1. Radiation Therapy for Pancreatic Cancers Eyad Abu-Isa, M.D. Assistant Professor, Radiation Oncology University of Michigan/Providence Cancer Institute February 28, 2015

2. EA 2015 Disclosures I have no actual or potential conflict of interest in relation to this presentation.

3. EA 2015 Overview Radiation Basics Review of Literature –Resected –Unresectable Radiation Techniques Future Directions Questions

4. EA 2015 Varian Truebeam

5. EA 2015 How radiation therapy works

6. EA 2015 Resected: Adjuvant Treatment

7. EA 2015 Kalser and Ellenberg, Arch Surg 1985. GITSG 9173 Methods: –Patients: 43 total patients enrolled  22 patients randomized to no adjuvant treatment, and 21 to chemoradiation  68% underwent Whipple, 32% had total pancreatoduodenectomy. All but 2 patients had head lesions. –Tumors: All patients underwent resection of localized pancreas cancer, and all had NEGATIVE MARGINS.  35% tumor confined to pancreas, 37% tumor extended beyond the pancreas, 28% had nodal involvement

8. EA 2015 GITSG 9173 Methods: –Treatment Arms:  Arm 1) No adjuvant therapy  Arm 2) Chemoradiotherapy arm:  Chemotherapy: 5-FU (500mg/m 2 ) given as bolus infusion on day 1,2,3 of radiation courses one and two, and once weekly for two years or until recurrence documented.  Radiation Therapy: Two 20 Gy courses, separated by two weeks. Fraction dose not specified.

9. EA 2015 GITSG 9173 Results: –Adjuvant chemoRT significantly improves median survival and DFS. Adjuvant TxMedian Survival (P=0.03) 2 yr survival Median DFS (P=0.01) None11 months15%9 months ChemoXRT20 months42%11 months

10. EA 2015 Resected: Adjuvant Treatment

11. EA 2015 ESPAC Purpose: To clarify benefits of chemoRT and maintenance chemo in adjuvant setting Methods: Prospective, multi-institutional, semi- randomized, semi- controlled trial. Primary endpoint: death. –Patients: 541 patients were enrolled with histologically proven ductal adenocarcinoma, with gross total resection and no evidence of local spread or distant metastasis. –Tumors: Allowed (+) margins Neoptolemos JP, Lancet 2001.

12. EA 2015 ESPAC 2 x 2 factorial design (285 pt subset) Treatment# PatientsMedian Survival (mo.) Chemoradiation14215.8 No chemoradiation14317.8 (NS) Treatment# PatientsMedian Survival Chemotherapy14620 No Chemotherapy13918 (SS)

13. EA 2015 Resected: Adjuvant Treatment

14. EA 2015 CONKO-001 Oettle et al. JAMA 2007 Phase III, multicenter, randomized, controlled trial Stratified for resection, tumor, and node status 368 pts with R0 (80%) or R1 pancreatic resection, T1-4 (82% T3), N0-1 (70% N1) Observation vs Gemcitabine 1000 mg/m2 x 6 cycles (days 1, 8, 15 q4 weeks)

15. EA 2015 CONKO-001 Results: Gemcitabine improved DFS –Median f/u 53 months –Median DFS: 13.4 vs 6.9 months (p<0.001) –1 year DFS: 58% vs. 31% –Relapse: 74% vs 92% –Median OS: 22.1 vs 20.2 months –5 year OS: 22% vs. 11% (p=0.06)

16. EA 2015 Resected: Adjuvant Treatment

17. EA 2015 RTOG 9704 Conventional chemo-RT CI 5-FU (250 mg/m2 daily)x 3 wks  chemo-RT (50.4 Gy with concurrent CI 5-FU)  3-5 weeks later: two-four week courses CI 5-FU (250 mg/m2 daily, with a two week break b/w courses), Gemcitabine Three weekly doses of gemcitabine alone (1000 mg/m2 per week)  Same chemoradiotherapy protocol as for the conventional chemoradiotherapy arm  3 to 5 weeks later, three months of single agent gemcitabine (1000 mg/m2 weekly for three of every four weeks).

18. EA 2015 RTOG 9704 Regine et al. JAMA 2008 Results: –Pancreatic head tumors(n=380) experienced significantly improved survival with gemcitabine vs 5-FU: MS= 18.8 vs. 16.7 (p=0.09) 3YS= 31% vs. 21% (p=0.047)

19. EA 2015 Resected: Adjuvant Treatment

20. EA 2015 RTOG 08-48

21. EA 2015 Resected: Adjuvant Treatment

22. EA 2015 Unresectable Disease Median survival for untreated patients is ~4 months, and ~7 months with palliative bypass Modern chemotherapy and radiation treatment can prolong survival

23. EA 2015 ECOG E4201 Loehrer PJ, J Clin Oncol 29:4105-4112, 2011 69 of planned 316 patients with unresectable disease. Closed to slow accual. –Arm 1) Gemcitabine alone 1000 mg/m2 x7 cycles –Arm 2) RT 50.4/28 + gemcitabine 600 mg/m2, then gemcitabine alone 1000 mg/m2 x5 cycles

24. EA 2015 ECOG E4201 Results Results: –Median OS 9 months vs. 11 months (SS) –Toxicity: Grade 4 GEM 6% vs. GEM/RT 41% (SS) Conclusion: Gem+RT had increased but generally manageable toxicity, with improved OS

25. EA 2015 Neoadjuvant Therapy No large, prospectively randomized studies for neoadjuvant therapy. Much of data from Phase I/II studies. Potential benefits: –Increase resectability rate –Decrease local recurrence –Decrease regional/metastatic spread through lymph nodes –Better tolerated than adjuvant therapy with higher numbers of patients completing intended treatment –Select out patients with rapid disease progression/aggressive tumor biology and spare them the morbidity of Whipple procedure

26. EA 2015 MDA Experience Prospective study of 132 consecutive patients who received preop chemoradiation followed by Whipple RT: –45.0 or 50.4 Gy radiation at 1.8 Gy per fraction in 28 fractions or –30.0 Gy at 3.0 Gy per fraction in 10 fractions Chemo: concomitant infusional chemotherapy (5-fluorouracil, paclitaxel, or gemcitabine). Then restaging studies--> if no evidence of disease progression, then Whipple. Results: –2YS 40% and MS was 21 months, despite 43% requiring vascular resections –Rate of clear resections: 88% –Rate of local recurrence: 6% Breslin, Ann Surg Onc, 2001

27. EA 2015 Radiation Planning

28. EA 2015 Motion assessment/control Methods of diaphragmatic motion control –ABC breath hold (if tolerated) – scan on expiration –Others use abdominal compression –If ABC not tolerated, 4D CT to accurately account for motion Treatment planning CT scan is fused with diagnostic study (PET/CT, MRI, CT)

29. EA 2015 Radiation Techniques Avoidance organs: duodenum/small bowel, liver, kidneys, spinal cord Pancreatic head lesions: include pancreaticoduodenal, suprapancreatic, celiac nodes, porta hepatis, duodenal loop Body/tail lesions: pancreaticoduodenal, lateral suprapancreatic, splenic hilar nodes Boderline/Unresectable patients: small field radiation to gross disease only.

30. EA 2015 Radiation Targets TargetPancreatic headPancreatic tailUnresectable/Bo rderline Primary tumorxxx Positive LNsxxx Parapanc LNsxx Pancduo LNsxx Celiac/SMA LNsxx Portal LNsx Splenic LNsx Avoidance organs: duodenum/small bowel, liver, kidneys, spinal cord

31. EA 2015 2D Radiation Techniques AP field with blocking for pancreatic head lesions Lateral field with blocking

32. EA 2015 Intensity Modulated RT (IMRT)

33. EA 2015 High activity low-dose rate brachytherapy Single or multiple high activity radioactive I-125 seeds are placed into a tumor under radiographic guidance. Advantages over external beam: –Low energy radiation emitted from inside out, meaning high dose to tumors, with quick dose fall-off –Continuous low dose radiation delivered over months, potential biologic advantage

34. EA 2015 HALDR 66 yo male with pancreatic tail adenocarcinoma.

35. EA 2015 X Pancreas tail mass (red) and intended seed position (X). No direct access in the axial plane due to obstruction by kidney(K), spleen(S), and bowel(B). K S B Figure 2

36. EA 2015 Needle access plane (green transparency) 2.4 cm below axial target slice

37. EA 2015 K S Needles advanced in a non-axial superior direction at the junction of the kidney and spleen. After passage beyond the critical organ it is again possible to angle the needle in the intended direction. Once past the organ the needle can safely displace the organ (spleen in the example)

38. EA 2015 Coaxial needle in position (blue arrow). Marker seed in place (red arrow)

39. EA 2015 Marker seed (red arrow) and radioactive seed (gold arrow) near intended position

40. EA 2015 Before After Response to HALDR

41. EA 2015 Conclusions Pancreatic survival rates are low, highlighting the need for future research. Role for adjuvant radiation treatment is controversial, but with careful radiation planning proper patient selection, and better systemic therapy, a benefit may exist Radiation improves local control in patients with borderline resectable and unresectable disease and may impact survival.

42. EA 2015 Thank you!