Simulation Software in Bio-Medical Research: Applications and Results

1. …with contributions from many users Simulation software: applications and results in the bio-medical domainFrom HEP computing to bio-medical research and vice versa Maria Grazia Pia INFN - Sezione di Genova, Italy S. Agostinelli, S. Chauvie, G. Cosmo, F.Foppiano, S. Garelli, F. Marchetto, P. Nieminen, P. Rodrigues, R. Taschereau, A. Trindade, M. Tropeano VII International Conference on Advanced Technologies and Particle Physics Como, 16 October 2001

2. Globalisation Sharing requirements and functionalities across diverse fields

3. Requirements for LowE p in • UR 2.1The user shall be able to simulate electromagnetic interactions of positive charged hadrons down to < 1 KeV. • Need: Essential • Priority: Required by end 1999 • Stability: T. b. d. • Source: Medical physics groups, PIXE • Clarity: Clear • Verifiability: Verified

4. LowE Hadrons and ions OOAD…

5. Geant4 LowE Working Group …and validation Experimental data: Bragg peak Test set-up at PSI • data O simulation INFN-Torino medical physics group Courtesy of R. Gotta, Thesis

6. Chandra X-ray Observatory Status Update September 14, 1999 MSFC/CXC CHANDRA CONTINUES TO TAKE SHARPEST IMAGES EVER; TEAM STUDIES INSTRUMENT DETECTOR CONCERN Normally every complex space facility encounters a few problems during its checkout period; even though Chandra’s has gone very smoothly, the science and engineering team is working a concern with a portion of one science instrument. The team is investigating a reduction in the energy resolution of one of two sets of X-ray detectors in the Advanced Charge-coupled Device Imaging Spectrometer (ACIS) science instrument. A series of diagnostic activities to characterize the degradation, identify possible causes, and test potential remedial procedures is underway. The degradation appeared in the front-side illuminated Charge-Coupled Device (CCD) chips of the ACIS. The instrument’s back-side illuminated chips have shown no reduction in capability and continue to perform flawlessly. Courtesy of R. Nartallo, ESA What could be the source of detector damage? Radiation belt electrons? Scattered in the mirror shells? Effectiveness of magnetic “brooms”? Electron damage mechanism? - NIEL? Other particles? Protons, cosmics? XMM-Newton

7. CCD displacement damage: front vs. back-illuminated. EPIC 30 mm Si  ~1.5 MeV protons RGS 2 mm 30 mm 2 mm 30 mm Active layerPassive layer “Electron deflector” Courtesy of ESA Space Environment & Effects Analysis Section Low-E (~100 keV to few MeV), low-angle (~0°-5°) proton scattering

8. What happened next? XMM was launched on 10 December 1999 from Kourou EPIC image of the two flaring Castor components and the brighter YY Gem Courtesy of

9. …and the other way round

10. Low energy e, g extensions Cosmic rays, jovian electrons …were triggered by astrophysics requirements X-Ray Surveys of Planets, Asteroids and Moons Solar X-rays, e, p Geant3.21 ITS3.0, EGS4 Courtesy SOHO EIT Geant4 Induced X-ray line emission: indicator of target composition (~100 mm surface layer) C, N, O line emissions included Courtesy ESA Space Environment & Effects Analysis Section

11. Fe lines GaAs lines Scattered photons Low Energy Processes: e,g 250 eV up to 100 GeV • Based on EPDL97, EEDL and EADL evaluated data libraries • cross sections • sampling of the final state

12. Photon attenuation: vs. NIST data Testing and Validation by IST - Natl. Inst. for Cancer Research, Genova Pb water Fe Courtesy of S. Agostinelli, R. Corvo, F. Foppiano, S. Garelli, G. Sanguineti, M. Tropeano

13. …the first user application Titanium encapsulated 125I sources in permanent prostate implants Exploiting X-ray fluorescence to lower the energy spectrum of photons (and electrons) and enhance the RBE 10 keV electron in water GEANT4 R. Taschereau, R. Roy, J. Pouliot Centre Hospitalier Universitaire de Quebec, Dept. de radio-oncologie, Canada Univ. Laval, Dept. de Physique, Canada Univ. of California, San Francisco, Dept. of Radiation Oncology, USA keV/µm Terrisol Distance (nm)

14. …and the same requirements in HEP too • Similar requirements on both low energy e/g and hadrons, K-shell transitions etc. from “underground” HEP experiments collected ~1 year later • Recent interest on these physics models from LHC for precision detector simulation • They profit of the fact that the code • does already exist, • has been extensively tested • and experimentally validated by other groups

15. A lesson to learn Open mind… What may look far from the scope of HEP today, may be required as an essential functionality tomorrow

16. What can HEP propose? Tools Methodologies

17. Specific facilities controlled by a friendly UI Advanced functionalities in geometry, physics, visualisation etc. A rigorous software process Extensibility to accomodate new user requirements (thanks to the OO technology) What in a simulation software system is relevant to the bio-medical community? Quality Assurancebased on sound software engineering The transparencyof physics Independent validation by a large user community worldwide Use of evaluated data libraries User supportfrom experts Adoption of standardswherever available (de jure or de facto)

18. Geant4 Geant3 data shell effects Physics requirements Bragg peak Many new physics features w.r.t. Geant3 Fundamental also to HEP/astroparticle experiments e, down to 250 eV (EGS4, ITS to 1 keV, Geant3 to 10 keV) Hadron and ionelectromagnetic models based on Ziegler and ICRU data and parameterisations Based on EPDL97, EEDL and EADL evaluated data libraries New multiple scattering model • And much more: • fluorescence • radioactive decay • hadronic models • etc… • And many relevant functionalities in other domains too, not only physics! ions

19. with attention to UR Physics open to evolution facilitated by the OO technology Guidelines for physics From the Minutes of LCB (LHCC Computing Board) meeting on 21 October, 1997: “It was noted that experiments have requirements for independent, alternative physics models. In Geant4 these models, differently from the concept of packages, allow the user to understand how the results are produced, and hence improve the physics validation. Geant4 is developed with a modular architecture and is the ideal framework where existing components are integrated and new models continue to be developed.” The transparency of the physics implementation: fundamental for “sensitive”applications, such as medical ones

20. Geant4 architecture Domain decomposition hierarchical structure of sub-domains Uni-directional flow of dependencies Use of Standards • de jure and de facto Software Engineering plays a fundamental role in Geant4 • formally collected • systematically updated • PSS-05 standard User Requirements Software Process • spiral iterative approach • regular assessments and improvements • monitored following the ISO 15504 model • OOAD • use of CASE tools Object Oriented methods • essential for distributed parallel development • contribute to the transparency of physics • commercial tools • code inspections • automatic checks of coding guidelines • testing procedures at unit and integration level • dedicated testing team Quality Assurance

21. Applications Verification of conventional radiotherapy treatment planning (as required by protocols) Investigation of innovative methods in radiotherapy Radiodiagnostics

22. Brachytherapy Brachytherapy is a medical therapy used for cancer treatment Radioactive sources are used to deposit therapeutic doses near tumors, while preserving surrounding healthy tissues Strict protocols The IST group follows the direction of Basic Dosimetry on Radiotherapy with Brachytherapy Source of the Italian Association of Biomedical Physics (AIFB) Protocols require testing the treatment planning systems

23. Simulation Nucletron Data Transverse distance (mm) Distance along Z (mm) Depth (mm) Superficial brachytherapy Brachytherapy at the Natl. Inst. for Cancer Research (IST-Genova) Experimental validation Leipzig applicators Courtesy F. Foppiano, M. Tropeano

24. Endocavitary brachytherapy Especially for uterus, vagina and lung cancer Source anisotropy Treatment planning systems include algorithms to account for source anisotropy

25. Simulation Plato Data Simulation Plato Distance along X (mm) Distance along Z (mm) Role of the simulation: Longitudinal axis of the source Difficult to make direct measurements  rely on simulation to get better accuracy than conventional treatment planning software precise evaluation of the effects of source anisotropy in the dose Transverse axis of the source Comparison with experimental data  validation of the software Effects of source anisotropy Courtesy F. Foppiano, M. Tropeano

26. F() Source anisotropy Plato-BPS treatment planning algorithm makes some crude approximation ( dependence, no radial dependence) Courtesy of S. Agostinelli, R. Corvo, F. Foppiano, S. Garelli, G. Sanguineti, M. Tropeano, IST Genova Plato treatment planning

27. Photoelectric effect Ejection spectrum Ejection spectrum Fluence spectrum RBE enhancement of a 125I brachytherapy seed with characteristic X-rays from its constitutive materials Goal: improve the biological effectiveness of titanium encapsulated 125I sources in permanent prostate implants by exploiting X-ray fluorescence Compton Interaction Titanium shell (50 µm) Silver core (250 µm) Percentage 4.5 mm All the seed configurations modeled and simulated with Energy (keV) R. Taschereau, R. Roy, J. Pouliot Centre Hospitalier Universitaire de Québec, Dépt. de radio-oncologie, Canada Univ. Laval, Dépt. de Physique, Canada Univ. of California, San Francisco, Dept. of Radiation oncology, USA

28. 20 µm thick RBE … up to 300 µm Y Zr Nb Mo Ru Rh Element Shell experiments Results (RBE at 1 cm) 39  Z  45 Shell = molybdenum Up to 10% improvement Various materials and thicknesses studied with to replace the Ti shell Optimisation of RBE enhancement 50-60 mm shell Molibdenum R. Taschereau, R. Roy, J. Pouliot

29. RBE ++ tumors -- healthy tissues Distance away from seed Results of the study Enhanced RBE combined with relatively long half-life of iodine could mean higher cell kill • Possible to improve RBE • Applications • Prostate • Ocular melanoma • Coronary brachytherapy (where a highly localized dose distribution is desired) R. Taschereau, R. Roy, J. Pouliot

30. M.C. Lopes 1, L. Peralta 2, P. Rodrigues 2, A. Trindade 2 1 IPOFG-CROC Coimbra Oncological Regional Center - 2 LIP - Lisbon

31. Central-Axis depth dose curve for a 10x10 cm2 field size,compared with experimental data (ionization chamber) testing and validation Validation of phase-space distributions from a Siemens KD2 linearaccelerator at 6 MV photon mode identified as experimental problem M. C. Lopes 1, L. Peralta 2, P. Rodrigues 2, A. Trindade 2 1 IPOFG-CROC Coimbra Oncological Regional Center 2 LIP - Lisbon

32. Central-Axis depth dose Deviation at –6 cm identified as an experimental problem Comparison with commercial treatment planning systems M. C. Lopes 1, L. Peralta 2, P. Rodrigues 2, A. Trindade 2 1 IPOFG-CROC Coimbra Oncological Regional Center - 2 LIP - Lisbon CT-simulation with a Rando phantom Experimental data obtained with TLD LiF dosimeter CT images used to define the geometry: a thorax slice from a Rando anthropomorphic phantom Profile curves at 9.8 cm depth PLATO overestimate the dose at ~ 5% level

33. Beam plane Skull bone A more complex set-up Tumor M. C. Lopes1, L. Peralta2, P. Rodrigues2, A. Trindade2 1 IPOFG-CROC Coimbra Oncological Regional Center - 2 LIP - Lisbon Head and neck with two opposed beams for a 5x5 and 10x10 field size An off-axis depth dose taken at one of the slices near theisocenter PLATO fails on the air cavities and bone structures andcannot predict accurately the dose to tissue that is surrounded byair Deviations are up to 25-30%

34. Pixel ionisation chamber Relative dose in water CT interface + fast/full simulation Many other applications and new projects • Use GEANT4 to obtain digitally reconstructed radiographs (DRRs), including full scatter simulation • This represents a great improvement over approaches based on ray-casting • Hadrontherapy studies • In vivo dosimetry (mammography, colonscopy), • Superposition and fusion of anatomic and functional images • PET • Intra-operatory radiotherapy • etc. Also theoretical developments to improve the evaluated data libraries

35. http://www.ge.infn.it/geant4/dna/ -DNA Study of radiation damage at the cellular and DNA level in the space radiation environment (and other applications, not only in the space domain) • Relevance for space: astronaut and airline pilot radiation hazards, biological experiments • Applications in radiotherapy, radiobiology... Multi-disciplinary Collaboration of • astrophysicists/space scientists • particle physicists • medical physicists • computer scientists • biologists • physicians 5.3 MeV  particle in a cylindricalvolume. The inner cylinder has a radius of 50 nm. Prototyping

36. Courtesy A. Brahme (KI) User Requirements • It is a complex field • ongoing active research • Complexity increased by the multi-disciplinary nature of the project • no one masters all the scientific components (biology, chemistry, physics etc.) A rigorous approach to the collection of the requirements is essential A challenge for problem domain analysis and design!

37. What benefits for HEP? • Identification of requirements of common interest • Contribution to sharper requirement specification • … User requirements Testing • Substantial contributions from medical groups Feedback from usage in diverse environments • Improves the quality and robustness of the code Discipline of strict protocols • Contribution to software process improvement • Incentive to better quality assurance methods • Profit of other fields’ experience in software process for reliable products Technology transfer is a helpful argument with funding agencies for supporting HEP

38. The www was born from HEP… Geant4 in every hospital?

39. Savona in Savona Brachytherapy at the Hospital of Savona • A project in progress for the simulation with of brachytherapy 125I sources for prostate cancer therapy • Calibration • Precise dose distribution • installed on the PC of the Medical Physics Service of the Hospital

40. Meditations… • HEP computing has a potential for technology transfer • not only the WWW… • not only Geant4… • The role of HEP: expertise, but also reference • Physics and software engineering expertise • Reference to many small groups and diverse activities • Technology transfer: collaboration rather than colonisation • Valuable contributions from the medical domain (requirements, testing, rigorous methodologies…) • New resources into projects of common interest • Plenty of valuable applications and results

41. Thanks! • ESA/ESTEC (R. Nartallo, P. Nieminen) • INFN Cosenza (E. Lamanna) • INFN Torino (S. Chauvie, R. Gotta, F. Marchetto, V. Rolando, A. Solano) • IST (S. Agostinelli, R. Corvo, F. Foppiano, S. Garelli, G. Sanguineti, M. Tropeano) • LIP (P. Rodrigues, A. Trindade) • Univ. Laval / UCSF (R. Taschereau) • PSI (N. Crompton, P. Juelke) • Savona Hospital (G. Ghiso, R. Martinelli) • Geant4 medical users (impossible to mention all…) • Geant4 Collaboration • CERN (G. Cosmo, S. Giani, J. Knobloch)