Abstract
Pancreatic adenocarcinoma is the most lethal of the solid tumors and the fourth leading cause of cancer-related death in North America. Most patients present with locally advanced or metastatic disease that precludes curative resection. These patients have an extremely poor prognosis. In the absence of effective screening methods, considerable efforts have been made during the past decade to identify better systemic treatments. Unfortunately most trials have not shown a survival advantage for most therapies. In tandem with this increased clinical research, there has also been an expansion of preclinical laboratory investigation. These preclinical studies revealed many of the molecular mechanisms involved in pancreatic cancer development, which has provided insights into why current therapies are ineffective. These new discoveries provide some optimism that new agents inhibiting specific targets will improve outcome and overcome the resistance of pancreatic cancer to most standard treatments. We review the current standards of care for patients with locally advanced and metastatic pancreatic carcinoma and outline some future directions for the development of new treatment strategies.
Key Points
-
Pancreatic adenocarcinoma has a high propensity for locoregional invasion and early development of distant metastases
-
Approximately 80% of patients present with locally advanced or metastatic disease that precludes curative surgery, and long term survival is poor
-
In 1997 gemcitabine was established as the standard first-line treatment for patients with advanced disease based on clinical benefit and survival improvement compared with 5-fluorouracil-based chemotherapy
-
During the past decade several clinical trials assessing different cytotoxic agents and combination chemotherapy failed to improve treatment outcomes
-
The combination of a targeted agent, erlotinib, with gemcitabine resulted in a small but significant improvement in survival compared with gemcitabine alone
-
A better understanding of the biology and molecular changes that occur in pancreatic cancer will permit the development of new agents to overcome resistance
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Jemal, A. et al. Cancer statistics. CA Cancer J. Clin. 58, 71–96 (2008).
Canadian Cancer Society/National Cancer Institute of Canada: Canadian Cancer Statistics 2008, Toronto, Canada, 2008. April 2008, ISSN 0835–2976.
Cubilla, A. L. & Fitzgerald, P. J. Tumors of the exocrine pancreas. in Atlas of Tumor Pathology (Eds Hartmann, W. H. & Sobin, H.), 2nd series, fascicle 19 (Armed Forces Institute of Pathology, Washington, 1984).
Solcia, E., Capella, C. & Kloppel, G. Tumors of the exocrine pancreas. in Tumors of the Pancreas (Eds Rosai, J. & Sobin, L. H.) 145 (Armed Forces Institute of Pathology, Washington, 1997).
Chu, G. C., Kimmelman, A. C., Hezel, A. F. & DePinho, R. A. Stromal biology of pancreatic cancer. J. Cell. Biochem. 101, 887–907 (2007).
Mahadevan, D. & Von Hoff, D. D. Tumor–stroma interactions in pancreatic ductal adenocarcinoma. Mol. Cancer Ther. 6, 1186–1197 (2007).
Winter, J. M. et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J. Gastrointest. Surg. 10, 1199–1211 (2006).
Sohn, T. A. et al. Resected adenocarcinoma of the pancreas—616 patients: results, outcomes, and prognostic indicators. J. Gastrointest. Surg. 4, 567–579 (2000).
Yeo, C. J. et al. Pancreaticoduodenectomy for cancer of the head of the pancreas: 201 patients. Ann. Surg. 221, 721–731 (1995).
Wong, H. H. & Lemoine, N. R. Pancreatic cancer: molecular pathogenesis and new therapeutic targets. Nat. Rev. Gastroenterol. Hepatol. 6, 412–422 (2009).
Royal, R. E., Wolff, R. A. & Crane, C. H. in Cancer Principles and Practice of Oncology (Eds De Vita Jr, V. T., Lawrence, T. & Rosenberg, S. A.) 8th edition, 1, 1118–1120 (Lippincott Williams and Wilkins, Philadelphia, USA, 2008).
Khorana, A. A. & Fine, R. L. Pancreatic cancer and thromboembolic disease. Lancet Oncol. 5, 655–663 (2004).
Sohail, M. A. & Saif, M. W. Role of anticoagulation in the management of pancreatic cancer. JOP 10, 82–87 (2009).
Icli, F. et al. Low molecular weight heparin (LMWH) increases the efficacy of cisplatinum plus gemcitabine combination in advanced pancreatic cancer. J. Surg. Oncol. 95, 507–512 (2007).
von Delius, S. et al. Effect of low-molecular weight heparin on survival in patients with advanced pancreatic adenocarcinoma. Thromb. Haemost. 98, 434–439 (2007).
Riess, H. et al. Rational and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy [abstract]. BMC Cancer 8, a361 (2008).
Heinemann, V. & Boeck, S. Perioperative management of pancreatic cancer. Ann. Oncol. 19 (Suppl. 7), vii273–vii278 (2008).
Kalser, M. H. & Ellenberg, S. S. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch. Surg. 120, 899–903 (1985).
Klinkenbijl, J. H. et al. Adjuvant radiotherapy and 5-fluorouracil after resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer group. Ann. Surg. 230, 776–784 (1999).
Neoptolemos, J. P. et al. European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N. Engl. J. Med. 350, 1200–1210 (2004).
Crane, C. H., Ben-Losef, E. & Small, W. Jr. Chemotherapy for pancreatic cancer. N. Engl. J. Med. 350, 2713–2715 (2004).
Oettle, H. et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer. JAMA 297, 267–277 (2007).
Neuhaus, P. et al. CONKO-001: final results of the randomized, prospective, multicentre phase III trial of adjuvant chemotherapy with gemcitabine versus observation in patients with resected pancreatic cancer [abstract]. J. Clin. Oncol. 26 (Suppl. 18), a4504 (2008).
Regine, W. F. et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma. JAMA 299, 1019–1026 (2008).
Neoptolemos, J. et al. ESPAC-3(v2): A multicenter, international, open-label, randomized, controlled phase III trial of adjuvant 5-fluorouracil/folinic acid (5-FU/FA) versus gemcitabine (GEM) in patients with resected pancreatic ductal adenocarcinoma [abstract]. J. Clin. Oncol. 27 (Suppl. 18), a4505 (2009).
Wolff, R. A., Varadhachary, G. R. & Evans, D. B. Adjuvant therapy for adenocarcinoma of the pancreas: Analysis of reported trials and recommendations for future progress. Ann. Surg. Oncol. 15, 2773–2786 (2008).
Burris III, H. A. et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J. Clin. Oncol. 15, 2403–2413 (1997).
Heinemann, V. et al. Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer. J. Clin. Oncol. 24, 3946–3952 (2006).
Colucci, G. et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: A prospective, randomized phase III study of the Gruppo Oncologico dell'Italia Meridionale. Cancer 94, 902–910 (2002).
Louvet, C. et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: Results of a GERCOR and GISCAD phase III trial. J. Clin. Oncol. 23, 3509–3516 (2005).
Poplin, E. et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J. Clin. Oncol. 27, 3778–3785 (2009).
Berlin, J. D. et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern cooperative oncology group trial E2297. J. Clin. Oncol. 20, 3270–3275 (2002).
Riess, H. et al. A randomised, prospective, multicenter, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs gemcitabine alone in patients with advanced pancreatic cancer [abstract]. J. Clin. Oncol. 23 (Suppl. 16), a4009 (2005).
Herrmann, R. et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J. Clin. Oncol. 25, 2212–2217 (2007).
Cunningham, D. et al. Phase III randomized comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer [abstract]. Eur. J. Cancer 3 (Suppl. 3), a12 (2005).
Rocha Lima, C. M. et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J. Clin. Oncol. 22, 3776–3783 (2004).
Stathopoulos, G. P. et al. A multicenter phase III trial comparing irinotecan-gemcitabine (IG) with gemcitabine (G) monotherapy as first-line treatment in patients with locally advanced or metastatic pancreatic cancer. Br. J. Cancer 95, 587–592 (2006).
Abou-Alfa, G. K. et al. Randomized phase III study of exatecan and gemcitabine compared with gemcitabine alone in untreated advanced pancreatic cancer. J. Clin. Oncol. 24, 4441–4447 (2006).
Oettle, H. et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann. Oncol. 16, 1639–1645 (2005).
Colucci, G. et al. A randomized trial of gemcitabine (G) versus G plus cisplatin in chemotherapy-naive advanced pancreatic adenocarcinoma: The GIP-1 (Gruppo Italiano Pancreas— GOIM/GISCAD/GOIRC) study. J. Clin. Oncol. 27 (Suppl. 15), a4504 (2009).
Heinemann, V., Boeck, S., Hinke, A., Labianca, R. & Louvet, C. Meta-analysis of randomized trials: Evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8, 82 (2008).
Sultana, A. et al. Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy. Br. J. Cancer 96, 1183–1190 (2007).
Boeck, S. & Heinemann, V. Second-line therapy in gemcitabine-pretreated patients with advanced pancreatic cancer. J. Clin. Oncol. 26, 1178–1179 (2008).
Demols, A. et al. Gemcitabine and oxaliplatin (GEMOX) in gemcitabine refractory advanced pancreatic adenocarcinoma: A phase II study. Br. J. Cancer 94, 481–485 (2006).
Tsavaris, N. et al. Second-line treatment with oxaliplatin, leucovorin and 5-fluorouracil in gemcitabine-pretreated advanced pancreatic cancer: A phase II study. Invest. New Drugs 23, 369–375 (2005).
Cantore, M. et al. Combined irinotecan and oxaliplatin in patients with advanced pre-treated pancreatic cancer. Oncology 67, 93–97 (2004).
Xiong, H. Q. et al. Phase 2 trial of oxaliplatin plus capecitabine (XELOX) as second-line therapy for patients with advanced pancreatic cancer. Cancer 113, 2046–2052 (2008).
Pelzer, U. et al. A randomized trial in patients with gemcitabine refractory pancreatic cancer.Final results of the CONKO 003 study [abstract]. J. Clin. Oncol. 26 (Suppl.), a4508 (2008).
Welch, S. A. & Moore, M. J. Combination chemotherapy in advanced pancreatic cancer: Time to raise the white flag? J. Clin. Oncol. 25, 2159–2161 (2007).
Lemoine, N. R. et al. Ki-ras oncogene activation in preinvasive pancreatic cancer. Gastroenterology 102, 230–236 (1992).
Van Cutsem, E. et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J. Clin. Oncol. 22, 1430–1438 (2004).
Lobell, R. B. et al. Evaluation of farnesyl: protein transferase and geranylgeranyl: protein transferase inhibitor combinations in preclinical models. Cancer Res. 61, 8758–8768 (2001).
Jones, L., Ghaneh, P., Humphreys, M. & Neoptolemos, J. P. The matrix metalloproteinases and their inhibitors in the treatment of pancreatic cancer. Ann. NY Acad. Sci. 880, 288–307 (1999).
Bramhall, S. R., Rosemurgy, A., Brown, P. D., Bowry, C. & Buckles, J. A. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: A randomized trial. J. Clin. Oncol. 19, 3447–3455 (2001).
Bramhall, S. R. et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br. J. Cancer 87, 161–167 (2002).
Moore, M. J. et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12–9566 in patients with advanced or metastatic adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 21, 3296–3302 (2003).
Seo, Y., Baba, H., Fukuda, T., Takashima, M. & Sugimachi, K. High expression of vascular endothelial growth factor is associated with liver metastasis and a poor prognosis for patients with ductal pancreatic adenocarcinoma. Cancer 88, 2239–2245 (2000).
Kindler, H. L. et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J. Clin. Oncol. 23, 8033–8040 (2005).
Kindler, H. L. et al. A double-blind, placebo controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine (G) plus placebo (P) in patients with advanced pancreatic cancer (PC). A preliminary analysis of cancer and Leukemia Group B (CALGB) 80303 [abstract]. J. Clin. Oncol. 25 (Suppl.), a4508 (2007).
Vervenne, W. et al. A randomized, double-blind, placebo controlled, multicenter phase III trial to evaluate the efficacy and safety of adding bevacizumab to erlotinib and gemcitabine in patients with metastatic pancreatic cancer [abstract]. J. Clin. Oncol. 26 (Suppl.), a4507 (2008).
Spano, J. P. et al. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet 371, 2101–2108 (2008).
Ueda, S. et al. The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: Poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas 29, E1–E8 (2004).
Bruns, C. J. et al. Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res. 60, 2926–2935 (2000).
Moore, M. J. et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J. Clin. Oncol. 25, 1960–1966 (2007).
Moore, M. J. et al. The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3. J. Clin. Oncol. 25 (Suppl. 18), a4521 (2007).
Siena, S., Sartore-Bianchi, A., Di Nicolantonio, F., Balfour, J. & Bardelli, A. Biomarkers predicting clinical outcome of epidermal growth factor receptor-targeted therapy in metastatic colorectal cancer. J. Natl Cancer Inst. 101, 1308–1324 (2009).
Xiong, H. Q. et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J. Clin. Oncol. 22, 2610–2626 (2004).
Philip, P. et al. Phase III study of gemcitabine [G] plus cetuximab [C] versus gemcitabine in patients [pts] with locally advanced or metastatic pancreatic adenocarcinoma [PC]: SWOG S0205 study [abstract]. J. Clin. Oncol. 25, a4509 (2007).
Schinchi, H. et al. Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer. Int. J. Radiat. Oncol. Biol. Phys. 53, 146–150 (2002).
Moertel, C. G., Frytak, S. & Hahn, R. G. Therapy of locally unresectable pancreatic carcinoma: a randomized comparison of high dose (6000 rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high dose radiation + 5-fluorouracil. The Gastrointestinal Tumor Study Group. Cancer 48, 1705–1710 (1981).
Cohen, S. J. et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern cooperative oncology group study E8282. Int. J. Radiat. Oncol. Biol. Phys. 62, 1345–1350 (2005).
[No authors listed] Treatment of locally unresectable carcinoma of the pancreas: Comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumour Study Group. J. Natl Cancer Inst. 80, 751–755 (1988).
Hazel, J. J., Thirlwell, M. P., Huggins, M., Maksymiuk, A. & MacFarlane, J. K. Multi-drug chemotherapy with and without radiation for carcinoma of the stomach and pancreas: a prospective randomized trial. J. Can. Assoc. Radiol. 32, 164–165 (1981).
Klaassen, D. J., MacIntyre, J. M., Catton, G. E., Engstro, P. F. & Moertel, C. G. Treatment of locally unresectable cancer of the stomach and pancreas: A randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil–an Eastern Cooperative Oncology Group study. J. Clin. Oncol. 3, 373–378 (1985).
Chauffert, B. et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabime alone for locally advanced pancreatic cancer. Definitive results of the 2000–01 FFCD/SFRO study. Ann. Oncol. 19, 1592–1599 (2008).
Loehrer, P. J. et al. A randomized phase III study of gemcitabine in combination with radiation therapy versus gemcitabine alone in patients with localized, unresectable pancreatic cancer: E4201 [abstract]. J. Clin. Oncol. 26 (Suppl. 214), a4506 (2008).
Krishnan, S. et al. Induction chemotherapy selects patients with locally advanced, unresectable pancreatic cancer for optimal benefit from consolidative chemoradiation therapy. Cancer 110, 47–55 (2007).
Huguet, F. et al. Impact of chemoradiotherapy after disease control with chemotherapy in locally advanced pancreatic adenocarcinoma in GERCOR phase II and III studies. J. Clin. Oncol. 25, 326–331 (2007).
Maitra, A. & Hruban, R. H. Pancreatic cancer. Ann. Rev. Pathol. Mech. Dis. 3, 157–188 (2008).
Sian, J. et al. Core signaling pathways in human pancreatic cancer revealed by global genomic analyses. Science 321, 1801–1806 (2008).
Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).
Lee, C. J., Dosch, J. & Simeone, D. Pancreatic cancer stem cells. J. Clin. Oncol. 26, 2806–2812 (2008).
Kern, S. et al. A white paper: the product of a pancreas cancer think tank. Cancer Res. 61, 4923–4932 (2001).
Acknowledgements
Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Stathis, A., Moore, M. Advanced pancreatic carcinoma: current treatment and future challenges. Nat Rev Clin Oncol 7, 163–172 (2010). https://doi.org/10.1038/nrclinonc.2009.236
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrclinonc.2009.236
This article is cited by
-
Integrative proteomics and n-glycoproteomics reveal the synergistic anti-tumor effects of aspirin- and gemcitabine-based chemotherapy on pancreatic cancer cells
Cellular Oncology (2024)
-
Nomogram predicts risk of perineural invasion based on serum biomarkers for pancreatic cancer
BMC Gastroenterology (2023)
-
The pro- and antineoplastic effects of deoxycholic acid in pancreatic adenocarcinoma cell models
Molecular Biology Reports (2023)
-
Clinical sonochemotherapy of inoperable pancreatic cancer using diagnostic ultrasound and microbubbles: a multicentre, open-label, randomised, controlled trial
European Radiology (2023)
-
Role of contrast-enhanced ultrasound with time-intensity curve analysis for differentiating hypovascular solid pancreatic lesions
European Radiology (2023)