What is the Role of Chemoradiation in Locally Advanced Pancreatic Cancer?

1. What is the Role of Chemoradiation in Locally Advanced Pancreatic Cancer? Christopher H. Crane, M.D. Professor Program Director and Section Chief, Gastrointestinal Section Department of Radiation Oncology

2. No Disclosures

3. Why is pancreatic cancer a bad disease? Anatomy: proximity to critical vessels Biology: early metastatic spread localized disease at dx: 30% will not metastasize Physiology: exocrine insufficiency, cachexia Poor tolerance to treatment Treatment resistance

4. Rationale for Local treatment Pancreatic Cancer • Resected patients • 15-25% 5 yr OS • Locally advanced patients • 30% Local only disease JHU Autopsy Series • 30-40% Local progression - MDACC phase II trial • Selection based on SMAD4(DPC4)? Iacobuzio-Donahue et al, JCO, 2009 Crane et al, JCO, 2011

5. Patients commonly die of • Stent complications / biliary sepsis • Gastric outlet obstruction • Acute SMV / PV occlusion

6. JHU Rapid Autopsy Series Local only- 30% LAPD limited metastatic Iacobuzio-Donahue et al, JCO, 2009

7. Time to Radiographic Local Tumor Progression n=67 1st Site LF/ (mo): 32.7 31.2, 25.0, 23.3 20.1 18.3, 16.7, 16.5, 16.1 Median LP– 18.4 1yr – 22.0% 2yr – 59.0% Crane, JCO 2011

8. Localized Pancreatic Cancer: Role of XRT vs Arterial Involvement T 1-3 T4 “borderline” T4 Surgery helpful? Yes Maybe No XRT helpful? Maybe HELPS the MOSTYes

9. SMV Locally Advanced Occluded SMV SMA involved Chennisi 528261

10. Borderline Resectable PDAC R1 resection likely NCCN Pancreatic Reference, Abrams Ann SurgOncol 2009

11. FFCD-SFRO Phase III R A N D O M I Z E Gemcitabine Locally Advanced PC N= 119 (of 176) 5-FU + Cisplatin + Radiation (60 Gy) ↓ Gemcitabine Eligibility • ECOG PS 0 or 1; No mets • Stratify Prior exploratory surgery Primary Endpoint: Overall Survival Chauffert, et al. Ann Oncol, 2008

12. FFCD-SFRO Phase III 5FU-Cis-RT + Gem vs Gemcitabine Chauffert, et al. Ann Oncol, 2008

13. ECOG 4201 R A N D O M I Z E Gemcitabine Locally Advanced PC N= 316 Gem + Radiation ↓ Gemcitabine Eligibility • ECOG PS 0 or 1; No mets Primary Endpoint: Overall Survival (88% power, 50% improvement from 8 → 12 months) Loehrer, et al. ASCO, 2008 (LBA #4504)

14. ECOG 4201 (N= 71) Loehrer, et al. JCO 2011

15. GERCOR LAP07 Phase III (NCT00634725) R A N D O M I Z E Gemcitabine x 4 cycles 2nd Randomization +/- ChemoRT LAPC N= 900 Gemcitabine + Erlotinib x 4 Primary Endpoints: Overall Survival +/- Erlotinib +/- Capecitabine-Radiation P. Hammel (PI, GERCOR)

16. Overall Survival by Random 1 status

17. Overall survival by Random 2 status

18. Questions about LAP-07 • Quality assurance of CXRT • # of patients treated off study with CXRT was at least 20% • How many were non-complaint with CXRT?

19. Treatment Results – LADPhase II and III data Multi-inst

20. Treatment Results single institution

21. Phase II trial Cetuximab based chemoradiation2004-0983 2 mo. Gemcitabine / Oxaliplatin / Cetuximab XRT/ Capecitabine / Cetuximab Doses: Gem: 1000mg/m2 over 100 min Q2wk Oxaliplatin: 100mg/m2 over 2 Hrs Q2wk Cetuximab (400 mg/m2, then 500mg/m2) Q2wk Radiotherapy: 50.4 Gy* *3DCRT to Gross tumor only Crane, JCO 2011

22. Overall Survival: Resected vsUnresected Tumors Resected, n=7 Unresected, n=60 Median - 19.2 months 1yr – 67.2% 2yr – 27.0% 5yr – 10.2% Crane, JCO 2011

23. SMAD4/DPC4 • Tumor suppressor gene • SMAD4/DPC4 Gene Status • Encodes for protein in TGFβ pathway • Inactivation/mutation associated with poor prognosis and higher risk of metastases • Loss of SMAD4/DPC4 expression increases with more advanced metastatic tumor burden Iacobuzio-Donahue, C. J Clin Oncol, 2009. Blackford, A. Clin Can Res, 2009.

24. JHU Rapid Autopsy Series Local only- 22% SMAD4 loss p=0.032 Extensive metastatic- 78% SMAD4 loss limited metastatic Iacobuzio-Donahue et al, JCO, 2009

25. Correlative studies • IHC of available diagnostic cytology specimens • (60 pts, 49 available slides, 41 enough material) • Destained slides, harvested DNA for Sequenom • 41 samples, majority would not work • Possibly due to the de-staining process Crane, JCO 2011

26. Crane, JCO 2011

27. University of Michigan: IMRT dose Escalation trial * BED=Biological Effective Dose; a/b=10 ** The initial dose level was Level 3 Ben-Josef E,. IJROBP2012

28. IMRT FOR PANCREAS CANCERDOSE DISTRIBUTION BenJosef, IJROBP 2012

29. Median OS 14.8 months; 2-year OS 30% 2-year freedom from local progression is 59% 12 patients underwent resection (10 R0, 2 R1) 2- pCR BenJosef, IJROBP 2012

30. Phase II Multi-Institutional Study of Stereotactic Body Radiation Therapy for UnresectablePanceatic Cancer LAPC (1 Cycle Gem allowed)* Gemcitabine Chemotherapy (3 wks on, 1 wk off) Until toxicity or progression SBRT 6.6 Gy x 5 Mon-Fri >2 week break 2 week break Trial open at Stanford, Johns Hopkins., Memorial Sloan Kettering.

31. Median survival: 15.9 months (95% CI, 9.14 – upper limit not yet reached) Median follow-up: 12.0 months (range, 2.1-22.6) Herman, pASTR0, 2011

32. Hazard ratio for CA19-9 >= 90 U/mL at diagnosis: 6.18 (p=0.021) Herman, pASTR0, 2011

33. IGRT - Monitoring Stomach PositionHfx XRT PancCa 67.5 Gy- 15 fx - 45Gy

34. RTOG 1201: SMAD4/DPC4 Directed Treatment Original Proposal: Integral Biomarker SMAD4/DPC4 Status IMRT 63Gy Gem x 3 mo “INTACT” 50.4 Gy Gem x3 mo 3D CRT “LOSS” 50.4 Gy FOLFIRINOX x 3 mo Eligibility: Locally Advanced Unresectable No prior Chemotherapy or RT, PS 0-1

35. RTOG 1201: SMAD4 Directed Treatment Locally Advanced Pancreatic Cancer IMRT 63Gy Gem x 3 mo LAPC Stratify: SMAD4 Status Ca 19-9 < 90 50.4 Gy Gem x3 mo 3D CRT 50.4 Gy FOLFIRINOX x 3 mo Eligibility: Locally Advanced Unresectable No prior Chemotherapy or RT, PS 0-1

36. RTOG 1201: Proposed modification IMRT 63Gy Gem/Nab-paclitaxel x 3 mo LAPC Stratify: SMAD4 Status Ca 19-9 < 90 50.4 Gy 3D CRT *Maintanance chemo until progression in all arms Eligibility: Locally Advanced Unresectable No prior Chemotherapy or RT, PS 0-1

37. Smad4 identification: RTOG 1201 • IHC of cytology/core bx specimens • Cell blocks or Endoscopic core biopsies req’d • ETOH fixed Smears requested • Correlative study on smears • Next generation sequencing

38. Personalization of Care in PC • hENT1 identified from RTOG 9704 • CO101 designed for hENT1 low to overcome the transport limitation • Phase III trial announced as negative • Stromal SPARK correlated with responses to GEM/Nab-paclitaxel • Phase III trial announced as positive • No details of plans to evaluate SPARK • Smad4 (DPC4)

39. Success of local treatment intensification hinges on selection 2000-2010 - Clinical selection (CTX first) Select out early DM phenotype Location (away from duodenum), tumor size, low Ca 19-9, response to CTX 2010 and beyond - genotypic selection Identify ‘locally destructive’ phenotype SMAD4 intact?

40. Conclusions, Role of XRT Locally advanced PC Effective local therapy is necessary for long term survival in LAPC 12 mo MS is not good enough! CTX and CXRT are complementary modalities Standard sequencing is chemo (2-4 mo) then CXRT Select patients who may benefit from CXRT