1. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer: The Potential Role of Chemotherapy Robert A. Wolff, M.D. Associate Professor of Medicine Department of GI Medical Oncology U.T.M.D. Anderson Cancer Center Meet The Professor Session 2009 Gastrointestinal Cancers Symposium San Francisco January 16 th, 2009 rwolff@mdanderson.org

2. StudyN%R1%T3%N1%LF ESPAC-128918 NS5463 CONKO-00119416 82 70 38 ID98-020646 673811 ID01-341524 83 60 25 Neoptolemos JP et al. NEJM, 2004 Evans DB, et al. JCO, 2008 Oettle H, et al. JAMA, 2007 Varadhachary GR, et al. JCO, 2008 Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons from Resectable Pancreatic Cancer Point #1. Pre-Operative Chemoradiation decreases local failure.

3. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons from Resectable Pancreatic Cancer Point #2. Pre-Operative Chemotherapy Data is more limited. Author# PtsTreatmentResection Rate %R1Median Overall Survival Heinrich28Gem/Cis86%NS26.5 M Palmer 26 24 Gem/Cis Gem 70% 38% 25% 28.4 M Heinrich S, et al. Ann Surg Onc, 2008.Palmer DH, et al. Ann Surg Onc, 2007. %LF ????

4. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons from Resectable Pancreatic Cancer Pre-Operative Regimen Elapsed Time to Restaging Resection Rate %R1Median Survival (Resected Patients) Gem + XRT12 Weeks74%11%34 months Gem/Cis Gem + XRT 17 weeks66%4%31 months Point #3. Chemotherapy does not add benefit over Pre-Operative ChemoXRT Evans DB, et al. JCO, 2008.Varadhachary GR, et al. JCO, 2008.

5. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons Learned in Resectable Pancreatic Cancer Point #3. Well, maybe more chemotherapy does help. Pre- Operative Regimen Number of Resected Patients pT3pN1 Median Survival Gem + XRT6467%38%34 months Gem/Cis Gem + XRT 5283%60%31 months

6. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons from Resectable Pancreatic Cancer Point #4. Full Dose Chemotherapy is NOT a factor. StudyGemcitabine Dose (mg/m 2 ) Total Intended Gemcitabine Dose (mg/m 2 ) Median Survival CONKO 0011,000 mg/m 2 3 wk on,1 off X 6 cycles 18,000 mg/m 2 23 months Gem/XRT400 mg/m 2 Weekly X 7 2,800 mg/m 2 34 months Gem/Cis Gem/XRT 750 mg/m 2 q 2 wks X 4 doses 400 mg/m2 X 4 4,600 mg/m 2 31 months

7. Pre-Operative Therapy for Borderline Resectable Pancreatic Cancer Lessons from Resectable Pancreatic Cancer Point #5. The criteria used to decide on surgery MATTERS! Author Year Regimen# Patients Resection Rate Median Survival Resected Evans 2008 Gem/XRT8474%34 M Varadhachary 2008 Gem/Cis Gem/XRT 9666%31 M Katz 2008 Variable84 (Type A) 38%40 M Can’t Progress! Must Respond! Evans DB, et al. JCO, 2008. Varadhachary GR, et al. JCO, 2008. Katz MH, et al. J Am Coll Surg, 2008.

8. Borderline Resectable Pancreatic Cancer Current Challenges ● It remains unclear if borderline resectable pancreatic cancer is biologically distinct from resectable pancreatic cancer, or if the role of neoadjuvant therapy is simply to help achieve a negative margin. ● What is best approach? ● Chemoradiation? ● Systemic chemotherapy and chemoradiation? ● How long to treat to determine favorable biology?

9. Investigational Strategies for Locally advanced pancreatic cancer Induction Chemotherapy with molecular agent Restage Localized ChemoXRT + Molecular Agent Metastatic 2 nd Line Rx or Best Supportive Care Targeted Rx as Maintenance

10. Current MDACC Strategy for Borderline Resectable Pancreatic cancer Induction Chemotherapy with molecular agent Restage Localized ChemoXRT + Molecular Agent Metastatic 2 nd Line Rx or Best Supportive Care Vote surgery up or down! Restage

11. Current MDACC Protocol: Gemcitabine-Oxaliplatin-Cetuximab followed by Chemoradiation for Locally Advanced Pancreatic Cancer C Week 12345678 C C C Gem/Ox C Induction chemotherapy gemcitabine 1000 mg/m 2 with oxaliplatin 100 mg/m 2 day 1, 15, 29, 43. Cetuximab 400 mg/m 2 load day 1, with 250 mg/m 2 weekly thereafter. Capecitabine + Cetuximab +Radiation Therapy Week 1011121314

12. Truly Resectable Upfront Surgery Restage Gem-based adjuvant chemotherapy Borderline Resectable Restage Protocol-based PreOperative Rx RestageSurgery ?XRT ALL Patients SHOULD UNDERGO Neoadjuvant Therapy: On or Off Protocol Restage

13. Borderline Resectable Pancreatic Cancer Current Clinical Research Challenges ● No broad consensus as to what constitutes borderline resectable disease. ● Primary tumor anatomy? ● Elevated CA19-9? ● Equivocal evidence for metastatic disease? ● No consensus about response criteria to proceed with surgery. ● All Therapies are Empiric!!!!!!!! ● Cytotoxic chemotherapy ● Molecular therapy ● Radiation therapy WANTED: Personalized cancer therapy!

14. Borderline Resectable Pancreatic Cancer Personalized Cancer Therapies Borderline Resectable Pre-Rx Biopsy Treatment ATreatment B Treatment C

15. Summary ●Borderline resectable pancreatic cancer is a distinct clinical entity that must be recognized as putting the patient at risk for a positive surgical margin with upfront surgery. ●Preoperative therapy for resectable pancreatic cancer that includes radiation appears to lower rates of positive surgical margins and decrease the risk of local failure. ●This approach is particularly relevant for patients with borderline resectable disease. ●Limited single-institutional experience is encouraging. ●Definitions for borderline resectable disease and response criteria require further refinement if clinical research is to be fruitful. ●Therapies that are personalized will likely lead to more success for patients with all stages of pancreatic cancer.