1. Radiation Oncology

2. “ What’s the big deal about radiotherapy in cancer clinical trial design?”

4. The treatment of cancer with ionising radiation is called Radiotherapy (RT) or Radiation Oncology. External RT + Intensity Modulated Radiotherapy (IMRT) Phillipe Lambin 180º 310º 217º Brachytherapy Radiosurgery - Stereotactic RT Particle therapy with Protons or light ions

5. The Evolution of Radiation Therapy High resolution IMRT Multileaf Collimator Dynamic MLC and IMRT 1960’s 1970’s 1980’s 1990’s 2000’s Cerrobend Blocking Electron Blocking Blocks were used to reduce the dose to normal tissues MLC leads to 3D conformal therapy which allows the first dose escalation trials. Computerized IMRT introduced which allowed escalation of dose and reduced compilations Functional Imaging IMRT Evolution evolves to smaller and smaller subfields and high resolution IMRT along with the introduction of new imaging technologies The First Clinac Computerized 3D CT Treatment Planning Standard Collimator The linac reduced complications compared to Co60

6. Effect Tumor Dose Effect of underdosage and overdosage Late normal tissue damage Tumor control

10. Interpretation of radiotherapy trials: Radiotherapy outcomes are dependent upon technical factors Advice: Always perform Quality Assurance (QA) & particularly in phase III trials Phillipe Lambin

12. De Ruysscher et al. J Clin Oncol. 2006 Mar 1;24(7):1057-63.) Treatment Time: the SER (Start of any treatment to End of Radiation) Phillipe Lambin

15. Multi-leaf Collimator

16. Multileaf Collimator in LINAC

19. Image-guidance: The Next Generation

20. Advances in Radiation Therapy - The New Pyramid Early Period Current Period GTV Normal Tissue Precise localization Geographic miss BTV

21. Advances in Radiation Therapy - The Pyramid Early Period Current Period GTV Normal Tissue Precise localization Geographic miss

22. CTV CTV PTV PTV Without Imaging With Imaging CTV – volume containing disease PTV – volume that needs to be irradiated to ensure CTV is always treated Objectives of IGRT & Dynamic Targeting

25. Multi-Modality Radiation Trials

28. Cell Cycle

29. Radiobiologic principles of therapy. An understanding of the radiobiology that governs the interaction of ionizing radiation with living matter is the key to improving the therapeutic ratio in radiation oncology. A, Varying levels of sensitivity to radiation. It has been well known for decades that there are varying levels of sensitivity to radiation depending on the phase of the cell cycle that malignant cells are in when treatment occurs. ( Adapted from Sinclair)/ www.lungcancerslides.com

30. Radiation Survival Curve DMF = ratio of doses that give a particular level of cell kill

33. Effect Tumor Dose Therapeutic Gain Late normal tissue damage Tumor control

34. Seiwert T, Salama T, Vokes E; Nat Clin Pract Oncol. 2007 Feb; 4(2):86-100

37. Question # 1

38. Question # 2

39. Phase I Studies of Drugs and Radiation

51. Day 0 - Abnormal Day 1 and 2 – Normalized Normal Day 5 - Inadequate Jain, Nature Medicine (2001) Normalization Hypothesis Tong et al. (2003) VEGF Blockade Normalizes Tumor Vasculature

52. Radiation Dose, Gy Tumor control probability RAD + 1/2mAb + mAb 66.2 54.8 39.1 (59.6-73.6) (45.1-66.6) (31.7-48.1) (95% CI) 54A RAD + 1/2mAb + mAb 97.8 (85.3-112.0) 86.3 (74.6-99.8) 74.8 (63.7-87.7) U87 Anti-VEGF-R2 mAb enhances radiation therapy Kozin et al. Cancer Research (2001) RAD + 1/2mAb + mAb (95% CI) 80 60 40 20 0 0.00 0.25 0.50 0.75 1.00 TCD , Gy 50 140 120 100 80 60 40 20 0 0 TCD , Gy 50

54. Phase I Study Bevacizumab Bevacizumab EBRT 5-FU SURGERY cT3 or T4 Rectal Ca 7 weeks

57. Endoscopic IFP Measurements Mean IFP before and 12 days after the first AVASTIN infusion Interstitial fluid pressure (mmHg) Bars- SE, p<0.05 * * * *

58. Brown, A. P. et al. J Clin Oncol; 26:3987-3994 2008 Proposed clinical trial design to evaluate targeted agents in combination with radiation or other cytotoxic therapies