Recent Results. in Cancer Research

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3 Recent Results 177 in Cancer Research Managing Editors P. M. Schlag, Berlin H.-J. Senn, St. Gallen Associate Editors P. Kleihues, Zürich F. Stiefel, Lausanne B. Groner, Frankfurt A. Wallgren, Göteborg Founding Editor P. Rentchnik, Geneva

4 H. Riess A. Goerke H. Oettle (Eds.) Pancreatic Cancer With 48 Figures and 16 Tables 123

5 Prof. Dr. med. Hanno Riess Andrea Goerke Priv.-Doz. Dr. med. Helmut Oettle Library of Congress Control Number: ISSN ISBN Springer Berlin Heidelberg New York This work is subject to copyright. All rights reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in databanks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September, 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable to prosecution under the German Copyright Law. Springer is a part of Springer Science + Business Media springer.com Springer-Verlag Berlin Heidelberg 2008 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. Ute Heilmann, Heidelberg Desk editor: Dörthe Mennecke-Bühler, Heidelberg Production editor: Anne Strohbach, Leipzig Cover design: Frido Steinen-Broo, estudio Calamar, Spain Typesetting: LE-TEX Jelonek, Schmidt & Vöckler GbR, Leipzig Printed on acid-free paper SPIN /3100/YL

6 Preface Pancreatic cancer is one of the most frequent malignant tumor entities with increasing incidences reported for both females and for males and yet it still has a poor prognosis. Therefore, it is surprising that no volume in the Recent Results in Cancer Research series has been dedicated to this tumor entity until now. It remains speculative whether this is related to the lack of firm findings concerning the pathogenesis, to a missing breakthrough in treatment, or simply to general therapeutic frustration. We are pleased to present this volume, compiled by a team of competent authors, representing the recent achievements and the present state of the art in the management of pancreatic cancer. The different chapters emanate rays of hope and pioneering spirit in terms of more precise diagnostics and of improved therapeutic strategies. However, the challenges we are still facing with this disease are obvious: Deficiencies in the understanding of pancreatic tumor biology (e.g., initiation, progression, resistance to chemo- and radiotherapy). Lack in achieving sustained success with standard methods of surgery, radiotherapy, and chemotherapy in contrast to the success in multimodal treatments for other solid tumors. Sufficiently effective drugs are missing and the testing of already existing and of new compounds and therapies in well-planned and adequately recruiting prospective clinical trials is cumbersome and time consuming. We therefore hope that the present volume will initiate novel ideas and approaches to overcome these challenges. It is our vision and desire that this RRCR volume on pancreatic cancer promotes genuine interest in this mostly incurable disease and launches promising and interdisciplinary efforts among basic researchers, surgeons, medical oncologists, radiologists, gastroenterologists, and pathologists, which lead to significant therapeutic and prognostic progress. October 2007 P. M. Schlag, Berlin H.-J. Senn, St. Gallen

7 Contents Contents VII 1 Pancreatic Cancer: Step by Step Forward H. Riess, A. Goerke, H. Oettle Part I Diagnosis 2 CT and MR Imaging of Pancreatic Cancer C. Stroszczynski, R. Grützmann, T. Kittner 3 Nuclear Medical Methods for the Diagnosis of Pancreatic Cancer: Positron Emission Tomography H. Amthauer, J. Ruf Part II Therapy and Monitoring of Disease 4 Surgical Techniques for Resectable Pancreatic Cancer M. Bahra, U. Neumann 5 Postoperative Staging of Pancreatic Cancer C. Röcken, M. P. A. Ebert 6 Adjuvant Therapy in Patients with Pancreatic Cancer L. Roll 7 First-Line Chemotherapy in Advanced Pancreatic Cancer U. Pelzer 8 Second-Line Chemotherapy in Advanced Pancreatic Cancer U. Pelzer

8 VIII Contents 9 Neoadjuvant and Adjuvant Strategies for Chemoradiation A. Kaiser, V. Budach 10 Primary Advanced Unresectable Pancreatic Cancer R. Wilkowski, M. Wolf, V. Heinemann 11 Brachytherapy of Liver Metastases T. Denecke, E. Lopez Hänninen 12 Detection of Disease Recurrence and Monitoring of Therapy J. Ruf, H. Amthauer 13 Surgical Palliation of Advanced Pancreatic Cancer M. Bahra, D. Jacob Part III New Treatment Strategies and Outlook 14 Antiangiogenic Strategies in Pancreatic Cancer H. Riess 15 Targeted Therapy of the Epidermal Growth Factor Receptor in the Treatment of Pancreatic Cancer S. Heeger 16 Antisense Therapeutics for Tumor Treatment: The TGF-beta2 Inhibitor AP in Clinical Development Against Malignant Tumors K.-H. Schlingensiepen, B. Fischer-Blass, S. Schmaus, S. Ludwig 17 NF-κ B as a Molecular Target in the Therapy of Pancreatic Carcinoma S. Sebens, A. Arlt, H. Schäfer 18 Immunotherapeutic Approaches in Pancreatic Cancer J. Stieler 19 Src Kinase and Pancreatic Cancer A. Hilbig

9 List of Contributors IX List of Contributors Holger Amthauer, MD Klinik für Strahlenheilkunde Alexander Arlt, MD Klinik für Allgemeine Innere Medizin Labor für Molekulare Gastroenterologie und Hepatologie Universitätsklinikum Schleswig-Holstein Campus Kiel Schittenhelmstraße Kiel Marcus Bahra, MD Klinik für Allgemein-, Visceralund Transplantationschirurgie Volker Budach, MD Campus Mitte Klinik für Strahlenheilkunde Charitéplatz Berlin Timm Denecke, MD Klinik für Strahlenheilkunde Matthias P. A. Ebert, MD, PhD II. Medizinische Klinik Klinikum rechts der Isar Technische Universität München Munich Birgit Fischer-Blass, PhD Antisense Pharma GmbH Josef-Engert-Str Regensburg Andrea Goerke Robert Grützmann, MD Klinik für Viszeral-, Thoraxund Gefäßchirurgie Universitätsklinikum Carl Gustav Carus Technische Universität Dresden Fetscherstr Dresden Steffen Heeger, MD, MSc Merck Pharma GmbH Alsfelder Str Darmstadt

10 X Volker Heinemann, PhD Klinik Bad Trissl GmbH & Co. KG Abt. für Strahlentherapie Bad-Trissl-Str Oberaudorf Andreas Hilbig, MD Dietmar Jacob, MD Klinik für Allgemein-, Visceralund Transplantationschirurgie Andreas Kaiser, MD Zentrum für Tumormedizin Klinik für Strahlentherapie CCM Charitéplatz Berlin Thomas Kittner, MD Chefarzt Krankenhaus Dresden-Friedrichstadt Städtisches Klinikum Akademisches Lehrkrankenhaus der Technischen Universität Dresden Friedrichstraße Dresden Enrique Lopez Hänninen, MD Klinik für Strahlenheilkunde Sylvia Ludwig, DVM Antisense Pharma GmbH Josef-Engert-Str Regensburg Ulf Neumann, MD, PhD Klinik für Allgemein-, Visceralund Transplantationschirurgie List of Contributors Helmut Oettle, MD Uwe Pelzer, MD, PhD Hanno Riess, MD, PhD Christoph Röcken, MD, PhD Institut für Pathologie Charitéplatz Berlin

11 List of Contributors XI Lars Roll, MD Juri Ruf, MD Klinik für Nuklearmedizin Heiner Schäfer, PhD Klinik für Allgemeine Innere Medizin Labor für Molekulare Gastroenterologie & Hepatologie Universitätsklinikum Schleswig-Holstein Campus Kiel Schittenhelmstraße Kiel Karl-Hermann Schlingensiepen, MD, PhD Antisense Pharma GmbH Josef-Engert-Str Regensburg Susanne Schmaus, PhD Antisense Pharma GmbH Josef-Engert-Str Regensburg Susanne Sebens, PhD Klinik für Allgemeine Innere Medizin Labor für Molekulare Gastroenterologie & Hepatologie Universitätsklinikum Schleswig-Holstein Campus Kiel Schittenhelmstr Kiel Jens Stieler, MD Christian Stroszczynski, MD Institut und Poliklinik für Radiologische Diagnostik Universitätsklinikum Carl Gustav Carus Technische Universität Dresden Fetscherstr Dresden Ralf Wilkowski, PhD Klinik Bad Trissl GmbH & Co. KG Abt. für Strahlentherapie Bad-Trissl-Str Oberaudorf Maria Wolf, MD Klinik Bad Trissl GmbH & Co. KG Abt. für Strahlentherapie Bad-Trissl-Str Oberaudorf

12 1 Pancreatic Cancer: Step by Step Forward H. Riess, A. Goerke, H. Oettle Recent Results in Cancer Research, Vol. 177 Springer-Verlag Berlin Heidelberg 2008 With the diagnosis of pancreatic cancer, the majority of patients are faced with an unexpected tragedy. There is a persistently low rate of curability, a so-called case fatality rate of around 95%. Complete resection is the prerequisite for curation, but only one-fifth of the patients are considered for surgical therapy. Even so, only about half of these individuals finally undergo successful, complete resection. Whereas nowadays surgery can be performed with low rates of perioperative morbidity and mortality at experienced high-volume centers, postoperative relapses are observed frequently. Neoadjuvant strategies to improve surgical resectability and the overall cure rate remain experimental, but due to the results of different trials, adjuvant treatments strategies are becoming standard worldwide. Transatlantic differences in the interpretation of study results with the use of chemoradiation probably will be overcome by the recent results of adjuvant chemotherapy in patients with adenocarcinoma of the pancreas, which have shown significant benefit in relapse-free survival, 3- and 5-year survival, and therefore most likely cure [1]. Ongoing studies will definitely clarify the role and kind of chemotherapy to be recommended for patients resected completely (R0) and those with microscopic involvement of the resection margin (R1). For the majority of patients with nonresectable, locally advanced, metastasized, or relapsing pancreatic cancer, progress has been limited for several years. It took more than 10 years from the approval of gemcitabine for the treatment of advanced adenocarcinoma of the pancreas and a great number of large-scaled phase III trials before a second improvement in systemic therapy was implemented in patient care. Erlotinib, a tyrosine kinase inhibitor blocking epidermal growth factor (EGF) receptor-mediated downstream signaling, succeeded in improving outcome in patients with advanced pancreatic cancer when applied in combination with gemcitabine, with a hazard ratio of 0.8 resulting in a 7% excess in 1-year survival as compared to gemcitabine plus placebo [2]. Due to this study, erlotinib obtained approval in the United States and Europe and is on the way to finding its place in routine treatment. Confirming former nonsignificant results of gemcitabine in combination with capecitabine, it was recently demonstrated that this combination of cytotoxic drugs improved median and 1-year survival in a prospective randomized but nonplacebo-controlled trial [3]. The impact of these data for standard care of patients with adenocarcinoma of the pancreas cancer needs to be defined. As adverse effects of cytotoxic drugs and targeted therapies differ, tailoring patient-specific first-line therapy has become a challenge for oncologists. An improvement in quality of life, estimated by the clinical benefit response, occurs in a relevant proportion of patients due to first-line therapy with gemcitabine [4]. Therefore an increasing number of patients with pancreatic cancer progressing while on first-line therapy need to be considered for second-line therapy, based on their good performance status. The identification of principally active cytotoxic drugs, such as oxaliplatin (together with folinic acid and fluorouracil) or taxanes, antibodies, and small molecules, such as erlotinib and sorafenib, offer second-line treatment alternatives that have to undergo evaluation in clinical trials. Initial results favor oxaliplatin-based therapy [5, 6].

13 These small steps forward in the systemic therapy of pancreatic cancer give rise to some prudent optimism. In order to alter the perspectives of patients with pancreatic cancer, further understanding of the basic aspect of disease development as well as methods for screening or early diagnosis of this disease have to be developed. It is the aim of this issue of Recent Results in Cancer Research to compile the available knowledge concerning pancreatic cancer. Acknowledgements The editors recognize and acknowledge the important contributions of the various authors, all of them involved in the challenging effort of fighting this frightening cancer. References Oettle H, Post S, Neuhaus P, et al (2007) Adjuvant chemotherapy with gemcitabine versus observation in patients undergoing curative-intent resection of pancreatic cancer. A multicenter randomized controlled trial. JAMA 297: Moore MJ, Goldstein D, Hamm J, et al (2007) Erlotinib plus gemcitabine compared with gem H. Riess, A. Goerke, H. Oettle citabine 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: Cunningham D, Chau I, Stocken D, Davies C, Dunn J, Valle J, et al (2005) Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer. Eur J Cancer 3:4 [Suppl] Burris HA 3rd, Moore MJ, Andersen J, et al (1997) 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: Oettle H, Pelzer U, Stieler J, Hilbig A, Roll L, Schwaner I, Adler M, Detken S, Dörken B, Riess H (2005) Oxaliplatin/folinic acid/5-fluorouracil [24 h] (OFF) plus best supportive care versus best supportive care alone (BSC) in second-line therapy of gemcitabine-refractory advanced pancreatic cancer (CONKO 003). Clin Oncol 23:16S, abstr 4031 Riess H, Pelzer U, Stieler J, Schwaner I, Heil G, Görner M, Mölle M, Hilbig A, Dörken B, Oettle H (2007) A randomized second line trial in patients with gemcitabine refractory advanced pancreatic cancer CONKO 003. J Clin Oncol 25:18S, abstr 4517

14 Part I Diagnosis

15 2 CT and MR Imaging of Pancreatic Cancer C. Stroszczynski, R. Grützmann, T. Kittner Recent Results in Cancer Research, Vol. 177 Springer-Verlag Berlin Heidelberg 2008 Abstract Computed tomography (CT) and magnetic resonance imaging (MRI) are emerging noninvasive techniques for imaging of the pancreas. Based on multislice technology, CT enables multiplanar imaging of the pancreas (multislice-ct, MSCT) with a high contrast between vessels and parenchyma. In addition, MRI of the pancreas including the imaging of the lumina of the biliary tree and the pancreatic duct (magnetic resonance cholangiopancreaticography, MRCP) and the abdominal vessels (MR angiography, MRA) has become available for daily clinical practice in most hospitals. The addition of multiplanar and curved reformations may increase the sensitivity of CT and improves its agreement with surgical findings. Beyond abdominal MR imaging, techniques such as magnetic resonance cholangiopancreaticography (MRCP) and MR angiography should be integrated in the imaging protocol whenever possible. 2.1 Introduction Pancreatic cancer is the third most common malignancy of the gastrointestinal tract, the incidence rate is estimated by 10 cases per 100,000 people per year. Surgery is the only therapy with curative intention and may result in long-term survival in those cases where the cancer is still confined to the organ itself. Surgery of the more advanced stages is being performed in some centers, but so far it has not become a routine procedure. Differentiating between pancreatic malignancy and focal chronic pancreatitis in particular when taking into account that longterm pancreatitis is a risk factor in pancreatic cancer is still a clinical challenge. The main tasks of diagnostic imaging of the pancreas are the detection of pancreatic lesions and the differentiation between malignant and benign (e.g., inflammatory) changes in the pancreas. In addition, computed tomography/magnetic resonance (CT/MR) imaging should ideally be able to permit staging of pancreatic tumors including the detection of malignant infiltration of lymph nodes and distant metastases (Malka et al. 2002). When surgery is considered, resectability of the tumor is usually defined by the presence or absence of the infiltration of the portal vein, the venous confluens, or the superior mesenteric vein. Moreover, the detection of anatomic variations of the branches of the celiac trunk and the superior mesenteric artery is of crucial importance (Fuhrman et al. 1994). CT and MRI are emerging noninvasive techniques for imaging of the pancreas. Based on multislice technology, CT enables multiplanar imaging (multislice-ct, MSCT) with a high contrast between vessels and parenchyma. In addition, MRI of the pancreas including the imaging of the lumina of the biliary tree and the pancreatic duct (magnetic resonance cholangiopancreaticography, MRCP) and the abdominal vessels (MR angiography, MRA) has become available for daily clinical practice in most hospitals. Therefore, invasive digital subtraction angiography (DSA) has lost its importance in many institutions for preoperative diagnosis of the pancreas.