Pancreatic Cancer Therapy: Current Status Timothy R. Donahue, MD UCLA Center for Pancreatic Diseases Institute for Molecular Medicine Department of Surgery David Geffen School of Medicine at UCLA Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer Epidemiology (2009) • # 4 cause of cancer-related deaths • # 2 cause from GI cancer • USA: • 42,770 new cases • 35,240 deaths • California: • 3700 new cases • Overall 5-year survival rate: 5% Pancreatic Cancer Poor Survival • Late presentation • Aggressive tumor biology • Poor response to available therapies: • Radiation therapy • Cytotoxic chemotherapy • Biologic therapies • Immunotherapy Pancreatic Cancer Late Presentation Pancreatic Cancer Late Presentation Prevalence • Resectable 15 – 20% • Metastatic 40% • Locally advanced 30 – 40% 80% Pancreatic Cancer Late Presentation • Surgical resection: Only treatment associated with cure • 5-year survival • Pancreatic resection: 25 – 35% • No cancer-directed treatment: 5% Sener S, JACS 1999 Pancreatic Cancer Late Presentation Median Survival (months) • Resectable 10 - 20 • Metastatic 3-6 • Locally advanced 8 – 12 Pancreatic Cancer Aggressive Biology Jones S, Science 2008 Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer Criteria for Unresectability • Extra-pancreatic involvement • LN or distant metastasis • SMV / Portal vein contact • > 50% or segmental occlusion • SMA, IVC, aorta, or celiac axis contact Pancreatic Cancer Resectable Disease: Improving Outcomes • Teaching hospitals • Lower perioperative mortality • Better patient selection • Greater use of adjuvant Rx Birkmeyer JD, N Engl J Med 2002 Lim JE, Ann Surg 2003 Pancreatic Cancer Resectable - Surgery • Head / uncinate process: pancreaticoduodenectomy (Whipple) • Standard = pylorus preserving • Body / tail: distal pancreatectomy +/splenectomy • 15 LN : adequate staging Tomlinson JS, Arch Surg 2007 Pancreatic Cancer Pylorus Preserving Whipple Pancreatic Cancer Resectable – Survival • Lymph node status: most predictive 5-Year Survival • LN positive 10% • LN negative 25 – 30% Cameron JL, Ann Surg 2006 Pancreatic Cancer Resectable - Survival • Other favorable predictors: • Tumor size (< 3 cm) • Negative margins • Location (head) • Grade (well differentiated) • Intraoperative blood loss (< 750 mL) Cameron JL, Ann Surg 2006 Pancreatic Cancer Resectable - Survival • TNM Staging System vs. Nomogram Brennan MF, Ann Surg 2004 Pancreatic Cancer Resectable – Neoadjuvant Rx • Regimens examined: • • Gemcitabine-based + RT 5-FU-based + RT • Safely administered • No adverse impact on perioperative morbidity / mortality • No clear benefit vs. surgery alone or adjuvant therapy Pancreatic Cancer Resectable – Adjuvant Rx • SEER Database (n=396) • • Improves survival Improves quality of life • No consensus on optimal Rx strategy • US: mixed chemotherapy / RT approach • • NCCN supports both RTOG 9704 Trial (2008) Lim JE, Ann Surg 2003 Regine WF, JAMA 2008 Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer Borderline Resectability: NCCN Criteria • Tumor abutment of the SMA • Severe unilateral SMV / PV impingement • GDA encasement to its origin • Invasion of the transverse mesocolon Katz MH, J Am Coll Surg 2008 Pancreatic Cancer Radiologic Staging Stage 1: up to 1/4 circ Stage 3: 1/2 -3/4 circ Stage 2: 1/4 - 1/2 circ Stage 4: > 3/4 circ Lu DSK, Am J Roentgenol 1997 Pancreatic Cancer Radiologic Staging Predicts Resection • • • • Stage 1 Stage 2 Stage 3 Stage 4 >90% 50% almost never never Lu DSK, Am J Roentgenol 1997 Pancreatic Cancer Borderline & Locally Advanced • High likelihood of R1 or R2 resection • No survival benefit • Course of neoadjuvant therapy • Chemotherapy +/- RT • Downstaged patients: 13 – 54% • Survival approaches resectable patients • Single institution trials Lowy AM, J Gastrointest Surg 2008 Pancreatic Cancer UCLA Downstaging Experience: Clinical Question • Which patients with locally advanced or borderline resectable pancreatic cancer who complete a course of treatment (chemo +/- RT) should be offered an operation for possible resection? Pancreatic Cancer UCLA Downstaging Experience: Clinical Question Before Tumor: 4.4 x 3.8cm PV invasion (+) After Tumor: 2.8 x 2.5cm (57% reduction) PV invasion (-) Pancreatic Cancer UCLA Downstaging Experience Methods • Criteria for exploration after treatment: • CT/MRI evidence of shrinkage or change in signs of vascular involvement • CA 19.9 decrease • Good functional status Pancreatic Cancer UCLA Downstaging Experience: Specific Aims • Review resection rate • Determine the accuracy of CT/MRI in predicting resectability after treatment • Identify other predictors of resectability • Examine the survival of the cohort Pancreatic Cancer UCLA Downstaging Experience Methods • UCLA Pancreatic Database 1992 – 2009 • 39 patients with pancreatic cancer: • Locally advanced & unresectable • Neoadjuvant treatment (chemo +/- radiation) • Downstaged • Re-explored Pancreatic Cancer UCLA Downstaging Experience Operative & Pathologic Findings Outcome (n = 39) Resectable 32 (82%) Unresectable 7 (18%) Lymph Nodes Positive (n = 32) Negative 6 (19%) 26 (81%) Pancreatic Cancer UCLA Downstaging Experience Results • CT/MRI: • Not accurate at detecting vascular involvement after treatment • Sensitivity: 71% • Specificity: 58% • CA19.9: • Resected patients: median decrease of 87% (P < 0.01) Pancreatic Cancer UCLA Downstaging Experience Survival 52 • • Median survival = 52 months Follow-up survivors (median) = 31 months Pancreatic Cancer UCLA Downstaging Experience Survival • Five-year survivors (n=9) • Observed five-year survival rate: 28% (9/32) • < 5 year follow-up but NED (n=8) • Maximum five-year survival rate: 53% (17/32) Pancreatic Cancer UCLA Downstaging Experience Conclusions • Patient selection strategy worked • High resection rate • CT/MRI not accurate after treatment • Low sensitivity / specificity • Change in vascular involvement not essential • Excellent survival • Long-term survivors Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer Unresectable – Cytotoxic Chemo • Large meta-analysis (n = 7043) • Single agent chemotherapy improves • Survival • Quality of life • Gemcitabine and platinum combinations • worked best No role for radiation therapy Yip D, Cochrane Database Syst Rev 2009 Pancreatic Cancer Unresectable – Molecular Rx (Phase III) • EGFR Moore MJ, J of Clin Oncology 2007 Philip PA, J of Clin Oncology 2009 van Cutsem E, J of Clin Oncology 2009 • KRAS • VEGF van Cutsem E, J of Clin Oncology 2004 Kindler H, J of Clin Oncology 2007 Pancreatic Cancer Unresectable – Palliation • Biliary obstruction • Endoscopic metal stents are best • Endoscopic stents vs. surgical bypass • UCLA: laparoscopic splenectomy • Duodenal obstruction • Hypersplenism and thrombocytopenia Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer NCI Meeting – Summary • Define direction over next 3 – 5 years • Molecular heterogeneity • Discovery and validation of biomarkers • Targeted agents • Cancer stem cell signaling • Stromal vs. epithelial component • Angiogenesis • Metastatic signature Philip PA, J Clin Oncol 2009 Pancreatic Cancer Outline • Epidemiology and prognosis • Treatment options • Resectable • Borderline resectable & locally advanced • Unresectable • NCI clinical trials • UCLA Center for Pancreatic Diseases Pancreatic Cancer UCLA Center for Pancreatic Diseases • Multi-disciplinary approach • 2009 Center Statistics: • 750 new patients seen • 85% for cancer • 150 pancreatic resections • 35% 5-year overall survival Pancreatic Cancer UCLA Center for Pancreatic Diseases Clinical Trials • Active: • Adjuvant vaccine: Killed yeast expressing KRAS • Gene therapy for locally advanced disease: Direct intratumoral TNFα injections • Future: • Src inhibitor Pancreatic Cancer UCLA Center for Pancreatic Diseases Molecular Signature Global PaCa genetic & molecular analysis: DNA, mRNA, and miRNA arrays Novel biomarkers and targets for tailored therapy Pancreatic Cancer Summary • Pancreatic cancer • Prevalent and poor prognosis • Treatment & survival slowly improving • Regionalization of care • Future treatment directions • Routine neoadjuvant therapy? • Molecular profiling: tailored therapy with targeted agents Sixth Annual Agi Hirshberg Symposium on Pancreatic Cancer