Session 2.3 Gabeau

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Darlene Gabeau

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  • Session 2.3 Gabeau

    1. 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. 2. HCC : Standard Treatment Algorithm Barcelona Clinic Liver Cancer System Llovet, J. M. et al. J. Natl. Cancer Inst. 2008 100:698-711
    3. 3. HCC : Standard Treatment Algorithm Barcelona Clinic Liver Cancer System Llovet, J. M. et al. J. Natl. Cancer Inst. 2008 100:698-711
    4. 4. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25%
    5. 5. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80%
    6. 6. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50%
    7. 7. HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60%
    8. 8. <ul><ul><ul><li>Eligibility criteria: 1 lesion  5 cm or  3 lesions/< 3 cm </li></ul></ul></ul><ul><ul><ul><li>Long wait list  interim tumor progression  >20% dropout </li></ul></ul></ul>HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60%
    9. 9. <ul><ul><ul><li>Eligibility criteria: 1 lesion  5 cm or  3 lesions/< 3cm </li></ul></ul></ul><ul><ul><ul><li>Long wait list  interim tumor progression  >20% dropout </li></ul></ul></ul>HCC: Limitations of Standard Modalities Survival 50 - 70% Local Control <25% Survival 50 - 80% Ablation Survival 10 - 50% TACE Survival 30 - 60% <ul><li>Might radiation therapy have a role: </li></ul><ul><li>Tumor downsizing? </li></ul><ul><li>Bridge to transplant? </li></ul>
    10. 10. Radiation Therapy: Important therapeutic modality <ul><li>Used to treat most solid tumors </li></ul><ul><li>Delivery of electromagnetic energy to a target volume </li></ul><ul><ul><li>X-rays, Electrons, Protons </li></ul></ul>
    11. 11. Radiation Therapy: Important therapeutic modality <ul><li>Cellular basis </li></ul>DNA repair Cell cycle regulation Apoptosis
    12. 12. Radiation Therapy: Important therapeutic modality <ul><li>Tumor Cell Kill </li></ul><ul><li>Must also consider normal tissues </li></ul>
    13. 13. Radiation Therapy: Important therapeutic modality <ul><li>Therapeutic Ratio: TCP/ NTCP </li></ul><ul><ul><li>Tumor control probability/normal tissue complication probability </li></ul></ul>
    14. 14. Radiation Therapy: Important therapeutic modality <ul><li>Improving the Therapeutic Ratio </li></ul><ul><ul><li>Fractionation : aliquoting radiation dose </li></ul></ul><ul><ul><ul><li>The “4 R’s” of radiation therapy </li></ul></ul></ul>Repair Normal Tissue > tumor Repopulation Normal Tissue, Some tumors Redistribution Not significant Reoxygenation Tumors
    15. 15. <ul><li>Improving the Therapeutic Ratio </li></ul><ul><ul><li>Fractionation : aliquoting radiation dose </li></ul></ul><ul><ul><ul><li>Standard: 1.8 - 2 Gy per fraction over 5 -7 weeks </li></ul></ul></ul><ul><ul><ul><li>Hyperfractionate: 1.5 Gy per fraction twice per day over shorter span </li></ul></ul></ul><ul><ul><ul><ul><li>Normal tissues repair sublethal damage between doses </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Minimizes repopulation of tumor </li></ul></ul></ul></ul><ul><ul><ul><li>Hypofractionate : >3 Gy per fraction over shorter span </li></ul></ul></ul><ul><ul><ul><ul><li>More lethal damage, less repopulation </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Limited by ability to spare normal tissues </li></ul></ul></ul></ul>Radiation Therapy: Important therapeutic modality
    16. 16. Radiation Therapy: Important therapeutic modality <ul><li>Improving the Therapeutic Ratio </li></ul><ul><ul><li>Optimize treatment planning </li></ul></ul><ul><ul><ul><li>Technology driven approach </li></ul></ul></ul><ul><ul><ul><li>Increase the conformality of the delivered radiation </li></ul></ul></ul><ul><ul><ul><li>Spare normal tissues relative to target </li></ul></ul></ul>TV IV Less conformal More conformal TV
    17. 17. Emerging Role for Radiation Therapy in HCC: Why not in intra-hepatic malignancies? <ul><li>Historical Data: </li></ul><ul><ul><li>low therapeutic ratio, hepatotoxicity, unable to deliver curative doses </li></ul></ul><ul><ul><li>Radiation induced liver disease (RILD) </li></ul></ul><ul><ul><ul><li>Triad of anicteric ascites, elevated alkaline phosphatase, hepatomegaly </li></ul></ul></ul><ul><ul><ul><li>Within 3 months of liver irradiation </li></ul></ul></ul><ul><li>Modern Clinical Data: </li></ul><ul><ul><li>NTCP depends on volume of liver irradiated </li></ul></ul><ul><ul><li>small liver volumes can tolerate high radiation doses </li></ul></ul>
    18. 18. Emerging Role for Radiation Therapy in HCC <ul><li>Small liver volumes can tolerate high radiation doses </li></ul>
    19. 19. Emerging Role for Radiation Therapy in HCC <ul><li>Small liver volumes can tolerate high radiation doses </li></ul>
    20. 20. Emerging Role for Radiation Therapy in HCC: <ul><li>C hallenges to safe radiation delivery: </li></ul><ul><ul><li>Low whole liver tolerance to radiation </li></ul></ul><ul><ul><li>Other radiosensitive tissues in upper abdomen </li></ul></ul><ul><ul><li>Tumor and organ motion </li></ul></ul><ul><ul><li>Baseline compromised hepatic function </li></ul></ul><ul><ul><li>Advanced disease at presentation </li></ul></ul>
    21. 21. Emerging Role for Radiation Therapy in HCC: <ul><li>C hallenges to safe radiation delivery: </li></ul><ul><ul><li>Low whole liver tolerance to radiation  conformality </li></ul></ul><ul><ul><li>Other radiosensitive tissues in upper abdomen  conformality </li></ul></ul><ul><ul><li>Tumor and organ motion </li></ul></ul><ul><ul><li>Baseline compromised hepatic function </li></ul></ul><ul><ul><li>Advanced disease at presentation </li></ul></ul>
    22. 22. Emerging Role for Radiation Therapy in HCC: <ul><li>C hallenges to safe radiation delivery: </li></ul><ul><ul><li>Low whole liver tolerance to radiation  conformality </li></ul></ul><ul><ul><li>Other radiosensitive tissues in upper abdomen  conformality </li></ul></ul><ul><ul><li>Tumor and organ motion  motion management, image guidance </li></ul></ul><ul><ul><li>Baseline compromised hepatic function </li></ul></ul><ul><ul><li>Advanced disease at presentation </li></ul></ul>
    23. 23. Emerging Role for Radiation Therapy in HCC: <ul><li>C hallenges to safe radiation delivery: </li></ul><ul><ul><li>Low whole liver tolerance to radiation  conformality </li></ul></ul><ul><ul><li>Other radiosensitive tissues in upper abdomen  conformality </li></ul></ul><ul><ul><li>Tumor and organ motion  motion management, image guidance </li></ul></ul><ul><ul><li>Baseline compromised hepatic function  patient selection </li></ul></ul><ul><ul><li>Advanced disease at presentation  patient selection </li></ul></ul>
    24. 24. Emerging Role for Radiation Therapy in HCC: Dependent on Advances in imaging <ul><li>Multi-modal imaging: CT, MR </li></ul><ul><ul><li>Arterial phase imaging for HCC </li></ul></ul><ul><ul><li>Venous phase imaging for portal vein thrombus </li></ul></ul><ul><li>Image registration and fusion  better target delineation </li></ul>
    25. 25. Emerging Role for Radiation Therapy in HCC: Stereotactic Body Radiotherapy (SBRT) <ul><li>Superior tumor imaging </li></ul><ul><li>Reliable patient immobilization </li></ul><ul><li>Respiratory motion management techniques </li></ul><ul><li>Real-time image guidance for conformal delivery (IGRT) </li></ul><ul><li> </li></ul><ul><li>Minimize dose to uninvolved liver </li></ul><ul><li>Improve conformality </li></ul><ul><li>Safer radiation dose escalation  hypofractionate </li></ul>
    26. 26. <ul><li>Can liver SBRT be delivered safely for HCC? </li></ul><ul><li>Phase I studies demonstrate safety (RILD rare) </li></ul><ul><li>No standard fractionation scheme </li></ul><ul><li>Must establish institutional approach </li></ul>Emerging Role for Radiation Therapy in HCC: Experimental Questions
    27. 27. <ul><li>Can liver SBRT be delivered safely for HCC? </li></ul><ul><li>Phase I studies demonstrate safety (RILD rare) </li></ul><ul><li>No standard fractionation scheme </li></ul><ul><li>Must establish institutional approach </li></ul><ul><li>Can liver SBRT effectively bridge HCC patients awaiting transplant? </li></ul>Emerging Role for Radiation Therapy in HCC: Experimental Questions
    28. 28. <ul><li>Can liver SBRT be delivered safely for HCC? </li></ul><ul><li>Phase I studies demonstrate safety (RILD rare) </li></ul><ul><li>No standard fractionation scheme </li></ul><ul><li>Must establish institutional approach </li></ul><ul><li>Can liver SBRT effectively bridge HCC patients awaiting transplant? </li></ul><ul><li>Can liver SBRT downsize HCC lesions for patients outside of criteria? </li></ul>Emerging Role for Radiation Therapy in HCC: Experimental Questions
    29. 29. <ul><li>Can liver SBRT be delivered safely for HCC? </li></ul><ul><li>Phase I studies demonstrate safety (RILD rare) </li></ul><ul><li>No standard fractionation scheme </li></ul><ul><li>Must establish institutional approach </li></ul><ul><li>Can liver SBRT effectively bridge HCC patients awaiting transplant? </li></ul><ul><li>Can liver SBRT downsize HCC lesions for patients outside of criteria? </li></ul><ul><li>Are there serologic and tissue biomarkers of hepatic radiation response? </li></ul>Emerging Role for Radiation Therapy in HCC: Experimental Questions
    30. 30. <ul><li>Objective : Confirm feasibility and safety of liver SBRT as a therapeutic option for patients with unresectable HCC </li></ul><ul><li>Fractionation : </li></ul><ul><li>Effective liver volume irradiated (V eff ) Dose per fraction </li></ul><ul><ul><ul><li>< 0.3 9 Gy x 5 </li></ul></ul></ul><ul><li>0.3 - 0.4 7.5 Gy x 5 </li></ul><ul><li>0.4 - 0.5 6.25 Gy x 5 </li></ul><ul><ul><ul><li>0.5 - 0.6 5.5 Gy x 5 </li></ul></ul></ul><ul><li>Primary safety endpoint : Treatment-related hepatic toxicity within 3 months of SBRT </li></ul>Emerging Role for Radiation Therapy in HCC: Montefiore-Einstein Liver SBRT Pilot Project
    31. 31. <ul><li>Secondary efficacy endpoints : radiographic response, time to progression, survival </li></ul><ul><li>Correlative endpoints : Serologic and explant biomarkers for radiation response </li></ul><ul><li>Acrrual : 20 patients over ≤20 months </li></ul>Emerging Role for Radiation Therapy in HCC: Montefiore-Einstein Liver SBRT Pilot Project
    32. 32. <ul><li>Investigate combined modality therapy: </li></ul><ul><li>-Liver SBRT + targeted agents? </li></ul><ul><li>-Liver SBRT + other locoregional therapies? </li></ul><ul><li>Profiling of human serologic and explant tissue for radiation response biomarkers? </li></ul><ul><ul><li>Genomic, proteomic, metabolomic </li></ul></ul><ul><li>Partner with cooperative clinical research groups for large prospective comparative effectiveness studies of liver SBRT? </li></ul>Emerging Role for Radiation Therapy in HCC: Potential Future Directions
    33. 33. Multidisciplinary Team <ul><li>Radiation Oncology </li></ul><ul><li>Niloy Deb </li></ul><ul><li>Chandan Guha </li></ul><ul><li>Linda Hong </li></ul><ul><li>Shalom Kalnicki </li></ul><ul><li>Nitika Thawani </li></ul><ul><li>Medical Oncology </li></ul><ul><li>Andreas Kaubisch </li></ul><ul><li>Epidemiology </li></ul><ul><li>Mimi Kim </li></ul>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

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