1. Using Spacers for Delivery of High Dose Radiation Theodore Hong, MD Director, Gastrointestinal Radiation Oncology Massachusetts General Hospital Associate Professor of Radiation Oncology Harvard Medical School

2. Disclosures No relevant financial disclosures to material in this presentation Research Funding- Novartis Advisory Board- Eisai

3. The problem of bowel toxicity High dose, advanced radiation is effective in the treatment of intrahepatic cholangiocarcinoma Protons/IMRT can not solve the problem of tumor in contact with a mucosal surface Solution- Manual Displacement Yoon SS, et al. Pract Radiat Oncol 2014

4. MGH/MDACC/UPENN phase II 43 patients –41 ICC, 2 mixed HCC/ICC 4 did not receive treatment –3 could not meet dosing constraints –1 became ineligible due to ECOG –Median longest tumor diameter (N=3): 6.9 cm (range 4.4 - 9.0 cm) Hong TS, et al. ASCO 2015

5. Treatment 15 Fractions Peripheral - 67.5 Gy Central (within 2 cm porta hepatis) – 58 Gy

6. Results 39 analyzed –37 ICC, 2 mixed HCC/ICC –Median age – 66 years (range 29-87 years) –Cirrhosis None- 1 (3%) Childs A – 34 (87%) Childs B – 4 (10%) –Prior systemic therapy – 24 pts (62%) –Number of tumors 1 lesion – 33 (85%) 2 lesions – 4 (10%) 3 lesions – 2 (5%)

7. Results VariableMinimumMedianMaximum Longest tumor dimension (cm)2.25.810.9 CA 19-9 at baseline (u/mL)07210,549 Dose prescribed (Gy)455867.5 Dose received (Gy)15.15867.5

8. Gr 3 Radiation-Related Toxicity 3 pts (8%) Hyperbilirubinemia – 1 pt Stomach ulcer – 1 pt Liver failure – 1 pt Ascites – 1 pt 1 patient had both liver failure and ascites. No grade 4 radiation-related toxicities.

9. Outcomes Endpoint1-year2-year Local Control97%90% Overall Survival69%44% Progression-Free Survival 40%28% Median follow up duration among 19 survivors: 13.2 months (range 0.6 – 50.4 months)

10. OS – All Treated Subjects n=39

11. PFS – All Treated Subjects n=39

12. Outcomes- Exclude Child’s B n=35 Endpoint1-year2-year Local Control96%90% Overall Survival75%48% Progression-Free Survival 45%32% Median follow up duration among 18 survivors: 14.9 months (range 0.6 – 50.4 months)

13. OS – Exclude Child’s B n=35

14. PFS – Exclude Child’s B n=35

15. Conclusions High dose, hypofractionated radiation (with protons) is associated with high rates of local control in ICC Radiation is safe Long term survival is possible These data form the foundation for NRG GI-001

16. Use of biologic spacers Ablative radiation dose can be limited by the immediate proximity of radiation- sensitive organs, including bowel Larger issue if hypofractionated doses are used.

17. MGH/MDACC experience 14 patients Retrospective review Patients selected if tumor was in contact or within 1 cm of mucosal surface Yoon SS, et al. PRO 2014

18. Biologic spacer Alloderm (Life cell) Cadaveric human skin Chemically processed to preserve the structural and biologically active dermal matrix.

19. Placement Laproscopically placed 12 mm Hasson port placed in the periunilical position Two 5 mm ports and one 12 mm port placed Lysis of adhesions if necessary Sheets of 8 x 16 cm sheets were folded into a 3 layer sandwich and sewn at four corners

20. Placement of Spacer AB C

21. Results: Patients with Spacers

22. Results: Net Change with Spacers

23. Results: Radiation Delivered

24. Results: Radiation Therapy Toxicity

25. Tumor GB Omental fat Alloderm

26. Liver Alloderm

27. Duodenum Alloderm Small bowel Alloderm

28. Pre/Post Alloderm Tumor Bowel

29. Plan Alloder m

32. Conclusions High dose radiation is an effective treatment for intrahepatic cholangiocarcinoma Biologic mesh spacers can allow patients not otherwise able to be treated to receive this therapy Biologic mesh spacers are associated with safe radiation treatments

33. Acknowledgements Sam Yoon, MD John Mullen, MD Alex Haynes, MD Christopher Crane, MD Jennifer Wo, MD