1. Pancreatic cancer chemotherapy Jarosław Reguła M.D. Department of Gastroenterology, Institute of Oncology, Warsaw, Poland

2. Pancreatic cancer 10-th common cancer10-th common cancer 4-th cause of cancer death4-th cause of cancer death Overall 5-year survival – ca. 4%Overall 5-year survival – ca. 4%

3. Diagnosis established general status (Karnofsky) general status (Karnofsky) supportive care TNM staging palliation surgery alone surgery + adjuvant therapy chemotherapy

4. Combined therapy Neo-adjuvant therapy = before surgery Neo-adjuvant therapy = before surgery Adjuvant = after surgery Adjuvant = after surgery Sequential or concomittant (eg. CTH & RTH) Sequential or concomittant (eg. CTH & RTH)

5. T staging

6. T3 –locally advanced Extends beyond pancreas but no involvement of celiac axis or superior mesenteric artery Potentially resectable in expert centres

7. T4 Involvement of celiac axis or superior mesenteric artery

8. No or N1 (number of lymph nodes involved does not need to be defined

9. Stage groups Stage 0Tis N0M0 Stage I AT1 N0M0 potentially resectable Stage I BT2 N0M0 Stage II AT3 N0M0 usually potentially resectable Stage II BT1-3 N1M0 Stage IIIT4 N0-1 M0 locally advanced, not resectable due to CA or SMA involvement Stage IVT1-4 N0-1 M1 metastatic

10. Resection R classification (residual tumour)R classification (residual tumour) –R0: tumour resected macroscopically and microscopically completely –R1: tumour resected completely macroscopically but incompletely microscopically –R2: resection incomplete macroscopically

12. Stage I/II patients

18. Neoptolemos NEJM, 2004

23. ESPAC-3 The largest ever trial on adjuvant therapy in pancreatic cancerThe largest ever trial on adjuvant therapy in pancreatic cancer 1100 patients in 17 European counties 1100 patients in 17 European counties Arm A: 5-FU/folinic acid Arm A: 5-FU/folinic acid Arm B: gemcitabine day 1,8,15 every 28 days Arm B: gemcitabine day 1,8,15 every 28 days Results are awaitedResults are awaited

24. Clear benefit from adjuvant chemotherapy after resection

25. Standard adjuvant therapies USA – adjuvant chemoradiotherapyUSA – adjuvant chemoradiotherapy Europe – adjuvant chemotherapyEurope – adjuvant chemotherapy Debate continues

26. Advanced disease - usual survival Localized disease – ca. 1 yearLocalized disease – ca. 1 year Metastatic disease – ca. 6 monthsMetastatic disease – ca. 6 months Endpoints:Endpoints: –Overall survival –Quality of life –Clinical benefit response (CBR): (pain, KPS, weight)

27. Main agents for chemotherapy 5-FU – 600 mg/m2 weekly5-FU – 600 mg/m2 weekly Gemcitabine – 1000 mg/m2 weekly for 7 weeks (1 week off) + wekly 3 weeks with 1 week offGemcitabine – 1000 mg/m2 weekly for 7 weeks (1 week off) + wekly 3 weeks with 1 week off

28. 5-FU vs gemcitabine 5-FUGemcitabine 5-FUGemcitabine Survival (median) 4,4 mo5,6 mo 12 month survival 2%18% CBR 4,8%23,8%

29. FDR Gemcitabine Increasing time of infusion holding the dose rate constantIncreasing time of infusion holding the dose rate constant Conflicting resultsConflicting results Most administer the drug in a standard wayMost administer the drug in a standard way

30. Capecitabine (Xeloda) OrallyOrally Pro-drug of 5-FUPro-drug of 5-FU Combination Gemcitabine+capecitabine vs gemcitabineCombination Gemcitabine+capecitabine vs gemcitabine for patients Karnofsky status 90-100 points overall survival benefit overall survival benefit 10,4 monts vs 7,4 months Herrmann 2007

31. Targeted therapies EGFR inhibitors:EGFR inhibitors: –Erlotinib –cetuximab VEGF inhibitorsVEGF inhibitors –Bevacuzimab OthersOthers

34. Real life (Institute of Oncology, Warsaw) Resectable tumour: Resectable tumour: - adjuvant chemotherapy (gemcitabine) – standard dosing - adjuvant radiochemotherapy as research programme Palliative therapyPalliative therapy Gemcitabine (standard) until progression or toxicityGemcitabine (standard) until progression or toxicity Gemcitabine + Xeloda (non standard approachGemcitabine + Xeloda (non standard approach Second lineSecond line FAM (5-FU+ adriamycin + mitomycin)FAM (5-FU+ adriamycin + mitomycin) Clinical trials with anti-EGFRClinical trials with anti-EGFR

35. Summary Proper staging is crucial for planning therapy Proper staging is crucial for planning therapy Selection of patients for a given therapy is difficult Selection of patients for a given therapy is difficult Resectable patients should have adjuvant therapy (gemcitabine) providing good general status Resectable patients should have adjuvant therapy (gemcitabine) providing good general status Palliative therapy (gemcitabine monotherapy) Palliative therapy (gemcitabine monotherapy) Numerous trials exist Numerous trials exist

36. Question 1 Tumour extending beyond pancreas, not inflitrating CA or SMA is: 1) T11) T1 2) T22) T2 3) T33) T3 4) T44) T4

37. Question 2 T4N1M0 is unresectable due to : 1) metastatic disease1) metastatic disease 2) involvement of SMA or CA2) involvement of SMA or CA 3) lymph node involvement3) lymph node involvement 4) Karnofsky status 30%4) Karnofsky status 30%

38. Question 3 : Capecitabine is 1) oral gemcitabine1) oral gemcitabine 2) oral 5FU2) oral 5FU 3) oral cetuximab3) oral cetuximab 4) oral oxaliplatine4) oral oxaliplatine