4D radiotherapy aims to account for tumor motion during radiation therapy by acquiring CT images over multiple phases of the breathing cycle (4D CT imaging) and using this information for treatment planning and delivery. It allows for more accurate targeting of tumors in organs affected by respiratory motion like the lungs. While 4D radiotherapy provides advantages over existing motion management techniques, there are still technological challenges and limitations like complexity, treatment time, and residual motion. Future work includes addressing these issues and further integrating 4D techniques with other advances in radiation oncology.

1. 4D Radiotherapy Paul Keall Virginia Commonwealth University

2. Outline Medical rationale Basic science and technology State-of-the-art Future needs, directions and opportunities Advice …

3. Medical rationale What is the purpose of your research?

4. What do we know? Where the ‘visible’ tumor is To within 1 cm (on day of imaging study) Where the microscopic tumor extends to To within 1 cm Where the patient’s skeleton is wrt the radiation beam To within 1 cm What the shape of the tumor is To within 1 cm Where the tumor is wrt the skeleton To within 2 cm

5. What can we do about it? Reduce the uncertainties Improved/functional imaging Ongoing commitment to education Daily 2D/3D imaging Monte Carlo dose calculation/optimization Intrafraction motion Develop methods to account for residual uncertainties Incorporate uncertainties into planning process Probabilistic planning Online planning

6. Why 4D? Chemo-response GI motion Inter-observer differences Tumor growth Tumor shrinkage Tumor spread Reoxygenation Repair Repopulation Redistribution Vascular growth Weight loss Cardiac motion Hormone response Diet Bladder filling Rectal filling Intra-observer differences Skeletal motion Respiratory motion Weight gain Respiratory motion

7. Respiratory motion affects: All tumor sites in the thorax and abdomen Lung cancer alone: 173 770 new cases in 2004 (ACS) 160 440 deaths (28% of cancer deaths) 15% five-year survival Evidence of tumor dose response 50%/30 month LPFS at 85 Gy (Martel et al ) Strong evidence of lung dose response (many 100+ patient studies)

8. Problems of respiratory motion in radiotherapy

9. The tumor moves with time

10. Distorted images, incorrect anatomical positions, volumes or shapes Conventional With gated imaging Keall et al Aust Phys Eng Sci Med 2002 Tumor

11. Treatment Planning: Large margins are added to the clinical target volume Increases normal tissue dose and limits target dose PTV CTV Conventional With gating CTV PTV

12. IMRT Delivery: Interplay between anatomy and MLC leaf motion leads to motion artifacts Dose Position Planned dose Delivered dose

13. Basic science and technology What is the underlying scientific/technological basis of your research?

14. “ The explicit inclusion of the temporal changes in anatomy during the imaging, planning and delivery of radiotherapy” What is 4D radiotherapy? 4D Radiotherapy Panel ASTRO 2003

15. The 4D radiotherapy process 4D Radiotherapy 4D CT Imaging 4D Treatment Planning 4D Treatment Delivery Acquisition of a sequence of CT image sets over consecutive phases of a breathing cycle The explicit inclusion of the temporal changes in anatomy during the imaging, planning and delivery of radiotherapy Designing treatment plans on CT image sets obtained for each phase of the breathing cycle Continuous delivery of the 4D treatment plans throughout the breathing cycle

16. 4D Radiotherapy I: 4D CT Imaging

17. 4D CT imaging

18. 4D CT images Vedam et al PMB 2003 48:45-62 8 respiratory phases Peak inhale Early inhale Mid inhale End inhale Peak exhale Early exhale Mid exhale Late exhale

20. 4D Radiotherapy II: 4D Planning

21. 4D Planning Flow Chart Acquire 4D CT Define anatomy Create/adjust treatment plan Evaluate dose distribution 1 4 3 2 Proceed to treatment 6 … Plan acceptable? No Yes Deformable registration … Automated planning … Deformable registration 5

22. 4D PTVs

23. BEVs 3D BEV 4D BEV

24. 3D (solid) vs 4D (dashed) DVHs

25. 4D Radiotherapy III: 4D Delivery

26. 4D radiotherapy delivery

27. MLC leaf motion 3D 4D Keall et al PMB 2001 46:1-10

28. MLC leaf motion 3D IMRT 4D IMRT

29. Tracking motion perpendicular and parallel to the MLC

30. Finite response time- need motion prediction

31. Respiratory motion causes problems during the imaging, planning and treatment stages of radiotherapy Several methods have been proposed to address respiratory motion 4D radiotherapy has some advantages over existing methods There are still many unanswered questions … 4D radiotherapy summary

32. State-of-the-art How does your research fit into the overall scheme of medical research?

33. Respiratory motion solutions Breath-hold techniques (ABC/DIBH) Uncomfortable for patients, limited applicability (MSKCC: 7/13 patients) Increases treatment time (MSKCC: 17 to 33 minutes for conventional RT) Respiratory gating Residual motion within gating window Increases treatment time Baseline shift 4D Radiotherapy Hardware/Software complexity

34. Future needs, directions and opportunities What is currently limiting your research or what change in direction do you anticipate in the future?

35. Limitations Ethics/IRB Length of grant review cycles Industry support We need them unless resource and time unlimited Why isn’t my project the highest priority? Distractions

36. Directions Incorporate recent scientific and technical developments Greater scope More general More scientifically rigorous Integrate with concurrent internal and external programs

37. Opportunities Many problems to solve Many different ways to solve problems

38. NCI Roadmap A focus on the following initiatives will move the work of NCI through the process of discovery, development, and delivery toward the goal of eliminating suffering and death from cancer by 2015 …

39. Advice

40. 1999 $4500 VCU faculty grant-in-aid 2001 $20 000 ACS Inst. Research Grant 2002 $1.5 million NCI grant 2003 $400 000 industrial grant 2003 Co-I $1 million NCI grant 2004 Consultant $1 million NCI grant 2004 Co-I STTR … How did you get started?

41. Why get a grant? Promotion Tenure Independence Invitations Staff Resources Travel Intangibles

42. What advice can you give? Write early Write often Work hard Work smart Think broadly Good luck

43. And get a great team! Ted Chung Rohini George Sarang Joshi Vijay Kini Radhe Mohan Jeffrey Siebers Sastry Vedam Krishni Wijesooriya Jeffrey Williamson ACS NIH MDACC MGH Philips Medical Systems Standard Imaging UNC Varian Medical Systems

44. Another great team!