1) Radiation therapy has an emerging role in the multidisciplinary management of hepatocellular carcinoma (HCC) due to advances that allow higher radiation doses to be safely delivered to small liver volumes. 2) Stereotactic body radiation therapy (SBRT) shows promise for HCC but questions remain about safety, effectiveness for bridging to transplant, and downsizing lesions. 3) A pilot study is investigating the safety and feasibility of liver SBRT for HCC.

1. Role of Radiation Therapy in Multidisciplinary Management of Hepatocellullar Carcinoma Darlene Gabeau, M.D., Ph.D. Assistant Professor Department of Radiation Oncology Department of Radiation Oncology

2. HCC : Standard Treatment Algorithm Barcelona Clinic Liver Cancer System Llovet, J. M. et al. J. Natl. Cancer Inst. 2008 100:698-711

3. HCC : Standard Treatment Algorithm Barcelona Clinic Liver Cancer System Llovet, J. M. et al. J. Natl. Cancer Inst. 2008 100:698-711

4. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25%

5. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80%

6. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50%

7. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60%

8. Eligibility criteria: 1 lesion  5 cm or  3 lesions/< 3 cm Long wait list  interim tumor progression  >20% dropout HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60%

9. Eligibility criteria: 1 lesion  5 cm or  3 lesions/< 3cm Long wait list  interim tumor progression  >20% dropout HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60% Might radiation therapy have a role: Tumor downsizing? Bridge to transplant?

10. Radiation Therapy: Important therapeutic modality Used to treat most solid tumors Delivery of electromagnetic energy to a target volume X-rays, Electrons, Protons

11. Radiation Therapy: Important therapeutic modality Cellular basis DNA repair Cell cycle regulation Apoptosis

12. Radiation Therapy: Important therapeutic modality Tumor Cell Kill Must also consider normal tissues

13. Radiation Therapy: Important therapeutic modality Therapeutic Ratio: TCP/ NTCP Tumor control probability/normal tissue complication probability

14. Radiation Therapy: Important therapeutic modality Improving the Therapeutic Ratio Fractionation : aliquoting radiation dose The “4 R’s” of radiation therapy Repair Normal Tissue > tumor Repopulation Normal Tissue, Some tumors Redistribution Not significant Reoxygenation Tumors

15. Improving the Therapeutic Ratio Fractionation : aliquoting radiation dose Standard: 1.8 - 2 Gy per fraction over 5 -7 weeks Hyperfractionate: 1.5 Gy per fraction twice per day over shorter span Normal tissues repair sublethal damage between doses Minimizes repopulation of tumor Hypofractionate : >3 Gy per fraction over shorter span More lethal damage, less repopulation Limited by ability to spare normal tissues Radiation Therapy: Important therapeutic modality

16. Radiation Therapy: Important therapeutic modality Improving the Therapeutic Ratio Optimize treatment planning Technology driven approach Increase the conformality of the delivered radiation Spare normal tissues relative to target TV IV Less conformal More conformal TV

17. Emerging Role for Radiation Therapy in HCC: Why not in intra-hepatic malignancies? Historical Data: low therapeutic ratio, hepatotoxicity, unable to deliver curative doses Radiation induced liver disease (RILD) Triad of anicteric ascites, elevated alkaline phosphatase, hepatomegaly Within 3 months of liver irradiation Modern Clinical Data: NTCP depends on volume of liver irradiated small liver volumes can tolerate high radiation doses

18. Emerging Role for Radiation Therapy in HCC Small liver volumes can tolerate high radiation doses

19. Emerging Role for Radiation Therapy in HCC Small liver volumes can tolerate high radiation doses

20. Emerging Role for Radiation Therapy in HCC: C hallenges to safe radiation delivery: Low whole liver tolerance to radiation Other radiosensitive tissues in upper abdomen Tumor and organ motion Baseline compromised hepatic function Advanced disease at presentation

21. Emerging Role for Radiation Therapy in HCC: C hallenges to safe radiation delivery: Low whole liver tolerance to radiation  conformality Other radiosensitive tissues in upper abdomen  conformality Tumor and organ motion Baseline compromised hepatic function Advanced disease at presentation

22. Emerging Role for Radiation Therapy in HCC: C hallenges to safe radiation delivery: Low whole liver tolerance to radiation  conformality Other radiosensitive tissues in upper abdomen  conformality Tumor and organ motion  motion management, image guidance Baseline compromised hepatic function Advanced disease at presentation

23. Emerging Role for Radiation Therapy in HCC: C hallenges to safe radiation delivery: Low whole liver tolerance to radiation  conformality Other radiosensitive tissues in upper abdomen  conformality Tumor and organ motion  motion management, image guidance Baseline compromised hepatic function  patient selection Advanced disease at presentation  patient selection

24. Emerging Role for Radiation Therapy in HCC: Dependent on Advances in imaging Multi-modal imaging: CT, MR Arterial phase imaging for HCC Venous phase imaging for portal vein thrombus Image registration and fusion  better target delineation

25. Emerging Role for Radiation Therapy in HCC: Stereotactic Body Radiotherapy (SBRT) Superior tumor imaging Reliable patient immobilization Respiratory motion management techniques Real-time image guidance for conformal delivery (IGRT)  Minimize dose to uninvolved liver Improve conformality Safer radiation dose escalation  hypofractionate

26. Can liver SBRT be delivered safely for HCC? Phase I studies demonstrate safety (RILD rare) No standard fractionation scheme Must establish institutional approach Emerging Role for Radiation Therapy in HCC: Experimental Questions

27. Can liver SBRT be delivered safely for HCC? Phase I studies demonstrate safety (RILD rare) No standard fractionation scheme Must establish institutional approach Can liver SBRT effectively bridge HCC patients awaiting transplant? Emerging Role for Radiation Therapy in HCC: Experimental Questions

28. Can liver SBRT be delivered safely for HCC? Phase I studies demonstrate safety (RILD rare) No standard fractionation scheme Must establish institutional approach Can liver SBRT effectively bridge HCC patients awaiting transplant? Can liver SBRT downsize HCC lesions for patients outside of criteria? Emerging Role for Radiation Therapy in HCC: Experimental Questions

29. Can liver SBRT be delivered safely for HCC? Phase I studies demonstrate safety (RILD rare) No standard fractionation scheme Must establish institutional approach Can liver SBRT effectively bridge HCC patients awaiting transplant? Can liver SBRT downsize HCC lesions for patients outside of criteria? Are there serologic and tissue biomarkers of hepatic radiation response? Emerging Role for Radiation Therapy in HCC: Experimental Questions

30. Objective : Confirm feasibility and safety of liver SBRT as a therapeutic option for patients with unresectable HCC Fractionation : Effective liver volume irradiated (V eff ) Dose per fraction < 0.3 9 Gy x 5 0.3 - 0.4 7.5 Gy x 5 0.4 - 0.5 6.25 Gy x 5 0.5 - 0.6 5.5 Gy x 5 Primary safety endpoint : Treatment-related hepatic toxicity within 3 months of SBRT Emerging Role for Radiation Therapy in HCC: Montefiore-Einstein Liver SBRT Pilot Project

31. Secondary efficacy endpoints : radiographic response, time to progression, survival Correlative endpoints : Serologic and explant biomarkers for radiation response Acrrual : 20 patients over ≤20 months Emerging Role for Radiation Therapy in HCC: Montefiore-Einstein Liver SBRT Pilot Project

32. Investigate combined modality therapy: -Liver SBRT + targeted agents? -Liver SBRT + other locoregional therapies? Profiling of human serologic and explant tissue for radiation response biomarkers? Genomic, proteomic, metabolomic Partner with cooperative clinical research groups for large prospective comparative effectiveness studies of liver SBRT? Emerging Role for Radiation Therapy in HCC: Potential Future Directions

33. Multidisciplinary Team Radiation Oncology Niloy Deb Chandan Guha Linda Hong Shalom Kalnicki Nitika Thawani Medical Oncology Andreas Kaubisch Epidemiology Mimi Kim Hepatology Paul Gaglio John Reinus Pathology Quiang Lu Kathryn Tanaka Surgery Milan Kinkhabwala Funding: Paul Calabresi Award in Clinical Oncology (K12) Prinicipal Investigator: Roman Perez-Soler