. J. Michalski, K. Winter, et al, presented at 2003 ASTRO Months at Risk Frequency RTOG 9406 Dose Level V (78 Gy, 2Gy/fx), Disease Group 1, Late Grade 3+ Toxicity p=0.0042 Expected based on RTOG 7506&7706

42. Protocol Design, Credentialing, QA,… ATC Interactions with Cooperative Groups other than RTOG ATC Interactions with Cooperative Groups other than RTOG –COG –PBTC –NCIC –NSABP

43. ATC INTERACTIONS - ATC INTERACTIONS - WORLD-WIDE JCOG EORTC ATC EORTC ( Dr. Bernard Davis, UniversitätsSpital Zürich at ASTRO) JCOG ( Dr. Satoshi Ishikura, National Cancer Center Hospital East, Kashiwa, Japan)

44. Challenges for ATC Supported Clinical Trials HDR Brachytherapy –No ATC compliant RTP systems –RTOG 0321 in development –NSABP/RTOG partial breast irradiation protocol in development

45. Challenges for ATC Supported Clinical Trials Stereotactic Radiosurgery and Radiotherapy –No ATC compliant stereotactic RTP systems –RTOG Lung 0236 in development –RTOG Liver 0245 in development

46. New Challenges for ATC Supported Clinical Trials PET (Quantitative) Image fusion QA –RTOG Lung 0238 in development Courtesy J. Bradley, M.D.

47. New Challenges for ATC Supported Clinical Trials Adaptive Radiotherapy, Image-Guided Therapy (Cone beam CT, Helical Tomotherapy) Daily Confirmation and Adjustment –On-Board Imaging (EPID, Cone Beam CT) Elekta Synergy System

48. New Challenges for ATC Supported Clinical Trials 4-D CT (several 100 MB) Time -> Moving Ball “Light Breathing” Courtesy G. Chen, Ph.D.

49. New Challenges for ATC Supported Clinical Trials 4-D CT (several 100 MB) Std light breathing scan0% Phase of 4D scan

50. SUMMARY AND CONCLUSIONS The ATC continues to pioneer the submission of digital data for clinical trials by fine-tuning the established Method 1 (FTP upload), while completing the development, testing, and deployment of Method 2 (WebSys secure upload to ATC Production Server). The ATC is working with RTP manufacturers and urging them to give the highest priority to implementing digital data submission capability on their systems.

51. SUMMARY AND CONCLUSIONS ATC has provided RTOG the unique ability to conduct 3DCRT, IMRT, and prostate brachytherapy clinical trials in which volumetric 3D treatment planning digital data is collected, reviewed, analyzed, and linked to clinical outcomes –over 1800 data sets have been successfully submitted. ATC is now in a strong position to extend these capabilities to other cooperative-groups planning to conduct advanced-technology clinical trials.

52. Thank you for your attention.