Advances in Peritoneal Surface Oncology (eBook)

Preface 5
Table of Contents 9
List of Contributors 11
1 Management of Peritoneal Surface Malignancy: A Short History 14
1.1 Introduction 14
1.2 Peritoneal Space to Plasma Barrier 14
1.3 A Requirement for Complete Cytoreduction Using Peritonectomy Procedures 15
1.4 Long-Term Intraperitoneal Chemotherapy 15
1.5 Early Postoperative Intraperitoneal Chemotherapy 16
1.6 Heated Intraoperative Intraperitoneal Chemotherapy 16
1.7 More Knowledgeable Use of Quantitative Prognostic Indicators for Combined Treatment 17
1.8 Development of Peritoneal Surface Oncology Treatment Centers 18
1.9 Future Directions 18
1.10 Respect for the Peritoneum as a First Line of Defense of Carcinomatosis 18
References 20
2 The Natural History of Free Cancer Cells in the Peritoneal Cavity 23
2.1 Molecular Mechanisms Involved in Peritoneal Dissemination 23
2.2 Detection of Free Cancer Cells in the Peritoneal Cavity 30
2.3 Clinical Implications and Signifificance of a Positive Cytology 31
References 33
3 Pathological Evaluation and Implications of Serosal Involvement in Gastrointestinal Cancer 36
3.1 Introduction 36
3.2 Anatomy and Microanatomy 36
3.3 Defifinition and Pathological Evaluation of Serosal Involvement 37
3.4 Cytological Assessment of Serosal Involvement 39
3.5 Signifificance of Serosal Involvement 40
3.5.1 Oesophagus 40
3.5.2 Stomach 41
3.5.3 Small Intestine 42
3.5.4 Appendix 42
3.5.5 Colon 44
3.5.6 Rectum 45
3.6 Summary and Conclusions 46
References 47
4 Principles of Perioperative Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis 50
4.1 The Rationale for Intraperitoneal Chemotherapy 50
4.2 The Pharmacokinetic Advantage 50
4.3 Drug Tissue Distribution and Tumour Penetration Depth 52
4.4 Timing of Intraperitoneal Chemotherapy 53
4.5 Hyperthermia 53
4.5.1 Direct Cytotoxic Effect of Hyperthermia 53
4.5.2 Thermal Enhancement of Chemotherapeutic Drugs 55
4.5.3 Tissue Penetration Depth of Hyperthermia During HIPEC 56
4.6 Drug Choice 56
4.7 Carrier Solutions 57
4.8 Duration of Hyperthermic Chemoperfusion 59
References 60
5 Experimental and Pharmacokinetic Studies in Intraperitoneal Chemotherapy: From Laboratory Bench to Bedside 63
5.1 Alkylating Agents 64
5.1.1 Melphalan 64
5.1.2 Cyclophosphamide and Ifosfamide 65
5.1.3 Mitomycin C 65
5.2 Platinum Derivatives 66
5.2.1 Cisplatin 66
5.2.2 Carboplatin 67
5.2.3 Oxaliplatin 68
5.3 Anthracyclins 69
5.3.1 Adriamycin 69
5.3.2 Mitoxantrone 70
5.4 Antimetabolites 70
5.4.1 Methotrexate 70
5.4.2 5-Fluorouracil and Floxuridine 71
5.4.3 Gemcitabine 72
5.5 Topoisomerase Inhibitors 73
5.5.1 Irinotecan 73
5.5.2 Topotecan 73
5.5.3 Etoposide 74
5.6 Taxanes 74
5.6.1 Paclitaxel 74
5.6.2 Docetaxel 75
5.7 Conclusions and Future Directions 76
References 77
6 Technology for the Delivery of Hyperthermic Intraoperative Intraperitoneal Chemotherapy: A Survey of Techniques 84
6.1 Introduction 84
6.2 Technique of Intraperitoneal Hyperthermic Chemoperfusion 84
6.3 Closed Technique 85
6.4 Open Abdomen (Coliseum) Technique 86
6.5 Peritoneal Cavity Expander Technique 88
6.6 Developing a HIPEC Program 89
6.7 Summary 90
References 91
7 Adjuvant Intraperitoneal Chemotherapy: A Review 92
7.1 Introduction 92
7.2 Gastric Cancer 92
7.3 Colorectal Cancer 95
7.4 Ovarian Cancer 96
7.5 Conclusion 97
References 97
8 Clinical Research Methodology in Peritoneal Surface Oncology: A Diffificult Challenge 99
8.1 Preoperative Variables 99
8.2 Peroperative Variables 100
8.2.1 Concerning the Peroperative Description of PC 100
8.2.2 Concerning the Completeness of Cytoreduction 102
8.3 HIPEC Variables 103
8.4 Postoperative Variables 103
8.5 Survival Results 105
8.6 Conclusion 105
References 105
9 Lessons Learnt from Clinical Trials in Peritoneal Surface Oncology: Colorectal Carcinomatosis 107
9.1 Introduction 107
9.2 Randomised Study in PC of Colorectal Origin 107
9.3 Lessons from This Study 109
References 111
10 Experimental Models and Questions in Basic Science Research for Pseudomyxoma Peritonei 112
10.1 Introduction 112
10.2 The Challenge 113
10.3 Neoplastic Mucin-Producing Goblet Cells of the Appendix 113
10.4 Questions 115
10.5 Experimental Models 115
10.6 Genetics 115
10.7 Cell Cycle 117
10.8 Apoptosis 117
10.9 Metastasis 118
10.10 MUC2 119
10.11 Future Investigations 119
References 120
11 Peritoneal Carcinomatosis of Colorectal Origin: Recent Advances and Future Evolution Toward a Curative Treatment 122
11.1 Introduction 122
11.2 The Primordial Prognostic Impact of Complete Cytoreduction 122
11.3 Results of Phase II Studies with CCS 123
11.4 Randomized Trial 125
11.5 Validated and Unvalidated HIPEC Techniques for Colorectal PC 126
11.6 Current Indications for CCS with HIPEC 126
11.7 Probable and Potential Improvements of the HIPEC Technique 127
11.8 Outlook for HIPEC in Colorectal PC 127
11.9 Conclusion 128
References 128
12 Pathologic Characterization and Differential Diagnosis of Malignant Peritoneal Mesothelioma 130
12.1 Introduction 130
12.2 Epithelioid Mesothelioma 130
12.2.1 Tubulopapillary Pattern 130
12.2.2 Acinar (Glandular) Pattern 130
12.2.3 Solid Pattern 131
12.2.4 Signet Ring Pattern 131
12.2.5 Deciduoid Pattern 131
12.2.6 Clear Cell Pattern 132
12.2.7 Rhabdoid Pattern 132
12.3 Sarcomatoid Mesothelioma 133
12.4 Mixed (Biphasic) Mesothelioma 133
12.5 Immunohistochemistry 133
12.5.1 Positive Mesothelioma Markers 134
12.5.1.1 Podoplanin and the D2-40 Monoclonal Antibody 134
12.5.1.2 Calretinin 134
12.5.1.3 Keratin 5/6 135
12.5.1.4 Mesothelin 136
12.5.1.5 Wilms Tumor 1 Protein 136
12.5.1.6 Thrombomodulin 136
12.5.2 Positive Carcinoma Markers 137
12.5.2.1 Monoclonal Antibody MOC-31 137
12.5.2.2 Monoclonal Antibody Ber-EP4 137
12.5.2.3 Monoclonal Antibody BG-8 137
12.5.2.4 Carcinoembryonic Antigen 138
12.5.2.5 B72.3 Monoclonal Antibody 138
12.5.2.6 Leu-M1 (CD15) 138
12.5.3 Miscellaneous Markers 139
12.5.3.1 Estrogen and Progesterone Receptors 139
12.5.3.2 Renal Cell Carcinoma Marker 139
12.5.3.3 Thyroid Transcription Factor 1 139
12.5.3.4 P63 139
12.6 Electron Microscopy 139
12.7 Conclusions 140
References 141
13 Advances in Clinical Research and Management of Diffuse Peritoneal Mesothelioma 144
13.1 Epidemiology 144
13.2 Etiology 144
13.2.1 Asbestos-Induced Oncogenesis 145
13.2.2 Oncogenesis Not Related to Asbestos 145
13.2.3 Molecular Biology 146
13.3 Pathology 147
13.4 Natural History 147
13.4.1 Clinical Presentation 148
13.4.2 Pattern of Spread 148
13.5 Diagnosis 149
13.5.1 Radiological Imaging 149
13.5.2 Serum Markers 150
13.6 Staging 150
13.7 Conventional Treatment 152
13.7.1 Systemic Chemotherapy and Biological Therapies 152
13.7.2 Intraperitoneal Chemotherapy 152
13.7.3 Combined Treatment 152
13.8 Cytoreductive Surgery and Intraperitoneal Hyperthermic Perfusion 153
13.8.1 Rationale 153
13.8.1.1 Cytoreductive Surgery 153
13.8.1.2 Intraperitoneal Chemotherapy 153
13.8.1.3 Antitumor Effffect of Hyperthermia 154
13.8.2 Patient Selection 155
13.8.3 Operative Technique 155
13.8.3.1 Cytoreductive Surgery 155
13.8.3.2 Hyperthermic Intraperitoneal Chemotherapy 156
13.8.4 Assessment of the Completeness of the Cytoreduction 157
13.9 Results 157
13.9.1 Morbidity and Mortality 157
13.9.2 Prognostic Factors 158
13.9.3 Biological Markers 158
13.10 Future Perspectives 159
References 159
14 Advances in the Management of Gastric Cancer with Peritoneal Dissemination 163
14.1 Results of Previous Clinical Studies in Carcinomatosis of Gastric Origin 163
14.2 Rationale and Results of Neoadjuvant Intraperitoneal-Systemic Chemotherapy 164
14.2.1 Methods and Results of NIPS 165
14.2.2 Peritonectomy After NIPS and Results 166
14.3 Conclusions and Directions for Future Clinical Research 168
References 169
15 Intraperitoneal Chemotherapy in the Management of Ovarian Cancer 171
15.1 Intraperitoneal Chemotherapy: Historical Perspective 171
15.2 Theoretical Rationale for Intraperitoneal Chemotherapy 171
15.3 Preclinical Evaluation of Intraperitoneal Chemotherapy 172
15.4 Objections to the Use of Intraperitoneal Therapy 173
15.4.1 Theoretical Concerns 173
15.4.2 Practical Concerns 173
15.4.3 Adequacy of Drug Distribution 173
15.5 Phase I Clinical Trials of Intraperitoneal Chemotherapy 174
15.6 Phase II Trials of Intraperitoneal Chemotherapy in Ovarian Cancer 174
15.6.1 Cisplatin-Based Second-Line Intraperitoneal Chemotherapy of Ovarian Cancer 175
15.7 Phase III Trials of Primary Cisplatin-Based Intraperitoneal Chemotherapy in the Management of Advanced Ovarian Cancer 176
15.7.1 Phase III Trial of Intraperitoneal versus Intravenous Cisplatin, with All Patients Also Receiving Intravenous Cyclophosphamide 176
15.7.2 Phase III Trial of Intraperitoneal versus Intravenous Cisplatin, with All Patients Also Receiving Intravenous Paclitaxel 176
15.7.3 Phase III Trial of Intravenous Cisplatin/Paclitaxel Versus Intraperitoneal Cisplatin plus Both Intravenous and Intraperitoneal Paclitaxel 177
15.8 Conclusions Regarding Primary Cisplatin-Based Chemotherapy in “Small-Volume Residual” Advanced Ovarian Cancer 178
15.9 What Is the “Optimal” Primary Intraperitoneal Chemotherapy Regimen in Small-Volume Residual Advanced Ovarian Cancer? 178
15.10 Use of Intraperitoneal Chemotherapy in Ovarian Cancer in Other Clinical Settings 179
15.11 Conclusion 179
References 180

"9 Lessons Learnt from Clinical Trials in Peritoneal Surface Oncology: Colorectal Carcinomatosis (p. 99-100)

Frans A. N. Zoetmulder and Vic J. Verwaal

9.1 Introduction

Very few surgical cancer therapies have been tested in randomised studies. An obvious reason for this is the fact that most cancer operations were developed in the age when randomised studies were simply not heard of. By now many cancer operations have proved to be curative in a considerable percentage of patients, and neither patients nor surgeons would want to miss that chance of permanent cure. After Sugarbaker had shown in a small randomised study that post-operative intraperitoneal 5-fluorouracil (5-FU) installations could prevent the development of peritoneal metastases in some high risk colon cancer patients [1] he developed this technique as treatment for patients with established peritoneal carcinomatosis (PC).

As he could show some promising results, a group of enthusiasts grew who invested heavily in this new approach towards an, until then, incurable disease. The post-operative 5-FU installation technique evolved into the hyperthermic intraperitoneal chemotherapy (HIPEC) technique with either mitomycin C or oxaliplatin, which is at present used in many centres. Notwithstanding promising results in phase II type studies from several centres [2– 13], it proved impossible to convince the wider medical oncology community of the benefits of cytoreduction and HIPEC in these patients. Gradually it became clear that only convincing evidence from a randomised study could achieve this goal.

9.2 Randomised Study in PC of Colorectal Origin

There is only one randomised study comparing the HIPEC approach with conventional treatment of PC of colorectal origin [14]. In this study from the Netherlands Cancer Institute patients with proven PC were randomised either to undergo limited palliative surgery followed by systemic treatment with 5-FU/leucovorin or to undergo cytoreduction and HIPEC, followed by the same systemic chemotherapy. One hundred and five patients were randomised in a 3-year period, 51 in the standard arm and 54 in the experimental arm.

Only 44 patients in the standard arm started their chemotherapy. Two patients refused the result of the randomisation and went abroad to undergo HIPEC treatment. The other patients did not start, mainly because of early progression. In the experimental arm five patients did not get their HIPEC therapy. One patient died while on the waiting list, one patient refused at the last minute, and three patients developed distant metastases in the time between randomisation and the planned operation date. HIPEC consisted of continuous peritoneal lavage with a solution containing mitomycin C at a dose of 35 mg/m2, with a maximum of 70 mg.

Half of this dose was administered at the start of the lavage, 25% after 30 min and 25% after 60 min, with a total lavage time of 90 min. The temperature was kept between 40°C and 42°C, at three measuring points in the abdomen. Thirty-five patients started their systemic chemotherapy after recovery from the HIPEC treatment. The main reason for not starting was a complicated post-operative period. Detailed information on the extent of PC was only available for the patients undergoing HIPEC.

Many patients had very extensive PC, with 54% having five or more of seven abdominal regions involved and over 30% having six or seven regions involved. It was possible to resect all macroscopic PC in 38% of patients. In 43% small residues (<2.5 mm) were left behind, whereas in 19% larger residues remained. To achieve this level of cytoreduction a multitude of surgical resections had to be done, including omentectomy and multiple bowel resections in most patients. In accordance with this extensive surgery complications have been frequent. Most common complications were infectious, related to small bowel leakage."