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Management of Advanced Pancreatic Cancer

Management of Advanced Pancreatic Cancer. Wenqing Zhang, MD Medical Oncology/Hematology Fellow James Graham Brown Cancer Cancer University of Louisville Multimodality Meeting 3/4/10. INTRODUCTION. CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20.

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Management of Advanced Pancreatic Cancer

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  1. Management of Advanced Pancreatic Cancer Wenqing Zhang, MD Medical Oncology/Hematology Fellow James Graham Brown Cancer Cancer University of Louisville Multimodality Meeting 3/4/10

  2. INTRODUCTION CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20. 4th leading cause of cancer-related death in the United States 2nd only to colorectal cancer as a cause of digestive cancer-related death Has the worst survival of ANY solid tumor. Only 1-4% of all pts will be cured Surgical resection is the only potentially curative treatment 15 to 20 percent of patients are candidates for pancreatectomy

  3. EPIDEMIOLOGY CA Cancer J Clin. 2008 Mar-Apr;58(2):71-96. Epub 2008 Feb 20. • 37000 more new diagnose each yr • 80% locally advanced or metastatic • Most patient diagnosed between 65-80 yo • Median survival • 8-12mths locally advance • 3-6 mths metastatic disease • American American has higher mortality than any other ethnic group

  4. EPIDEMIOLOGY • Stage at presentation: • Stage I: 20% • Stage II: 40% • Stage III-IV: 40% • 15-20% patients are candidates for pancreatectomy

  5. RISK FACTORS 1. Everhart & Wright JAMA 1995;273(20):1605-9 • Chronic pancreatitis(5% PC cases) • Obesity and physical activity: BMI> 30 kg/m2 • Smoking: RR 1.5(30% PC cases) • DM: A meta-analysis of 20 studies RR was 2.1(1) • Hereditary predisposition • Family history

  6. CLINICAL FEATURES *Kalser et al Cancer 1985;56:397-402 • PAIN 80-85% • WEIGHT LOSS, FATIGUE • JAUNDICE, PRUITUS • Painful jaundice 50% locally unresectable* • Painless jaundice 50% resectable and curable lesion * • ANOREXIA, NAUSEA/VOMITING • NEW ONSET DM • DEPRESSION

  7. Pathology • Exocrine carcinomas: • Adenocarcinoma(>90%) • Majority ductal:Desmoplasia • Rarely acinar: younger • Occasional cystic : less aggressive • Neuroendocrine carcinomas: • Important to distinguish • Usually more indolent

  8. Serum tumor markers J Clin Oncol. 2006 Nov 20;24(33):5313-27. Epub 2006 Oct 23. • CA 19-9…mucinous glycoprotein • Serial monitoring:1-3 mons • Rising CA 19-9 levels usually precede the radiographic appearance • Very high CA 19-9 levels (eg, >1000 U/mL) associated w/ unresectable disease • Inc CA 19-9 is not always due to tumor progression • Cholangitis, pancreatitis, billiary obstruction

  9. STAGE GROUPING

  10. Practical Real World Staging • Localized, resectable • Locally advanced, unresectable • Metastatic • Location • Head: 80%(more likely to be resectable) • Other: 20%

  11. Pancreatic cancer: stage at diagnosis Ries et al. SEER Cancer Statistics Review, 1975-2001

  12. Pancreatic cancer: 5-year survival(%) by stage

  13. Treatment options Surgery Chemo+/-XRT Supportive/Palliative care • Biliary decompression • Biliary-enteric bypass • Billiary stent • Percutaneous stenting at PTC • Pain management • Palliative XRT Diagnostic Curative Palliative Adjuvant Neoadjuvant Definitive

  14. Chemoradiation therapy • Radiation alone is effective in pain control • Chemotherapy concurrent with XRT improves survival over XRT alone • Toxicity: nausea, vomiting, anorexia and weight loss

  15. Whipple Procedure • Disease that is limited to the pancreas and peripancreatic nodes, Stage I-IIB disease • Five-year survival of 20-30% • Perioperative mortality rate <4% • Fourfold increase in mortality was noted <1 case/yr vs. > 16 cases /yr • Five-year survival • node-positive disease 10% • node-negative 25-30%

  16. Who can get surgery ? Only 5-15% are resectable PC Median survival 18-24 months , 5-year survival 5-20% after surgery.Surgicalmortality1-5%。

  17. CTA criteria for resectable pancreatic cancer • Absence of non-contiguous, extra-pancreatic disease • Patient of the superior mesenteric /splenic/portal vein confluence • SMV, portal vein can be resected with vein reconstruction • No e/o tumor extension to or encasement of the Superior mesenteric artery • SMA or celiac artery involvement are clearly unresectable

  18. Chemotherapy in pancreatic cancer • Pre-1996: Many drugs tested, nothing worked • 1996: Gemcitabine approved by FDA • 1996-2005:many drugs tested, no drug or drug combination is better than Gem • 2005: Erlotinib + Gem is better than Gem alone. Erlotinib is FDA approved for PC • 2005: Capecitabine+GEM is better than Gem alone • 2006: Oxaliplatin+Gem is not better than Gem alone • 2006: Bevacizuman + Gem is not better than Gem alone • 2006: Cisplatin + Gem is not better than Gem alone • 2007: Cetuximab + Gem is not better than Gem alone

  19. Single-agent activity against pancreatic cancer

  20. Long search for new single agent or combination regiment for advanced pancreatic cancer • Since 1996, many cytotoxic and targeted agents have been tested against, or combined with , gemcitabine in randomized phase III trials. • No single drug was showed to be superior to Gemcitabine • Some combination regimens showed promising results.(Gem based is better than 5-FU based combination)

  21. Why the response rate is so low? • Very resistant to most tested drugs! • Biology of the disease not well understood • Most diagnoses are made late due to indolent nature and lack of screening test GEMCITABINE is the best!

  22. In phase III trial, single agent Gemcitabine consistently yields a median survival of 5-6 months and a 1-yr survival of ~20%

  23. Gemcitabine: The standard care for advanced pancreatic cancer since 1996 Burris. JCO 1997

  24. How about combination therapy in advanced pancreatic cancer? • Surgery+neoadjuvant chemo/XRT • Chemo/XRT • Combination of two or three drugs…..

  25. A randomized phase III study of gemcitabine in combination with XRT versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201. • Locally unresectable pancreatic adenocarcinoma, PS <2, without prior chemotherapy or radiation therapy were eligible. 316 eligible pts • ARM A: G alone(wkly x 3 every 4 wks) for 7 cyc • ARM B: RT plus G (wkly x 6) 5 cycles of G alone (wkly x 3 every 4 wks). • From April, 2003 to December, 2005 • 74 pts were enrolled J Clin Oncol 26: 2008 (May 20 suppl; abstr 4506)

  26. E4201: A phase III study of gemcitabine + RT VS. gemcitabine in local advanced PC RANDOM I ZE GEMCITABINE GEMCITABINE • Stratify: • PS(0 vs 1) • Wt loss • (>10% vs <=10%) Primary endpoint overall survival GEMCITABINE + Concurrent RT GEMCITABINE Study closed prematurely due to poor accural Loehrer et al： J Clin Oncol 26: 2008 (May 20 suppl; ab4506)

  27. Gemcitabine+/- RT in local advanced PC Loehrer et al： J Clin Oncol 26: 2008 (May 20 suppl; ab4506)

  28. Progression free survival

  29. Overall survival

  30. How to interpret this data? • Randomized, multi-center trial • Much smaller than planned: 25% of intended sample size • Survival benefit with Chemo/XRT in LAPC • More toxicity with Chemo/XRT • RR and PFS no different

  31. The most common design for Phase III trial for advanced PC • Drug X vs Gemcitabine • Drug X plus Gemcitabine vs Gemcitabine alone

  32. Phase III trial comparing intensive inductionchemoradiotherapy (60 Gy, infusional 5-FU andintermittent cisplatin) followed by maintenancegemcitabine with gemcitabine alone for locallyadvanced unresectable pancreatic cancer. Definitiveresults of the 2000–01 FFCD/SFRO study • B. Chauffert et al: Annals of Oncology 19: 1592–1599, 2008 The role of chemoradiation with systemic chemotherapy compared with chemotherapy alone in locally advanced pancreatic cancer (LAPC

  33. Total 119 LAPC • Primary end point: • Median OS • Secondary end points : • progression-free survival (PFS) • WHO PS grades 3–4 free survival

  34. Grade 3/4 toxic effects during the induction and maintenance phases

  35. Conclusion • This intensive induction schedule of CHRT was more toxic and less effective than gemcitabine alone • XRT has no rule in treatment of advanced pancreatic cancer

  36. CONSORT diagram

  37. Study design • 832 patients locally advanced or metastatic PC enrolled • The primary objective : to compare survival of GEMFDR and GEMOX each to GEM using pair-wise comparisons. • Secondary end points : • the comparison of survival , • the assessment of toxicity, • objective response to therapy, • patterns of failure, • PFS, • and symptom severity across the three regimens.

  38. Result

  39. Conclusion • Neither GEM FDR nor GEMOX resulted in substantially improved survival or symptom benefit over standard GEM in patients with advanced pancreatic cancer. • Grade 3/4 neutropenia and thrombocytopenia were greatest with GEM FDR. • GEMOX caused higher rates of nausea, vomiting, and neuropathy.

  40. GEM-CAP (gemcitabine plus capecitabine)trial Design

  41. GEM-CAP (gemcitabine plus capecitabine)trial Design • Between May 2002 and January 2005, 533 patients were recruited from 75 hospitals in the UK • Patients were randomly allocated to GEM(n266) and GEM-CAP(n267) arms • Primary end point: OS • 2nd end points: • Response rate • PFS • Toxicity, QOL

  42. Patient Characteristics

  43. Summary of Efficacy Results

  44. Grade 3-4 Toxicities

  45. meta-analysis of published randomized controlled trials(GEM vs GEM-CAP)

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