PERITONEAL CARCINOMATOSIS:

A MULTIDISCIPLINARY APPROACH

PERITONEAL CARCINOMATOSIS:

A MULTIDISCIPLINARY APPROACH

edited by

Wim P. Ceelen, MD Surgical Oncology University Hospital Ghent, Belgium

Wim P. Ceelen, MD Department of Surgery University Hospital B-9000 Ghent, Belgium

PERITONEAL CARCINOMATOSIS: A MULTIDISCIPLINARY APPROACH Library of Congress Control Number: 2006935881

Printed on acid-free paper. © 2007 Springer Science+Business Media, LLC. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. 9 8 7 6 5 4 3 2 1 springer.com

ISBN-10: 0-387-48991-6 e-ISBN-10: 0-387-48993-2 ISBN-13: 978-0-387-48991-9 e-ISBN-13: 978-0-387-48993-3

Foreword

Progression of gastrointestinal or ovarian cancer to the peritoneal surfaces remains a dreaded clinical condition. It remains a perplexing challenge with pitfalls in both diagnosis and treatment that continue to vex the oncologist. Recently, pharma-cologic studies, an aggressive surgical approach, and concentration of patients in peritoneal surface malignancy treatment centers have begun to generate a small optimism regarding the management of these patients.

A problem in the past now finding a partial solution is definitive diagnosis and lack of delay in treatment. Laparoscopy has greatly facilitated prompt diagnosis. Our interpretation of abdominal and pelvic CT scans has improved allowing char-acterization of this condition in order to select patients for elective treatment. Also, more accurate staging histopathologically shows promise. Systems of prog-nostic indicators are being tested in order to properly select patients for the broad array of treatment possibilities that exist. Standardization of these assessments be-tween institutions will be difficult but is necessary. A molecular diagnosis for this disease may be evident within the near future.

Another development promoting limited optimism in dealing with carcinoma-tosis concerns the concentration of patients in peritoneal surface malignancy treatment centers whereby natural history data plus clinical, radiological and histopathological correlates become evident. A well maintained database and suf-ficient patient accrual can provide the necessary information for progress in pa-tient management to occur.

A great value for these patients in going to a treatment center concerns the in-creased knowledge and skill of the caregivers at these centers. No longer are pa-tients being cared for by physicians treating only one or two patients a year. Treatment centers are now regularly managing a patient a week. Patients managed in an anecdotal fashion are unlikely to have optimal management and no knowl-edge is gained. With referral centers this disease can be managed more efficiently than at the community hospital level.

As awareness of the unique features of carcinomatosis becomes more evident, an increased number of global conferences devoted to the new and more aggres-sive treatment strategies bring the designated treatment centers together. Carcino-matosis has become a condition that “stands alone” and deserves to have its own basic science, radiologic, medical, and surgical cadre and support staff from nurses and other caregivers. Having these peritoneal surface oncologists get to-gether on a regular basis and share their new data has led to an escalation of pro-gress with this condition.

This book on peritoneal carcinomatosis attests to the fact that cooperative ef-forts in behalf of these patients are occurring. Assembling and disseminating the available information and the identification of “breakthroughs” in understanding this problem can occur. This book should act as an authoritative guide to medical

oncologists, radiation oncologists, surgical oncologists, gastroenterologists, and basic science individuals who wish to focus on a particular aspect of this disease or to broaden their knowledge concerning its many and varied complexities. These efforts should be taking place in the United States and Europe and need to be carried to the underdeveloped nations. This book can be of help in that regard. Much progress has been made and much more is required.

Paul H. Sugarbaker, MD, FACS, FRCS Director, Program in Peritoneal Surface Malignancy Washington Cancer Institute Washington, DC, USA

VI Foreword

Preface

Peritoneal carcinomatosis (PC) represents a fitting illustration of the complexities faced by modern medicine. On the one hand, recent data suggest that in a well se-lected group of patients with PC, extensive surgery with intraperitoneal (ip) che-motherapy can extend survival beyond five years, a figure rarely achieved even with modern palliative chemotherapy and attested by a growing number of expert centres offering this demanding therapy. On the other hand, however, most of these patients will not be cured and careful weighing of the possible benefits against the risks and quality of life consequences of extensive surgery should be the effort of a multidisciplinary team. Individual patient care decisions are fraught with a lack of a high quality evidence base re-garding essential treatment components such as patient selection, timing and ex-tent of surgery, and the relative contribution of chemotherapy and hyperthermia. National guidelines therefore recommend to treat all PC patients in the context of clinical trials [1,2]. Moreover, in contrast to the exponential growth in basic sci-ence literature concerned with cancer growth, angiogenesis and systemic metasta-sis, surprisingly little is known about the molecular mechanisms at the origin of PC.

The aim of the present volume was to bring together leading basic science and clinical investigators in the field of PC in order to provide a multidisciplinary ‘status praesens’ of current knowledge. It is hoped that their efforts will not only assist in individual patient care, but also facilitate consensus among surgical and medical oncologists, define future areas of basic research and help to overcome the major challenge in the field of PC: to extend the limited and indeed often an-ecdotal evidence supporting the various therapeutic options by well designed mul-ticenter clinical studies.

The Editor Ghent, 2006 References

1. Guide sur le traitement de la carcinomatose péritonéale par cytoréduction chi-

rurgicale et chimiothérapie hyperthermique intrapéritonéale peropératoire. Comité de l’évolution des pratiques en oncologie (CÉPO), Direction de la lutte contre le cancer (Québec), February 2006. Available at:

(Accessed October 4, 2006)

www.msss.gouv.qc.ca/sujets/prob_sante/cancer/download.php?id=584134,214,2

2. National Institute for Clinical Excellence (NICE) Interventional Procedures Programme. Interventional procedures overview of complete cytoreduction and heated intraoperative intraperitoneal chemotherapy (Sugarbaker tech-nique) in patients with peritoneal carcinomatosis, July 2004. Available at: www.nice.org.uk/download.aspx?o=ip256overview (Accessed October 4, 2006)

VIII Preface

Contents

Part 1. Peritoneal Carcinomatosis: Basic Concepts

1. Structure and Function of Mesothelial Cells ................................................... 1 Introduction......................................................................................................... 1 Structure of Mesothelial Cells ............................................................................ 1 Mesothelial Cell Functions ................................................................................. 3

Slippery Protective Layer............................................................................... 3 Inflammation and Immune Response ............................................................ 4 Tissue Repair.................................................................................................. 6 Fibrin Regulation ........................................................................................... 6

Role of Mesothelial Cells in Tumour Dissemination ......................................... 7 Cell Adhesion................................................................................................. 7 Cell Invasion ................................................................................................ 10 Tumour Growth............................................................................................ 11

Summary and Conclusions ............................................................................... 12 References......................................................................................................... 12

2. Molecular Biology of Peritoneal Carcinomatosis.......................................... 21 Introduction....................................................................................................... 21 Peritoneal Tumour Dissemination .................................................................... 22 Mesothelial Adhesion ....................................................................................... 22 Mesothelial Invasion......................................................................................... 24 Stromal Invasion and Proliferation................................................................... 27 Tumour-Peritoneal Angiogenesis ..................................................................... 30 Summary........................................................................................................... 30 References......................................................................................................... 31

3. Role of Adhesion Molecules in Locoregional Cancer Spread ...................... 35 The Micro-ecosystem of Peritoneal Carcinomatosis........................................ 35 Homotypic Cell-Cell Adhesion by the Cadherins ............................................ 37 Heterotypic Cell-Cell and Cell-Matrix Adhesion by the Integrins .................. 40 Other Adhesion Compounds relevant for Peritoneal Carcinomatosis.............. 42

CD44 and Hyaluronate................................................................................. 42 Sialyl Lewis and E-selectin.......................................................................... 43 CA 125 and Mesothelin ............................................................................... 43 L1 and Neuropilin-1..................................................................................... 44 Other Adhesion Molecules in the Peritoneum ............................................. 44

Conclusion and Future Perspectives................................................................. 44 Acknowledgements........................................................................................... 45 References ........................................................................................................ 45

4. Surgical Trauma, Minimal Residual Disease and Locoregional Cancer Recurrence ............................................................................................................ 51

Introduction ...................................................................................................... 51 Minimal Residual Disease following Surgery.................................................. 51

Tumour Associated Factors ......................................................................... 52 Surgery Related Factors ............................................................................... 52 Tumour Seeding during Laparoscopy.......................................................... 53 Postoperative Factors ................................................................................... 54

The Link between Residual Tumour Growth and Surgery .............................. 55 The importance of Inflammation ................................................................. 55 Surgery and Tumour Dormancy .................................................................. 57

Prevention and Treatment of Residual Tumour Growth .................................. 58 Prevention of Surgical Trauma .................................................................... 58 Nonspecific Intraperitoneal Therapy ........................................................... 58 Intraperitoneal Chemotherapy ..................................................................... 58 Inhibition of the Angiogenic Switch and Reversal of Tumour Dormancy.. 59 Inhibition of the Inflammatory Response .................................................... 59 Inhibition of Adhesion of Free Intraperitoneal Cancer Cells ...................... 60

Summary and Conclusion................................................................................. 60 References ........................................................................................................ 61

5. Pseudomyxoma Peritonei Syndrome: Classification of Appendiceal Mucinous Tumours .............................................................................................. 71

Introduction ...................................................................................................... 71 ‘Mucocele’........................................................................................................ 71 Mucosal Hyperplasia and Hyperplastic Polyp ................................................. 72 Serrated Adenoma (Mixed Hyperplastic-Adenomatous Polyp)....................... 74 Mucinous Adenoma (Mucinous Cystadenoma) ............................................... 75 Mucinous Neoplasm of Uncertain Malignant Potential (M-UMP).................. 79 Mucinous Neoplasm of Low Malignant Potential (M-LMP)........................... 81 Adenocarcinoma (Mucinous, Intestinal, and Signet Ring Types) ................... 86 Goblet Cell and Tubular Carcinoids................................................................. 89 ‘Pseudomyxoma Peritonei Syndrome’ ............................................................. 92 Conclusion ...................................................................................................... 102 References ...................................................................................................... 103

6. The Pathogenesis of Malignant Ascites ........................................................ 109 Introduction .................................................................................................... 109 Anatomical and Physiological Considerations............................................... 109

Anatomy of the Peritoneal Membrane....................................................... 109 The Peritoneal Lymphatic System............................................................. 110

Characteristics of Malignant Ascites - Intraperitoneal Protein Accumulation.................................................................................................. 111 Impaired Drainage or Increased Production?................................................. 111

X Contents

XI

Increased Capillary Permeability ............................................................... 113 Increased Filtration Surface Area .............................................................. 114 Increased Hydraulic Pressure Difference................................................... 114 Decreased Oncotic Pressure Difference..................................................... 115

Conclusion ...................................................................................................... 115 References....................................................................................................... 115

7. Natural History of Peritoneal Carcinomatosis from Digestive Origin...... 119 Introduction..................................................................................................... 119 Aetiology of Peritoneal Carcinomatosis......................................................... 119 Clinical Features of Peritoneal Carcinomatosis from Digestive Origin......... 120

Gastric Cancer ............................................................................................ 121 Colorectal Cancer....................................................................................... 123 Pancreatic Cancer....................................................................................... 123 Cancer with Unknown Primary.................................................................. 123

Natural History of Peritoneal Carcinomatosis................................................ 123 Discussion....................................................................................................... 127 References....................................................................................................... 128

Part 2. The Rationale for Intraperitoneal Heat and Drug Therapy

8. Intraperitoneal Drug Therapy: Physical and Biological Principles .......... 131 Background..................................................................................................... 131 IP Versus Systemic (IV) Chemotherapy ........................................................ 132

Pharmacokinetic Advantage....................................................................... 132 Compartmental Approach to IP Pharmacokinetics.................................... 133

Distributed Model and Challenges of the Peritoneal Barrier in Neoplasms .. 135 Anatomic Peritoneum................................................................................. 136 Interstitium and Tumour Microenvironment ............................................. 137 Microcirculation......................................................................................... 139 Summary of Neoplastic versus Normal Peritoneal Barrier........................ 140

Importance of Contact Area to Intraperitoneal Chemotherapy ...................... 141 Penetration of Antineoplastic Agents ............................................................. 142

Intraperitoneal Chemotherapy with Small Molecular Weight Drugs ........ 143 Intraperitoneal Therapy with Macromolecular Agents.............................. 144

Acknowledgment............................................................................................ 145 References....................................................................................................... 145

9. Current Status of Intraperitoneal Antineoplastic Drug Delivery ............. 153 Intraperitoneal Chemotherapy: Historical Perspective................................... 153 The “Dedrick Model” and Pre-clinical Evaluation of Intraperitoneal Chemotherapy................................................................................................. 153 Penetration of Cytotoxic Antineoplastic Agents into Tumour Tissue ........... 154

Starling’s law of Capillary Hemodynamics . .................................................. 112

Contents

Drug Delivery by Direct Penetration versus Capillary Flow..................... 155 Phase I Trial Experience with Intraperitoneal Antineoplastic Drug Delivery156 Phase II Trials of Intraperitoneal Antineoplastic Drug Delivery ................... 157 Phase III Trials of Cisplatin-based Intraperitoneal Chemotherapy as Primary Treatment of Advanced Ovarian Cancer........................................................ 159 Options for Use of Primary IP Chemotherapy of Ovarian Cancer ................ 161 Other Potential Uses of Intraperitoneal Antineoplastic Drug Delivery in the Management of Ovarian Cancer..................................................................... 162 Randomized Trial Experience with Intraperitoneal Antineoplastic Drug Delivery in Non-ovarian Cancers................................................................... 162 References ...................................................................................................... 163

10. The Biologic Rationale of Hyperthermia ................................................... 171 Abstract........................................................................................................... 171 Introduction .................................................................................................... 171 Basic Principles of Hyperthermic Cell Death ................................................ 174 Molecular and Cellular Effectors of Hyperthermia........................................ 176 Alterations of the Tumour Microenvironment ............................................... 177 Hyperthermia and the Immune System .......................................................... 178

Cellular Immune Response ........................................................................ 178 Heat Shock Proteins ................................................................................... 179

Summary......................................................................................................... 180 References ...................................................................................................... 180

11. Interactions between Hyperthermia and Cytotoxic Drugs ...................... 185 Abstract........................................................................................................... 185 Introduction .................................................................................................... 185 Principles of heat-drug interaction ................................................................. 187 Hyperthermia and drug resistance .................................................................. 188 Pharmacological studies ................................................................................. 189 Heat interactions of novel compounds ........................................................... 189 Summary......................................................................................................... 190 References ...................................................................................................... 191

12. Pharmacodynamic Aspects of Intraperitoneal Cytotoxic Therapy......... 195 Introduction .................................................................................................... 195 General Pharmacodynamic Aspects of Intraoperative Intraperitoneal Chemotherapy................................................................................................. 195 Pharmacodynamics of Cytotoxic Drugs used with HIPEC............................ 197

Alkylating Drugs........................................................................................ 198 Platinum Compounds................................................................................. 199 Topoisomerase Interactive Agents............................................................. 202 Antimetabolites .......................................................................................... 203 Antimicrotubule Agents............................................................................. 204

Approaches to Increase Tumour Drug Distribution ....................................... 205 Increasing Drug Supply ............................................................................. 205

XII Contents

XIII

Enhancing Drug Penetration ...................................................................... 206 Summary and Conclusion............................................................................... 207 References....................................................................................................... 207

Part 3. Cytoreductive Surgery for Peritoneal Carcinomatosis: Techniques and Methods

13. Patient Selection for Cytoreduction and Hyperthermic Intraperitoneal Chemoperfusion.................................................................................................. 215

Introduction..................................................................................................... 215 Indications for Cytoreduction and HIPEC...................................................... 216

Pseudomyxoma Peritonei........................................................................... 216 Colorectal Cancer....................................................................................... 218 Gastric Cancer ............................................................................................ 218 Ovarian Cancer........................................................................................... 219 Peritoneal Mesothelioma............................................................................ 219 Peritoneal Sarcomatosis ............................................................................. 220

Patient Selection ............................................................................................. 220 Preoperative Imaging...................................................................................... 222 Repeat Operations........................................................................................... 224 References....................................................................................................... 225

14. Staging and Scoring of Peritoneal Carcinomatosis................................... 231 Introduction..................................................................................................... 231 Extent of Prior Surgery................................................................................... 232

Prior Surgery Score (PSS).......................................................................... 232 Extent and Distribution of Disease................................................................. 233

Carcinomatosis Staging by the Japanese Research Society for Gastric Cancer (P-Score) ........................................................................................ 234 Japanese Research Society for Gastric Cancer P-Score ............................ 234 Gilly Staging for Peritoneal Carcinomatosis ............................................. 234 Peritoneal Cancer Index (PCI) ................................................................... 235 Simplified Peritoneal Cancer Index ........................................................... 238 Involved Regions (N-score) ....................................................................... 238

Assessment of Completeness or Extent of Surgery........................................ 239 Completeness of Cytoreduction Score....................................................... 240 Residual Disease (R) - Score ..................................................................... 240

Extent of Surgery............................................................................................ 241 Extent of Surgery Score ............................................................................. 242 Level of Cytoreduction .............................................................................. 242

Conclusion ...................................................................................................... 242 References....................................................................................................... 243

Contents

XIV

Introduction .................................................................................................... 247 Electroevaporative surgery............................................................................. 247

Patient Positioning ..................................................................................... 248

Parietal Peritoneal Stripping from the Anterior Abdominal Wall ............. 250 Stripping the Visceral Peritoneum from the Surface of the Bladder ......... 250 Parietal Peritoneal Dissection to the Paracolic Sulcus and Beyond .......... 251 Peritoneal Stripping from Beneath the Left Hemidiaphragm.................... 252 Greater Omentectomy and Splenectomy with Completion of the Left Subphrenic Peritonectomy ......................................................................... 253 Peritoneal Stripping from Beneath the Right Hemidiaphragm.................. 254 Removal of an Envelope of Tumour from Beneath the Right Hemidiaphragm, from the Right Subhepatic Space, and from the Surface of the Liver ..................................................................................................... 255 Completed Right Subphrenic Peritonectomy ............................................ 256 Cholecystectomy with Resection of the Hepatoduodenal Ligament......... 256 Circumferential Resection of the Hepatogastric Ligament and Lesser Omentum by Digital Dissection................................................................. 257 Limits of the Lesser Omentectomy with Stripping of the Floor of the Omental Bursa............................................................................................ 258 Limits of the Complete Pelvic Peritonectomy........................................... 260 Resection of Rectosigmoid Colon, Uterus, and Cul-de-sac of Douglas.... 260 Preparation for Perioperative Intraperitoneal Chemotherapy.................... 262

Discussion....................................................................................................... 263 References ...................................................................................................... 264

16. Continuous Peritoneal Perfusion: Techniques, Methods and Applications................................................................................................. 265

Introduction .................................................................................................... 265 Methods of Hyperthermic Intraperitoneal Chemotherapy ............................. 265 Open Perfusion Methods ................................................................................ 266 Partially Closed and Closed Perfusion Methods ............................................ 267 Safety Considerations for HIPEC................................................................... 269 Technical Parameters of Hyperthermic Chemoperfusion .............................. 270

Cytostatic Agents Suitable for HIPEC....................................................... 270 Intraperitoneal Temperature....................................................................... 270 Carrier solution .......................................................................................... 271 Volume....................................................................................................... 271 Duration ..................................................................................................... 271 Flow rate .................................................................................................... 272

Conclusions .................................................................................................... 272 References ...................................................................................................... 272

17. Handling of Chemotherapeutic Drugs in the OR: Hazards and Safety Considerations .................................................................................................... 275

Introduction .................................................................................................... 275

Contents

15. Peritonectomy Procedures........................................................................... 247

of the Abdomen and Pelvis ........................................................................ 249 Construction of the Surgical Field to provide Simultaneous Exposure

XV

Exposure and Effect Studies........................................................................... 276 Routes and mechanisms of exposure.............................................................. 277

Inhalation of Airborne Compounds ........................................................... 277 Ingestion and Eye Contact ......................................................................... 278 Skin Contact ............................................................................................... 279 Injection through Accidental Injury with Sharp Tools .............................. 279

Recommendations for Safety Precautions...................................................... 279 Organizational measures................................................................................. 280

Use of Technical and Personal Protective Equipment ............................... 281 Spill Management, Cleaning and Decontamination Protocols .................. 282 Proper Waste Handling and Disposal ........................................................ 283 Information and Training ........................................................................... 284 Medical Surveillance and Monitoring........................................................ 285

References....................................................................................................... 286

Part 4. Clinical Results of Surgery with or without Intraperitoneal Heated Drug Therapy

18. Results of Cytoreduction followed by HIPEC in Carcinomatosis of Colorectal Origin................................................................................................ 291

Introduction..................................................................................................... 291 Surgery for Peritoneal Carcinomatosis of Colorectal Origin ......................... 292 Prognostic Factors .......................................................................................... 294

Completeness of Cytoreduction ................................................................. 294 Extent of Disease before Surgery............................................................... 295 Other Prognostic Factors............................................................................ 295

Complications of Surgery ............................................................................... 296 The Learning Curve of Cytoreduction with HIPEC....................................... 297 Conclusion ...................................................................................................... 299 References....................................................................................................... 299

Introduction..................................................................................................... 303 Patient Eligibility and Surgical Procedures .................................................... 304 Hyperthermic Intraperitoneal Chemotherapy (HIPEC).................................. 304 Results of a Phase I Study of HIPEC with Oxaliplatin .................................. 305

Methods...................................................................................................... 305 Results ........................................................................................................ 305 Conclusion.................................................................................................. 306

Results of a Phase I Study with Oxaliplatin using Hypotonic Solutions ....... 306 Introduction ................................................................................................ 306 Methods...................................................................................................... 306 Results ........................................................................................................ 307

Contents

of Colorectal Origin............................................................................................303 19. HIPEC with Oxaliplatin in the Treatment of Peritoneal Carcinomatosis

XVI

Results of a Phase II Study of HIPEC with Oxaliplatin................................. 307 Patients and methods.................................................................................. 307 Results ........................................................................................................ 308 Discussion .................................................................................................. 309 Conclusion ................................................................................................. 310

Comparison of HIPEC with Oxaliplatin versus Standard Systemic Chemotherapy................................................................................................. 310

HIPEC group.............................................................................................. 310 Standard Group .......................................................................................... 310 Overall survival rates ................................................................................. 311 Discussion .................................................................................................. 312

Phase I study of HIPEC combining Oxaliplatin and Irinotecan..................... 313 Methods...................................................................................................... 313 Results ........................................................................................................ 313 Conclusion ................................................................................................. 313

Relation between the Extent of Cytoreductive surgery and the Rate of Postoperative Hematological Toxicity ........................................................... 314

Background ................................................................................................ 314 Methods...................................................................................................... 314 Results ........................................................................................................ 314 Conclusion ................................................................................................. 315

Future Directions and Conclusion .................................................................. 315 Aknowledgement............................................................................................ 316 References ...................................................................................................... 316

20. Clinical Results of Cytoreduction and HIPEC in Pseudomyxoma Peritonei .............................................................................................................. 319

Introduction .................................................................................................... 319 Site of Origin of PMP..................................................................................... 319 Pathological Classification of Appendiceal Neoplasms................................. 320 Clinical Trials of Cytoreduction and Intraperitoneal Chemotherapy............. 321 Conclusion ...................................................................................................... 324 References ...................................................................................................... 325

21. The Impact of Therapy in the Treatment of Pseudomyxoma Peritonei . 329 Introduction .................................................................................................... 329 Memorial Sloan-Kettering Cancer Center Experience................................... 331 Methods .......................................................................................................... 332 Clinicopathologic Features............................................................................. 333 Operative Results............................................................................................ 333 Long term overall survival ............................................................................. 335 Evaluating the Impact of Therapy for PMP ................................................... 336 References ...................................................................................................... 340

Contents

XVII

Introduction..................................................................................................... 343 Results of Cytoreduction and HIPEC............................................................. 345 Summary......................................................................................................... 352 References....................................................................................................... 353

23. Cytoreduction and Intraperitoneal Chemotherapy for Carcinomatosis from Gastric Cancer .......................................................................................... 357

Introduction..................................................................................................... 357 Diagnosis of Peritoneal Carcinomatosis......................................................... 357 Results of Systemic Chemotherapy in the Treatment of PC of Gastric Origin .............................................................................................................. 360 Treatment of PC of Gastric Origin with Intraperitoneal Chemotherapy........ 362 Perioperative Intraperitoneal Chemotherapy.................................................. 363

Neoadjuvant Intraperitoneal and Systemic Chemotherapy........................ 363 Hyperthermic Intraperitoneal Chemoperfusion ......................................... 365 Early Postoperative Intraperitoneal Chemotherapy ................................... 368 Peritonectomy Procedures.......................................................................... 368

Conclusion ...................................................................................................... 369 References....................................................................................................... 369

24. Cytoreduction and Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Ovarian Cancer .................................................................. 375

Introduction..................................................................................................... 375 Cytoreductive Surgery .................................................................................... 376 Hyperthermic Intraperitoneal Chemotherapy................................................. 378

Intraperitoneal Chemotherapy.................................................................... 378 Intraperitoneal Hyperthermic Chemotherapy ............................................ 378 Effects of HIPEC........................................................................................ 378

Refractory Ovarian Cancer ............................................................................. 381 Prognostic Factors Affecting Patient Survival ............................................... 381 Conclusion ...................................................................................................... 382 References....................................................................................................... 382

25. The role of Neoadjuvant Chemotherapy versus Primary Surgery in the Management of Stage III Ovarian Cancer ...................................................... 387

Introduction..................................................................................................... 387 Primary Cytoreductive Surgery ...................................................................... 388

Biological basis of Cytoreductive Surgery ................................................ 388 Optimal versus Suboptimal Cytoreductive Surgery .................................. 388 Variables influencing Cytoreductive Surgery............................................ 389 Outcome of Cytoreductive Surgery ........................................................... 390 FIGO Stage IV Disease.............................................................................. 391

Neoadjuvant Chemotherapy and Interval Cytoreduction ............................... 392 Neoadjuvant Chemotherapy followed by Interval Cytoreduction after Suboptimal Primary Cytoreduction ........................................................... 392

Contents

22. Clinical Results of Cytoreduction and HIPEC for Malignant Peritoneal Mesothelioma...................................................................................................... 343

XVIII

Neoadjuvant Chemotherapy followed by Interval Cytoreduction as an Alternative to Primary Cytoreduction........................................................ 393

Laparoscopy to select Patients for Neoadjuvant Chemotherapy.................... 396 References ...................................................................................................... 397

26. Morbidity and Quality of Life following Cytoreduction and HIPEC..... 403 Introduction .................................................................................................... 403 Morbidity and Mortality following Cytoreduction and HIPEC ..................... 403 Milano National Cancer Institute Experience ................................................ 406 Bowel Complications following Cytoreduction and HIPEC ......................... 410 Quality of Life following Cytoreduction and HIPEC .................................... 415 References ...................................................................................................... 415

27. Detection and Treatment of Recurrent Disease after Cytoreduction

Follow-up after Cytoreduction ....................................................................... 419 Treatment of Recurrent Disease ..................................................................... 422 References ...................................................................................................... 423

Part 5. Nonoperative and Multimodal Management of Peritoneal Carcinomatosis

28. Systemic Chemotherapy in Patients with Peritoneal Carcinomatosis

Introduction .................................................................................................... 425 Peritoneal Carcinomatosis in Trials of Systemic Chemotherapy................... 425

Systemic Therapy with 5-Fluorouracil ...................................................... 427 New cytotoxic drugs: Irinotecan and Oxaliplatin ...................................... 430 Oral Fluoropyrimidines.............................................................................. 432 Antibodies in Treatment of Colorectal Cancer .......................................... 433

Treatment strategy .......................................................................................... 435 References ...................................................................................................... 435

29. Systemic Chemotherapy in patients with Peritoneal Carcinomatosis

Introduction .................................................................................................... 441 Systemic Therapy ........................................................................................... 442 Conclusion ...................................................................................................... 445 References ...................................................................................................... 446

30. The Role of Radiotherapy in the treatment of Peritoneal Carcinomatosis ................................................................................................... 449

Introduction .................................................................................................... 449 PC Originating from Gastrointestinal Cancers............................................... 450 PC Originating from Gynaecological Cancers ............................................... 451

Contents

and HIPEC.......................................................................................................... 419

from Non Colorectal Origin .............................................................................. 441

from Colorectal Cancer ..................................................................................... 425

XIX

PC Originating from Other Cancers ............................................................... 452 Conclusions and Future Prospects for Radiotherapy - the Role of Intensity Modulated Arc Therapy.................................................................................. 453 References....................................................................................................... 455

31. Medical and Palliative Management of Malignant Ascites ...................... 459 Introduction..................................................................................................... 459 Pathophysiology and Diagnosis...................................................................... 459 Symptomatic Management by Paracentesis ................................................... 460 Symptomatic Management by Diuretics ........................................................ 461 Symptomatic Management by Peritoneovenous Shunts ................................ 461 New Treatments.............................................................................................. 462 Management of Symptomatic Malignant Ascites .......................................... 463 References....................................................................................................... 464

Part 6. Experimental Approaches

32. Targeted Intraabdominal Chemotherapy for Peritoneal Carcinomatosis ................................................................................................... 469

Summary......................................................................................................... 469 Intentions and Basic Concepts of Targeted Chemotherapy ........................... 470 Clinical Experience......................................................................................... 470 Experimental Evidence................................................................................... 472

Animals and Experimental Design ............................................................ 472 Cell Culture and Tumour Cell Inoculation ................................................ 473 Intraperitoneal Treatment........................................................................... 473

Tumour Growth and Response to Treatment............................................. 474 Discussion....................................................................................................... 478 Perspectives .................................................................................................... 478 References....................................................................................................... 479

33. Immunotherapy of Peritoneal Carcinomatosis ......................................... 483 Immunological Defence Mechanisms of the Peritoneal Cavity ..................... 483

Stimulation of Immunocompetent Cells by Defined Cytokines .................... 484 Antibody Constructs ....................................................................................... 485 Summary......................................................................................................... 488 References....................................................................................................... 489

34. Intraperitoneal Photodynamic Therapy .................................................... 493 Introduction..................................................................................................... 493 Mechanisms of PDT Mediated Cell Death..................................................... 494 Preclinical Studies of Intraperitoneal PDT..................................................... 496

Contents

to Treatment ............................................................................................... 474 Assessment of Peritoneal Tumour spread, Tumour Growth and Response

Unspecific Immunotherapy/Cytokines ........................................................... 484

XX

Clinical Applications of Intraperitoneal PDT ................................................ 499 New Frontiers in Intraperitoneal PDT: Molecularly Targeted Therapy ........ 503 Summary and Conclusions ............................................................................. 504 References ...................................................................................................... 505

35. Intraperitoneal Gene Therapy .................................................................... 515 Introduction .................................................................................................... 515 Vectors............................................................................................................ 515 Gene Therapy Strategies................................................................................. 516

Targeting p53 tumour suppressor gene...................................................... 516 Targeting HER-2/neu proto-oncogene....................................................... 517 Other adenovirus based approaches........................................................... 518

Experimental Approaches .............................................................................. 519 Conclusion ...................................................................................................... 520 References ...................................................................................................... 520

36. Index ............................................................................................................. 525

Contents

List of Contributors

H. Richard Alexander, MD Department of Surgery University of Maryland Medical Center 22 S. Greene Street S4B05A Baltimore, Md 21201, USA e-mail: HRAlexander@smail.umaryland.edu Frederic Amant, MD, PhD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium

Eturou Bando Peritoneal Dissemination Program Shizuoka Cancer Center, Sunto-gun 411-8777, Japan Dario Baratti Department of Surgery, National Cancer Institute via Venezian n.1, 20133 Milano, Italy Annie Claude Beaujard, MD Department of Anesthesiology and Intensive Care Lyon 1 University Centre Hopitalo-Universitaire Lyon Sud 69495, Pierre Bénite cedex, France Gerhild Becker, MD MSc Department of Internal Medicine II University Hospital Freiburg Hugstetter Str. 55, D-79106 Freiburg i. Br., Germany e-mail: becker@medizin.ukl.uni-freiburg.de Patrick Berteloot, MD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium Tom Boterberg MD, PhD Department of Radiotherapy University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: tom@krtkg1.ugent.be

Marc Bracke Laboratory of Experimental Cancerology University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: brackemarc@hotmail.com Wim P. Ceelen, MD Department of Surgery University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: wim.ceelen@ugent.be Keith A. Cengel Department of Radiation Oncology University of Pennsylvania School of Medicine 3400 Spruce Street, Philadelphia, PA 19104, USA Eddy Cotte, MD Lyon 1 University, Surgical department Centre Hopitalo-Universitaire Lyon Sud 69495, Pierre Bénite cedex, France Marc H. Dahlke Department of Surgery University of Regensburg 93042 Regensburg, Germany Wilfried De Neve MD, PhD Department of Radiotherapy University Hospital De Pintelaan 185, B-9000 Ghent, Belgium Hannelore Denys, MD, PhD Department of Medical Oncology University Hospital De Pintelaan 185, B-9000 Ghent, Belgium Marcello Deraco Department of Surgery, National Cancer Institute via Venezian n.1, 20133 Milano, Italy e-mail: marcello.deraco@istitutotumori.mi.it

XXII List of Contributors

XXIII

Wim Duthoy, MD, PhD Department of Radiotherapy University Hospital De Pintelaan 185, B-9000 Ghent, Belgium Dominique Elias, MD, PhD Chief of the Department of Surgical Oncology Institut Gustave Roussy, Département de Chirurgie 39 Rue Camille Desmoulins, 94805 Villejuif, France e-mail: elias@igr.fr Yoshio Endo Department of Experimental Therapeutics Shizuoka Cancer Center, Sunto-gun 411-8777, Japan Michael F. Flessner, MD, PhD Department of Medicine/Nephrology University of Mississippi Medical Center 2500 North State Street Jackson, MS 39216-4505, USA e-mail: mflessner@medicine.umsmed.edi Gunnar Folprecht University hospital “Carl Gustav Carus” Medical Dep. I, Fetscherstr. 74, 01307 Dresden, Germany Trivadi S Ganesan, MD, PhD, MNAMS, FRCP Chairman of Cancer Institute & Institute of Molecular Medicine Amrita Institute of Medical Sciences Kochi, Kerala, 682 026, India e-mail: tsganesan@aims.amrita.edu Olivier Glehen, MD Lyon 1 University, Surgical department Centre Hopitalo-Universitaire Lyon Sud 69495, Pierre Bénite cedex, France François Noël Gilly, MD, PhD Professor of Surgery Lyon 1 University, Surgical department Centre Hopitalo-Universitaire Lyon Sud 69495, Pierre Bénite cedex, France e-mail : francogi@lyon-sud.univ-lyon1.fr

List of Contributors

XXIV

Eli Glatstein Department of Radiation Oncology University of Pennsylvania School of Medicine 3400 Spruce Street, Philadelphia, PA 19104, USA Diane Goere Institut Gustave Roussy, Département de Chirurgie, 39 Rue Camille Desmoulins, 94805 Villejuif, France Claudia Hadtstein Junior scientist, Institute of Applied Pharmacy (IFAP), Cologne Bitburgerstrasse 4, 54668 Echternacherbrück, Germany Stephen M. Hahn Henry K. Pancoast Professor and Chair Department of Radiation Oncology University of Pennsylvania School of Medicine 3400 Spruce Street, Philadelphia, PA 19104, USA e-mail: hahn@xrt.upenn.edu Nader Hanna, MD Department of Surgery University of Maryland Medical Center 22 S. Greene Street S4B05A Baltimore, Md 21201, USA Markus M. Heiss Department of Surgery Merheim Medical Center University of Witten/Herdecke Ostmerheimer-Strasse 200, D-51109 Koln-Merheim, Germany Bert Hildebrandt Charité-Centrum Tumormedizin Charité Universitätsmedizin Berlin Augustenburger Platz 1, D-13353 Berlin, Germany e-mail: hyperthermia@charite.de Hiroaki Ito Peritoneal Dissemination Program Shizuoka Cancer Center, Sunto-gun 411-8777, Japan

List of Contributors

XXV

Joachim Jähne, MD, PhD Clinic for General and Visceral Surgery Center for Endocrine and Oncological Surgery, Henriettenstiftung Hannover Marienstrasse 72 – 90, D - 30171 Hannover, Germany e-mail: avg.chirurgie@henriettenstiftung.de Mr David Jayne Senior Lecturer in Surgery Academic Surgical Unit St. James’s University Hospital Leeds LS9 7TF, United Kingdom e-mail: david.jayne@leedsth.nhs.uk Taiich Kawamura Peritoneal Dissemination Program Shizuoka Cancer Center Sunto-gun 411-8777, Japan Thekla Kiffmeyer Head of Department. of Environmental Medicine Institute of Energy and Environmental Technology (IUTA) Bliersheimer Straße 60, D-47229 Duisburg, Germany e-mail: kiffmeyer@iuta.de Kouichi Kiyosaki Department of Surgery Jichi Medical School Oomiya Saitama 330-8503, Japan Claus-Henning Köhne Klinikum Oldenburg gGmbH Dept. of Oncology and Hematology Dr.Eden Str.10, 26133 Oldenburg, Germany Stefan Kübler, MD Clinic for General and Visceral Surgery Center for Endocrine and Oncological Surgery, Henriettenstiftung Hannover Marienstrasse 72 – 90, D - 30171 Hannover, Germany e-mail: stefan.kuebler@henriettenstiftung.de Shigeki Kusamura Department of Surgery National Cancer Institute via Venezian n.1, 20133 Milano, Italy

List of Contributors

XXVI

Joon-Mo Lee, MD Department of Obstetrics & Gynecology The Catholic University of Korea Kangnam St. Mary’s Hospital, Seocho-go Banpo-dong, 137-701 Seoul, South Korea e-mail : leejm@catholic.ac.kr Karin Leunen, MD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium Edward A. Levine, MD Professor of Surgery Chief, Surgical Oncology Wake Forest University, Winston-Salem, NC 27106, USA e-mail: elevine@wfubmc.edu Jean Christophe Lifante, MD Lyon 1 University, Surgical department Centre Hopitalo-Universitaire Lyon Sud 69495, Pierre Bénite cedex, France Matthias Löhr Dept. of Medicine II University Hospital Mannheim, University of Heidelberg, D-68135 Mannheim, Germany Teri A. Longacre, MD Department of Pathology Stanford University School of Medicine Room L235, 300 Pasteur Drive Stanford, CA, 94305, USA e-mail: longacre@stanford.edu Nicholas J. Lutton North Hampshire Hospital Aldermaston Road Basingstoke, Hampshire, RG24 9NA United Kingdom Manfred P. Lutz Caritasklinik St. Theresia Rheinstrasse 2, 66113 Saarbrücken, Germany e-mail: m.lutz@caritasklinik.de

List of Contributors

XXVII

Srinivasan Madhusudan Cancer Research UK Medical Oncology Unit The Churchill Hospital Oxford OX3 7LJ, United Kingdom Haile Mahteme, MD, PhD Department of surgical sciences Section of Surgery University hospital of Uppsala Akademiska sjukhuset, Uppsala, Sweden e-mail: haile.mahteme@surgsci.uu.se Maurie Markman, MD University of Texas M.D. Anderson Cancer Center Mail Box #121, 1515 Holcombe Boulevard, Houston, Texas 77005, USA e-mail: mmarkman@mdanderson.org Thomas J. Miner, MD, FACS Assistant Professor of Surgery Director of Surgical Oncology Department of Surgery Brown Medical School 593 Eddy St, APC 439, Providence, RI, 02903, USA e-mail: TMiner@usasurg.org Masahiro Miura Department of Anatomy Oita University School of Medicine Oita, Japan Mr. Brendan J. Moran, MCh, FRCS Director, Pseudomyxoma Peritonei Centre North Hampshire Hospital Aldermaston Road Basingstoke, Hampshire, RG24 9NA United Kingdom e-mail: Brendan.Moran@nhht.nhs.uk Sophie Morris Research Fellow Academic Surgical Unit 10th Floor QEQM Wing, St Mary's Hospital London W2 1NY, United Kingdom

List of Contributors

XXVIII

Steven E. Mutsaers, PhD Adjunct Associate Professor Centre for Asthma, Allergy and Respiratory Medicine University of Western Australia and Senior Research Scientist Asthma & Allergy Research Institute 4th Floor G Block, Sir Charles Gairdner Hospital Hospital Avenue, Nedlands WA 6009, Australia e-mail: mutsaers@aari.uwa.edu.au Patrick Neven, MD, PhD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium Lars Påhlman Department of surgical sciences Section of Surgery University hospital of Uppsala Akademiska sjukhuset Uppsala, Sweden Reetesh K. Pai, MD Department of Pathology Stanford University School of Medicine Room L235, 300 Pasteur Drive, Stanford, CA, 94305, USA Mr Paraskevas Paraskeva, PhD, FRCS Senior Lecturer Academic Academic Surgical Unit 10th Floor QEQM Wing, St Mary's Hospital London W2 1NY, United Kingdom Piet Pattyn, MD, PhD Department of Surgery University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: piet.pattyn@ugent.be Marc Peeters, MD, PhD Department of Gastroenterology University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: marc.peeters@ugent.be

List of Contributors

XXIX

James F. Pingpank, MD Department of Surgery University of Maryland Medical Center 22 S. Greene Street S4B05A Baltimore, MD 21201, USA Pompiliu Piso Department of Surgery University of Regensburg 93042 Regensburg, Germany e-mail: pompiliu.piso@klinik.uni-regensburg.de Marc Pocard Institut Gustave Roussy, Département de Chirurgie, 39 Rue Camille Desmoulins 94805 Villejuif, France Stephan Samel, MD University of Göttingen Waldweg 1, D-37073 Göttingen, Germany e-mail: Stephan.samel@web.de Takuma Sasaki Laboratory of Bio-organic Chemistry School of Pharmacy Aichi Gakuin University Nagoya 464-8650, Japan Hans J. Schlitt Department of Surgery University of Regensburg 93042 Regensburg, Germany Perry Shen, MD Surgical Oncology Wake Forest University Winston-Salem, NC 27106, USA John H. Stewart, IV, MD Surgical Oncology Wake Forest University Winston-Salem, NC 27106, USA

List of Contributors

XXX

Michael A Ströhlein Department of Surgery Merheim Medical Center University of Witten/Herdecke Ostmerheimer-Strasse 200, D-51109 Koln-Merheim, Germany e-mail: StroehleinM@kliniken-koeln.de Paul H. Sugarbaker, MD Washington Cancer Institute 106 Irving St., NW Suite 3900, Washington, DC 20010, USA e-mail: Paul.Sugarbaker@medstar.net Jouke T. Tamsma, MD, PhD Leiden University Medical Center (LUMC) Vascular Medicine, Dept. of Endo & Gen.Int.Med, C4-R66 PO Box 9600, 2300 RC Leiden, The Netherlands e-mail: jttamsma@lumc.nl Toon Van Gorp, MD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium Sybile Van Lierde, MD Department of gastroenterology University Hospital De Pintelaan 185, B-9000 Ghent, Belgium e-mail: sybvanlierde@hotmail.com Ignace Vergote, MD, PhD Division of Gynaecological Oncology Department of Obstetrics and Gynaecology University Hospitals, Katholieke Universiteit Herestraat 49, B-3000 Leuven, Belgium Ignace.Vergote@uz.kuleuven.ac.be Vic J Verwaal, MD, PhD Department of Surgery The Netherlands Cancer Institute Plesmanlaan 121 NL-1066 CX Amsterdam The Netherlands e-mail: v.verwaal@nki.nl

List of Contributors

XXXI

Sylwia Wilkosz Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research University of Western Australia Sir Charles Gairdner Hospital, Nedlands, WA 6009, Australia Peter Wust Charité-Centrum Tumormedizin Charité Campus Virchow Klinikum Charité Universitätsmedizin Berlin Augustenburger Platz 1 D-13353 Berlin, Germany e-mail: hyperthermia@charite.de Yutaka Yonemura Peritoneal Dissemination Program Shizuoka Cancer Center Sunto-gun 411-8777, Japan e-mail: y.yonemura@scchr.jp

List of Contributors