1. Neoadjuvant Treatment for Pancreatic Adenocarcinoma CH MAN Department of Surgery Caritas Medical Centre

2. Background Aggressive malignancy Overall median survival: 5-6 months 5-year survival rate: approx. 5% Risk factors: Smoking Heavy alcohol consumption Chronic pancreatitis Family history

3. Background (cont’d)

4. History of Pancreatic AdenoCa Treatment The only chance of cure: SURGICAL RESECTION Outcome not satisfactory Median survival: 15-19 months 5-year survival after resection: less than 20% Recurrence in 30-50% of patients after presumed curative resection J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.

5. History of Pancreatic AdenoCa Treatment (cont’d) In 1985, Gastrointestinal Tumor Study Group reported: Median survival of patients after resection prolonged for almost twofold by adjuvant chemoradiation 2-year survival: 42% in adjuvant chemoradiation group VS 15% in control group Arch Surg. 1985 Aug;120(8):899-903. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Kalser MH, Ellenberg SS.

6. RCT in 2008 Treatment with gemcitabine for 6 months after complete resection Significantly increases 5 years disease-free survival: 16% Median overall survival: 22.8 months J Clin Oncol26: 2008 Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotheraoy with gemcitabine versus observation in patients with resected pancreatic cancer. Neuhaus P, Riess H, etal. History of Pancreatic AdenoCa Treatment (cont’d)

7. Questions How to enhance the chance of resection? How to further improve the survival after resection besides adjuvant therapy?

8. Therapies Neoadjuvant Chemotherapy and Radiotherapy Is there a role? Who will benefit? What is the optimal regimen?

9. Pancreatic AdenoCa Resectable Absence of extrapancreatic disease Clear tissue plane around celiac axis, hepatic artery and SMA A patent SMV-PV confluence

10. Pancreatic AdenoCa Borderline resectable Absence of extrapancreatic disease Tumor involvement or occlusion of SMV/PV confluence amenable to resection and reconstruction Short segment of abutment/encasement of hepatic artery Tumor abutment of the SMA < 180 degrees of the circumference of the vessel

11. Pancreatic AdenoCa Unresectable Distant metastases Lymph nodes metastases beyond the field of resection Aortic invasion Greater than 180 degrees SMA encasement Unreconstructible SMV/portal occlusion

12. Potential Benefit of Neoadjuvant Therapy in Resectable Disease The administration is not affected by the surgical morbidities 20% of patients did not receive the assigned adjuvant therapy Occult metastases is allowed to manifest exclude patient from resection avoid the surgical morbidity Improve the chance of negative resection margin Ann Surg 1999; 230:776–82. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.

13. Neoadjuvant Therapy in Resectable Disease Involved resection margins are a poor prognostic factor

14. Neoadjuvant Therapy in Resectable Disease Negative impact on survival with an increasing number of positive margins J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.

15. Neoadjuvant Therapy in Resectable Disease Neoadjuvant therapy can improve the chance of R0 resection and decrease the number of multiple positive margins J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL.

16. Neoadjuvant Therapy in Resectable Disease The overall median survival from the time of tissue diagnosis was 21 months At median 14 weeks of follow-up, 31% of patients showed no evidence of disease Survival duration is improved by the combination of neoadjuvant therapy and surgery

17. Neoadjuvant Therapy in Resectable Disease Phase II trial for preoperative gemcitabine-based chemoradiation and surgical treatment

18. Neoadjuvant Therapy in Resectable Disease Median survival was 34 months for patients who underwent neoadjuvant therapy and surgery

19. Neoadjuvant Therapy in Resectable Disease However, 15% of the patients developed into unresectable disease because of disease progression J Clin Oncol. 2008 Jul 20;26(21):3496-502. doi: 10.1200/JCO.2007.15.8634. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA, Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA.

20. Potential Disadvantages of Neoadjuvant Therapy Requirement for biliary decompression before chemotherapy Potential complications from biliary stents Requirement for tissue diagnosis before chemotherapy Procedure related Cx including seeding of tumor cells Percutaneous FNA causing 16.3% peritoneal seeding Side effects from chemotherapy Gastrointest Endosc. 2003 Nov;58(5):690-5. Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. Micames C, Jowell PS, White R, Paulson E, Nelson R, Morse M, Hurwitz H, Pappas T, Tyler D, McGrath K.

21. Conclusion of Neoadjuvant Therapy on Resectable Pancreatic Cancer The adoption is still controversial Improvement of survival but risk of disease progression at the same time No global consensus is reached at the moment National Comprehensive Cancer Network (NCCN): Does not recommend Except on clinical trial

22. Potential benefit of neoadjuvant therapy in borderline resectable disease The administration is not affected by the surgical morbidities 20% of patients did not receive the assigned adjuvant therapy Occult metastases are allowed to manifest exclude patient from resection avoid the surgical morbidity Improve the chance of negative resection margin Increase the chance of resection Ann Surg 1999; 230:776–82. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Klinkenbijl JH, Jeekel J, Sahmoud T, et al.

23. Neoadjuvant therapy in borderline resectable disease Several trials have revealed that neoadjuvant treatment is effective in borderline resectable case

24. Recent retrospective study on borderline resectable disease 61.7% negative margin of resection with neoadjuvant chemoradiation 38.3% negative margin of resection without neoadjuvant chemoradiation J Clin Oncol 30, 2012 (suppl 4; abstr 304) Margin status and neoadjuvant chemoradiation in patients with borderline resectable pancreatic cancer Pavlos Papavasiliou, Jonathan R Piposar, Rodrigo Arrangoiz, Kathryn T Chen, Fang Zhu, Yun Shin Chun, John Parker Hoffman Neoadjuvant therapy in borderline resectable disease

25. Respective review on patients with pancreatic cancer resection Patients with borderline resectable cancer received neoadjuvant therapy 46% underwent surgical resection 67% had margin-negative (R0) resection Neoadjuvant therapy in borderline resectable disease

26. Median survival: 23.3 months Similar to resectable disease HPB (Oxford). 2010 Feb;12(1):73-9. doi: 10.1111/j.1477-2574.2009.00136.x. Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable pancreatic cancer. McClaine RJ, Lowy AM, Sussman JJ, Schmulewitz N, Grisell DL, Ahmad SA. Neoadjuvant therapy in borderline resectable disease

27. No randomized phase III trials for comparison Although there is no high level evidence supporting its use Neoadjuvant therapy is still an option Improve treatment outcome Neoadjuvant therapy in borderline resectable disease

28. Neoadjuvant Regimen There is no standard regimen at the moment In early days Radiotherapy Progress to switch to chemoradiation EBRT + 5-FU Recently Gemcitabine-based chemoradiation

29. Conclusion Pancreatic cancer is an aggressive malignancy with minority of the patients suitable for surgical resection Adjuvant therapy can improve the outcome of the illness The role of neoadjuvant therapy is still under further exploration

30. Conclusion Resectable case Suggest proceeding to surgery ASAP Except in clinical trial Borderline resectable case Neoadjuvant therapy is an option

31. Reference J Gastrointest Surg. 2001 Mar-Apr;5(2):121-30. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. Pingpank JF, Hoffman JP, Ross EA, Cooper HS, Meropol NJ, Freedman G, Pinover WH, LeVoyer TE, Sasson AR, Eisenberg BL. Arch Surg. 1985 Aug;120(8):899-903. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Kalser MH, Ellenberg SS. J Clin Oncol26: 2008 Final results of the randomized, prospective, multicenter phase III trial of adjuvant chemotheraoy with gemcitabine versus observation in patients with resected pancreatic cancer. Neuhaus P, Riess H, etal. Ann Surg 1999; 230:776–82. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Ann Surg Oncol. 2001 Mar;8(2):123-32. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Breslin TM, Hess KR, Harbison DB, Jean ME, Cleary KR, Dackiw AP, Wolff RA, Abbruzzese JL, Janjan NA, Crane CH, Vauthey JN, Lee JE, Pisters PW, Evans DB. J Clin Oncol. 2008 Jul 20;26(21):3496-502. doi: 10.1200/JCO.2007.15.8634. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. Evans DB, Varadhachary GR, Crane CH, Sun CC, Lee JE, Pisters PW, Vauthey JN, Wang H, Cleary KR, Staerkel GA, Charnsangavej C, Lano EA, Ho L, Lenzi R, Abbruzzese JL, Wolff RA. Gastrointest Endosc. 2003 Nov;58(5):690-5. Lower frequency of peritoneal carcinomatosis in patients with pancreatic cancer diagnosed by EUS-guided FNA vs. percutaneous FNA. Micames C, Jowell PS, White R, Paulson E, Nelson R, Morse M, Hurwitz H, Pappas T, Tyler D, McGrath K. J Clin Oncol 30, 2012 (suppl 4; abstr 304) Margin status and neoadjuvant chemoradiation in patients with borderline resectable pancreatic cancer Pavlos Papavasiliou, Jonathan R Piposar, Rodrigo Arrangoiz, Kathryn T Chen, Fang Zhu, Yun Shin Chun, John Parker Hoffman HPB (Oxford). 2010 Feb;12(1):73-9. doi: 10.1111/j.1477-2574.2009.00136.x. Neoadjuvant therapy may lead to successful surgical resection and improved survival in patients with borderline resectable pancreatic cancer. McClaine RJ, Lowy AM, Sussman JJ, Schmulewitz N, Grisell DL, Ahmad SA.

32. THANK YOU!