PIPAC: Pressurized IntraPeritoneal Aerosol Chemotherapy – Cancer under Pressure

Preface\nAcknowledgments\n1 Introduction\n2 Peritoneal carcinomatosis: a neglected disease\n	2.1 An unmet medical need\n	2.2 Role of the physician in provision of care in advanced peritoneal cancer\n	2.3 Palliative care in peritoneal carcinomatosis\n3 Normal and diseased peritoneum\n	3.1 Ontology\n	3.2 Anatomy\n		3.2.1 Blood supply\n		3.2.2 Lymphatics\n		3.2.3 Lymphatic stomata\n		3.2.4 Milky spots\n		3.2.5 Greater omentum\n		3.2.6 Peritoneal nerves\n	3.3 Physiology of peritoneum\n		3.3.1 Peritoneum-plasma barrier\n		3.3.2 Intraperitoneal Hydrostatic Pressure\n	3.4 Pathophysiology of peritoneal carcinomatosis\n		3.4.1 Epithelial-mesenchymal transition\n		3.4.2 Interstitial intratumoral fluid pressure\n		3.4.3 Ascites\n		3.4.4 Hormonal changes\n4 Diagnosis and staging of peritoneal carcinomatosis\n	4.1 Diagnostic workup\n	4.2 Imaging studies\n		4.2.1 Computer tomography (CT scan)\n		4.2.2 Magnetic Resonance Imaging (MRI)\n		4.2.3 Ultrasound\n		4.2.4 FDG-Positron emission tomography (PET)\n	4.3 Diagnostic laparoscopy\n		4.3.1 Peritoneal Cancer Index\n	4.4 Peritoneal or pleural cytology\n		4.4.1 Gastric cancer\n		4.4.2 Ovarian cancer\n		4.4.3 Colorectal cancer\n5 Therapy of peritoneal carcinomatosis\n	5.1 Systemic palliative chemotherapy\n	5.2 Intraperitoneal chemotherapy\n	5.3 Drug uptake into tumoral tissue\n		5.3.1 Diffusion\n		5.3.2 Convection\n	5.4 Effect of peritonectomy on drug clearance\n	5.5 Influence of intraperitoneal drug concentration\n	5.6 Tissue penetration of various drugs\n		5.6.1 Doxorubicin (see also page 199)\n		5.6.2 Cisplatinum (see also page 198)\n		5.6.3 Oxaliplatinum\n		5.6.4 Taxanes (Paclitaxel, Docetaxel)\n	5.7 Perioperative intraperitoneal chemotherapy\n		5.7.1 CHPP\n		5.7.2 NIPS\n		5.7.3 EIPL\n		5.7.4 EPIC\n	5.8 Intraperitoneal chemotherapy for ascites\n	5.9 Limitations of intraperitoneal chemotherapy\n		5.9.1 Poor drug penetration\n		5.9.2 Poor surface exposition\n		5.9.3 Local toxicity\n		5.9.4 Peritoneal sclerosis\n	5.10 Intraperitoneal immunotherapy\n		5.10.1 Catumaxomab\n		5.10.2 Bevacizumab\n		5.10.3 Immunoradiotherapy\n	5.11 Intraperitoneal cytolytic virotherapy\n	5.12 Nanodrugs\n	5.13 Combined CRS with HIPEC\n		5.13.1 Cytoreductive surgery (CRS)\n		5.13.2 Hyperthermic IntraPEritoneal Chemotherapy (HIPEC)\n		5.13.3 Colorectal cancer\n		5.13.4 Ovarian Cancer\n		5.13.5 Gastric Cancer\n		5.13.6 Learning curve and expertise\n		5.13.7 Evidence of cost effectiveness\n		5.13.8 Safety\n		5.13.9 Indications for CRS and HIPEC\n6 Assessing tumor response in peritoneal carcinomatosis\n	6.1 Natural history of peritoneal carcinomatosis\n	6.2 RECIST criteria\n		6.2.1 RECIST criteria in peritoneal carcinomatosis\n	6.3 Laparoscopy in peritoneal carcinomatosis\n	6.4 Histology for determining tumor response\n	6.5 Tumor markers for determining tumor response\n		6.5.1 Gastric cancer\n		6.5.2 Ovarian cancer\n		6.5.3 Colorectal cancer\n	6.6 Determining clinical benefit rate in peritoneal carcinomatosis\n7 Principle of therapeutic capnoperitoneum\n	7.1 Material and methods\n		7.1.1 Design of the prototype\n	7.2 Results\n		7.2.1 In vitro trial\n		7.2.2 In vivo trial\n	7.3 Discussion\n		7.3.1 Increasing exposure of the peritoneal surface\n		7.3.2 Increasing hydrostatic intraabdominal pressure\n		7.3.3 Applications of therapeutic capnoperitoneum\n8 PIPAC Technology\n	8.1 Aerosol\n	8.2 Pressure\n	8.3 Micropump\n	8.4 High-pressure injector\n	8.5 Training and documentation\n	8.6 Limited sales\n9 Preclinical experiments\n	9.1 Xenograft intraperitoneal model in the pig\n		9.1.1 Material and methods\n		9.1.2 Anesthesia\n		9.1.3 Operative procedure: sigmoid colectomy\n		9.1.4 Postoperative care\n		9.1.5 Cell line\n		9.1.6 Labeling of HeLa cells\n		9.1.7 Immunohistochemistry\n		9.1.8 In vitro study of chromate toxicity\n		9.1.9 Intraoperative complications\n		9.1.10 Port site recurrence\n		9.1.11 Postoperative course\n		9.1.12 Discussion\n	9.2 Staining experiments with aerosolized methylene blue in the pig\n		9.2.1 Introduction\n		9.2.2 Material and Methods\n		9.2.3 Results\n		9.2.4 Discussion\n	9.3 Ex vivo experiments with Dbait on diseased peritoneum\n		9.3.1 Material and methods\n		9.3.2 Study design\n		9.3.3 Nebulizer\n		9.3.4 Patient characteristics, cytoreduction, and intraperitoneal hyperthermic chemotherapy\n		9.3.5 Tumor characteristics\n		9.3.6 Experimental protocol\n		9.3.7 Microscopic analysis\n		9.3.8 Results\n		9.3.9 Discussion\n10 First PIPAC in-human application\n	10.1 Introduction\n	10.2 Methods\n		10.2.1 Patients\n		10.2.2 Surgical procedures\n		10.2.3 Safety and Efficacy assessments\n		10.2.4 Histology and immunohistochemistry\n		10.2.5 Clinical Pharmacology\n	10.3 Results\n		10.3.1 Patient 1\n		10.3.2 Patient 2\n		10.3.3 Patient 3\n	10.4 Safety\n	10.5 Clinical Pharmacology\n	10.6 Discussion\n11 Renal and liver toxicities\n	11.1 Patients and methods\n		11.1.1 Study Design\n		11.1.2 Ethics\n		11.1.3 Patients\n		11.1.4 Therapy\n		11.1.5 Sampling\n	11.2 Statistical Analysis\n	11.3 Results\n	11.4 Discussion\n12 PIPAC in ovarian cancer\n	12.1 Off-label use\n		12.1.1 Patients and methods\n		12.1.2 Results\n		12.1.3 Discussion\n	12.2 PIPAC-OV1: a Phase-2 trial in the third-line palliative situation\n		12.2.1 Objectives\n		12.2.2 Study design\n		12.2.3 Target subject population\n		12.2.4 Investigational product, dosage, and mode of administration\n		12.2.5 Duration of treatment\n		12.2.6 Endpoints\n		12.2.7 Patient reported outcomes (PROs)\n		12.2.8 Pharmacokinetics\n		12.2.9 Safety\n		12.2.10 Statistical methods\n		12.2.11 Current stage\n	12.3 PIPAC-OV2: a Phase-1 dose-finding study\n	12.4 PIPAC-OV3: a prospective Phase-2-3 randomized trial\n13 PIPAC in gastric cancer\n	13.1 Off-label use\n	13.2 Results\n	13.3 Discussion\n	13.4 PIPAC-GA1: a Phase-2 trial in the third-line palliative situation\n		13.4.1 Objectives\n		13.4.2 Study design\n		13.4.3 Target subject population\n		13.4.4 Investigational product, dosage and mode of administration\n		13.4.5 Duration of treatment\n		13.4.6 Study endpoints\n		13.4.7 Current stage\n14 PIPAC in colorectal cancer\n	14.1 Patients and methods\n	14.2 Results\n	14.3 Discussion\n15 PIPAC in mesothelioma\n	15.1 Patients and methods\n	15.2 Results\n	15.3 Conclusions\n16 Quality of Life after PIPAC\n17 PIPAC and HIPEC\n	17.1 PIPAC as a neoadjuvant therapy before HIPEC\n18 Pressurized IntraThoracic Aerosol Chemotherapy (PITAC)\n	18.1 Patients\n	18.2 Technique\n		18.2.1 First in-human use\n	18.3 Results\n19 Future applications of therapeutic capnoperitoneum\n	19.1 Study design\n	19.2 Regulatory background and animals\n		19.2.1 Staining\n		19.2.2 Macroscopy\n		19.2.3 Microscopic analysis\n	19.3 Pressurized IntraVesical Aerosol Chemotherapy (PIVAC)\n	19.4 Pressurized IntraLuminal Aerosol Chemotherapy (PILAC)\n	19.5 Discussion\n20 Occupational health and safety aspects\n	20.1 Methods\n		20.1.1 Ethical, legal and regulatory background\n		20.1.2 Methodology\n		20.1.3 Nebulizer\n		20.1.4 Operating room characteristics\n		20.1.5 Chemotherapy\n		20.1.6 Experimental protocol\n	20.2 Results\n		20.2.1 Identification of hazardous substances and dose\n		20.2.2 Identification of possible exposure ways\n		20.2.3 First PIPAC simulation with NaCl 0.9% solution\n		20.2.4 Second PIPAC simulation with smoke and an artificial leak\n		20.2.5 Information and training of the team of volunteers\n		20.2.6 Performance of the first PIPAC procedures with chemotherapy\n	20.3 Conclusions\n	20.4 Second assessement\n	20.5 Biological monitoring\n21 PIPAC: Risks and dangers\n	21.1 Bowel access lesions\n	21.2 Simultaneous PIPAC and cytoreductive surgery\n	21.3 Port-site metastases\n	21.4 Tumor invasion of the laparotomy scar\n	21.5 Subcutaneous toxic emphysema\n	21.6 Therapy-resistant ascites\n	21.7 Small bowel obstruction\n	21.8 Secondary CRS and HIPEC\n22 Outlook\n	22.1 Radio- and Chemosensibilizers\n	22.2 Nanodrugs\n	22.3 Multimodal therapy\n	22.4 Preventive application in cancer\n	22.5 Applications outside cancer therapy\n23 How to start a PIPAC program at your own institution?\n	23.1 Regulatory aspects\n		23.1.1 Compassionate use program or off-label use?\n		23.1.2 Drug or medical product?\n		23.1.3 CE certification\n		23.1.4 Reimbursement\n	23.2 Technology access\n	23.3 Occupational health and safety\n	23.4 In-house Information and training\n	23.5 Research\n24 Training and Standard Operating Procedures\n	24.1 Training\n	24.2 Safety checklist for PIPAC\n	24.3 Peritoneal and pleural carcinomatosis index\n		24.3.1 Extent of Pleural Carcinomatosis (EPC) score\n	24.4 Registry data\nIndex