Liver Intra-arterial PRRT with 111In-Octreotide: The Tumoricidal Efficacy of 111In Auger Electron Emission

Preface
Acknowledgments
Contents
1: The Efficacy of?Auger and?Internal Conversion Electron Emission of?111In for?Treating Neuroendocrine Tumors
	1.1	 Introduction
	1.2	 Hepatic Intra-arterial Radiopeptide Flow Dynamics
		1.2.1	 Production and?Physical Characteristics of?111In
	1.3	 Recent Historical Background of?Radioactive Infusions for?Liver Tumors
	1.4	 Physics of?Radiation Therapy
		1.4.1	 Radiation Types
		1.4.2	 Auger Electrons
		1.4.3	 Radiation Dose
	1.5	 Radiobiology
		1.5.1	 Modifiers of?Radiation Response
	1.6	 The Effects of?Radiation on?the?Liver
	1.7	 The Rationale for 111In-Octreoscan Therapy
		1.7.1	 Anatomic Vascular Summary
		1.7.2	 Preclinical Reports on?Blood Supply in?Tumors
	1.8	 Human Studies with?111In-Octreoscan
	1.9	 Commercially Available 111In-Octreoscan for?Human Medical Use
	References
2: Somatostatin
	2.1	 Historical Corner
	2.2	 Somatostatin Receptors-Tissue Expression [4]
	2.3	 Somatostatin Analogues
	References
3: Gastro-entero-pancreatic Neuroendocrine Tumors
	3.1	 Syllabus- Classification-Epidemiology
	3.2	 Therapeutic Approaches Towards Neuroendocrine Tumors
		3.2.1	 Interventional Approach
		3.2.2	 Interferon Alfa (IFN-?)
		3.2.3	 Systemic Chemotherapy
	References
4: [111In-DTPA0-D-Phe1]-Octreotide: The Ligand?The Receptor?The Label
	4.1	 The Somatostatin Peptide Family
	4.2	 The Somatostatin Receptor Family (SSTRs)
		4.2.1	 Definitions
		4.2.2	 Somatostatin Receptors: Biological Function
		4.2.3	 Somatostatin Receptors: Signal Transduction
	4.3	 An Overview of?Atomic/Nuclear De-excitation: Internal Conversion and?Auger Electrons
	4.4	 The In-111 Decay Pathway
	4.5	 A Brief Reminder of?Indium Chemistry
	4.6	 The Preparation of?[111In-DTPA0-D-Phe1]-Octreotide
		4.6.1	 The Kit Components
		4.6.2	 Synthesis of [DTPA0-D-Phe1]- Octreotide
		4.6.3	 Labeling of?[DTPA0-D-Phe1]-Octreotide with?111In3+
		4.6.4	 Determination of?the?[111In-DTPA0-D-Phe1]-Octreotide Labeling Yield [72]
			4.6.4.1	 Required Materials
			4.6.4.2	 Preparation of?the?Sep-Pak? Cartridge
			4.6.4.3	 Sample Analysis
			4.6.4.4	 Assay
			4.6.4.5	 Calculations
		4.6.5	 Precautions
			4.6.5.1	 General
		4.6.6	 Adverse Reactions
		4.6.7	 Dosage and?Administration
	4.7	 Clinical Pharmacology of?[111In-DTPA0-D-Phe1]-Octreotide
		4.7.1	 Pharmacokinetics
		4.7.2	 Metabolism
		4.7.3	 Pharmacodynamics
	4.8	 Concluding Remarks
	References
5: Regulations and?Requirements of?Scientific Centers Performing Radiopeptide Therapies
	5.1	 Introduction
		5.1.1	 Multidisciplinary Approach
		5.1.2	 Radiopeptide Infusion Team
	5.2	 Legal Regulations of?Scientific Centers Performing Radiopeptide Therapies
		5.2.1	 Licensing
		5.2.2	 Appropriate Facilities and?Equipment
	5.3	 Quality Control and?Documentation of?Radionuclides Applied
		5.3.1	 Introduction
		5.3.2	 Documentation
			5.3.2.1	 Radionuclide Activity
			5.3.2.2	 Radiochemical Purity
			5.3.2.3	 Disposal of?Radioactive Waste
	5.4	 Release of?the?Patient
		5.4.1	 Radiation Safety Issues, General Principles
		5.4.2	 Discharge Limits (ICRP Recommendations)
			5.4.2.1	 Guidance Based on?Retained Activity
			5.4.2.2	 Specific Instructions at Releasing the?Radioactive Patient
	Appendix
	References
6: Intravenous Radiopeptide Infusions with?High Activity of?111In-Octreotide
	6.1	 Introduction
		6.1.1	 Patients
		6.1.2	 Preliminary Results
		6.1.3	 Equipment and?Procedure
		6.1.4	 Intravenous Infusion
		6.1.5	 Blood Sampling
	6.2	 111In-Octreotide Treatment Results
		6.2.1	 Liver Metastatic Load
		6.2.2	 Follow-Up
	6.3	 Discussion
	6.4	 Conclusion
	References
7: Intra-arterial Radiopeptide Infusions?with High Activity of?111In-Octreotide: From??Aretaieion Protocol? to?the?Temporal Intra-arterial Port Installation
	7.1	 Introduction
	7.2	 The Therapeutic Approach of?NENs
		7.2.1	 NETs? Treatment Background
		7.2.2	 NETs and?Curative Surgery (In This Volume, Chaps. 18 and?19)
		7.2.3	 NETs and?Minimally Invasive Modalities
		7.2.4	 NETs and?Systemic Standard Treatment [32?35]
		7.2.5	 NETs and?the?Intra-arterial Peptide Receptor Radionuclide Therapy (PRRT) Concept; A?Brief Introduction
	7.3	 Patients and?Methods
		7.3.1	 Follow-Up and?In?Vivo Measurements
			7.3.1.1	 Posttreatment and?Follow-Up Studies
	7.4	 111In-Octreotide Treatment Evaluation
	7.5	 Discussion
		7.5.1	 The ?Gnosti-Thera? Principle [?Gnosti-Thera? vs. ?Thera-Nostics?]
		7.5.2	 The Intra-arterial Infusion Concept
		7.5.3	 Co-infusion of?DTPA During Peptide Receptor Radionuclide Therapy with?111In-Octreotide Reduces the?Ionic Indium Contaminants
	7.6	 Conclusion
	References
8: Radiopeptide Infusions of?Hepatic Metastases After Temporal Implementation of?an? Intra-arterial Port System
	8.1	 Introduction
	8.2	 Installation of?the?Drum-Port System
		8.2.1	 Technical Details
		8.2.2	 Advantages of?the?Port System After the?Implemented Catheterization of?the?Hepatic Artery
	8.3	 Material and?Methods
		8.3.1	 Selection of?Patients
		8.3.2	 Methodology
		8.3.3	 Evaluation/Dosage Protocol
		8.3.4	 Results
	8.4	 The Personalized Treatment Concept in?the?Peptide Receptor Radionuclide Therapeutic Schemes
	8.5	 Therapeutic Evaluation/Discussion
	8.6	 Conclusion
	References
9: Non-invasive Radiological Modalities for?the?Evaluation of?Neuroendocrine Liver Tumors
	9.1	 Introduction
	9.2	 The Radiological Evaluation of?Patients with?Hepatic Tumors of?Neuroendocrine Character
		9.2.1	 Computed Tomography
		9.2.2	 Magnetic Resonance Imaging
		9.2.3	 Ultrasound
			9.2.3.1	 Enhancement Results of?111In-Octreotide Therapy After Sonoporation
		9.2.4	 Angiography
	9.3	 Summary and?Conclusion
	9.4	 Perspectives
	References
10: Angiographic Anatomy on?the?Course of?Liver Intra-arterial Infusion
	10.1	 Introduction
	10.2	 Liver Arterial Anatomy
		10.2.1	 Classical Description and?Anatomical Variations
		10.2.2	 Terminology
		10.2.3	 Michels? Classification of?Anatomical Variants
		10.2.4	 Other Anatomical Variants
	10.3	 Extrahepatic Vessels Originating from?the?Hepatic Vasculature
		10.3.1	 Vessels Originating from?the?Common- (CHA) and?Proper Hepatic Artery (PHA)
			10.3.1.1	 Gastro-Duodenal Artery (GDA) and?Pancreato-Duodenal Arcade (PDA)
			10.3.1.2	 Peribiliary Plexus Arteries (PPA)
		10.3.2	 Vessels Originating from?the?LHA
			10.3.2.1	 Right Gastric Artery (RGA)
			10.3.2.2	 Falciform Artery (FA)
			10.3.2.3	 Accessory Left Gastric Artery (aLGA)
			10.3.2.4	 Accessory Left Phrenic Artery (aLPA)
		10.3.3	 Vessels Originating from?the?Right Hepatic Artery (RHA)
			10.3.3.1	 Cystic Artery (CA)
	10.4	 Hepatic Vessels Originating from?the?Extrahepatic Vasculature
	References
11: Intra-arterial Radiopeptide Infusions: Identifying Anatomic Variants
	11.1	 Normal, Variant, and?Parasitized Extrahepatic Arterial Supply to?the?Liver
	11.2	 Extrahepatic Arterial Anatomy: Identification and?Treatment
	11.3	 Conclusion
	References
12: Dosimetry and?Dose Calculation: Its Necessity in?Radiopeptide Therapy
	12.1	 Introduction
	12.2	 Liver Tolerance to?Ionizing Radiation
		12.2.1	 Neuroendocrine Tumor Imaging
		12.2.2	 Hepatic Cancer, ?Aretaieion? Protocol
	12.3	 Peptide Receptor Radionuclide Therapy (PRRT)
		12.3.1	 Radionuclide Selection
	12.4	 Indium-111 as?a?Therapeutic Isotope
		12.4.1	 Indium-111 Properties
		12.4.2	 Production of?Carrier-Free [111In] In+
		12.4.3	 111In-DTPA-Phe-Octreotide
	12.5	 Internal Dosimetry
		12.5.1	 The Basics of?Internal Dosimetry
		12.5.2	 Method 1: The?MIRD Formalism and?S Values
			12.5.2.1	 The Cumulated Activity and?Effective Half Time te
			12.5.2.2	 The Residence Time ?
		12.5.3	 Method 2: Dose Voxel Kernel Dosimetry
			12.5.3.1	 Dose Point Kernels
			12.5.3.2	 The Voxel S Value Approach
		12.5.4	 Method 3: Monte Carlo
		12.5.5	 Strengths and?Limitations of?the?Dosimetry Methods
		12.5.6	 Problems and?Uncertainties
		12.5.7	 Internal Dosimetry in?Clinical Practice
			12.5.7.1	 Dosimetry on?an?Organ Level
				Planar Scintigraphy: Conjugate View Method
			12.5.7.2	 Red Marrow Dosimetry
	12.6	 Indium Dose Calculations
		12.6.1	 Treatment Protocol
			12.6.1.1	 Protocol Development
			12.6.1.2	 Gamma Camera Setup
				Phantom Preparation
				Determination of?Effective Attenuation Coefficient ?
				System Calibration Factor K
	12.7	 Clinical Results from?Patient Dosimetry
		12.7.1	 i.a and?i.v. Administration
		12.7.2	 Image Acquisition
		12.7.3	 Blood and?Urine Measurements
		12.7.4	 Absorbed Dose Determination
			12.7.4.1	 Example of?Dose Calculations
			12.7.4.2	 Tumor Regression
			12.7.4.3	 Biochemical Response
			12.7.4.4	 Retreatment
	12.8	 Conclusion
	Appendix
	References
13: Evaluation and?Assessment of?the?Radio-Peptide Treatment Efficacy
	13.1	 Introduction/Historical Corner
	13.2	 Response Assessment
		13.2.1	 WHO Criteria
		13.2.2	 RECIST Criteria
		13.2.3	 MD Anderson Cancer Center Criteria for?Bone Metastases
		13.2.4	 Choi Criteria for?Gastrointestinal Stromal Tumors (GISTs)
		13.2.5	 MacDonald and?RANO Criteria for?High-Grade Gliomas
		13.2.6	 Response Assessment Criteria for?Hepatocellular Carcinoma (HCC): EASL, mRECIST, and?RECICL
		13.2.7	 PET Response Criteria in?Solid Tumors (PERCIST)
		13.2.8	 The European Organization for?Research and?Treatment of?Cancer (EORTC) Criteria in?Solid Tumors
		13.2.9	 The Immune-Related Response Criteria (irRC) [9]
	13.3	 The Southwest Oncology Group (SWOG) Criteria
	References
14: 111In-Octreotide Infusions for?the?Treatment of?Bronchopulmonary Neuroendocrine Neoplasms
	14.1	 Introduction
	14.2	 111In-Octreotide Treatment Results
	14.3	 Discussion
	14.4	 Conclusion
	References
15: 111In-Octreotide Infusions for?the?Treatment of?Colorectal Carcinoma
	15.1	 Introduction
	15.2	 111In-Octreotide Treatment Results
	15.3	 Discussion
	15.4	 Conclusion
	References
16: 111In-Octreotide Infusions for?the?Treatment of?Paraganglioma
	16.1	 Introduction
		16.1.1	 Parasympathetic (Head and?Neck) Paragangliomas
		16.1.2	 Sympathetic Paragangliomas
		16.1.3	 Treatment Stratification
	16.2	 111In-Octreotide Treatment Results
	16.3	 Discussion
	16.4	 Conclusion
	References
17: Intra-arterial 111In-Octreotide Infusions for?the?Treatment of?Meningioma
	17.1	 Introduction
	17.2	 111In-Octreotide Treatment Results
	17.3	 Discussion
	17.4	 Conclusions
	References
18: Liver Surgery in?Neuroendocrine Tumors
	18.1	 Introduction
	18.2	 Neuroendocrine Liver Metastases and?Surgical Intervention
	18.3	 Exeresis of?Liver Neuroendocrine Metastases as?a?Curative Approach
		18.3.1	 Ergography on?Curative Liver Excision of?Neuroendocrine Liver Metastases
	18.4	 Resectability of?Neuroendocrine Liver Metastases
	18.5	 Width of?Resection Margins in?Neuroendocrine Liver Metastases
	18.6	 Hepatic Lymphadenectomy in?Neuroendocrine Liver Metastases
	18.7	 Role of?Prophylactic Cholecystectomy
	18.8	 Palliative Liver Resection for?NET Liver Metastases
		18.8.1	 Results of?Palliative Liver Resection for?NET Liver Metastases
	18.9	 Liver Transplantation for?Neuroendocrine Liver Metastases (NELM)
	18.10	 Surgery and?Combined Therapies
	18.11	 Perioperative Care and?Speculations
	18.12	 Conclusion
	References
19: Cytoreductive Surgery in?Peritoneal Neuroendocrine Neoplasm Metastases: The?Adjuvant Endoperitoneal PRRT with?111In-Octreotide Perspective
	19.1	 Introduction
	19.2	 Metastatic NENs
	19.3	 Peritoneal Carcinomatosis (PC) Due?to?NENs
	19.4	 Molecular Mechanism of?Peritoneal Metastases
	19.5	 Distribution of?Peritoneal Metastases Due?to?NENs
	19.6	 Diagnostic Procedures for?Peritoneal Carcinomatosis Due?to?NENs
	19.7	 Classification of?Peritoneal Metastases from?NENs
	19.8	 Management of?Peritoneal Metastases Due?to?NENs
	19.9	 Surgery/Surgery Combined Treatments
		19.9.1	 Surgery for?Peritoneal Dissemination
		19.9.2	 Cytoreductive Surgery
		19.9.3	 Cytoreduction vs Debulking
		19.9.4	 Cytoreduction Combined with?Intraperitoneal Chemotherapy or Peptide Receptor Radionuclide Therapy
		19.9.5	 Application of?This Combined Treatment in?Peritoneal Metastases Due?to?NENs
	19.10	 Conclusions and?Perspectives
	References
20: Yttrium-90 SIRT in?NET
	20.1	 Introduction
	20.2	 Patient Selection
		20.2.1	 Indication
		20.2.2	 Work-Up
		20.2.3	 Pre-treatment Angiography and?Imaging
	20.3	 Treatment
		20.3.1	 Dose Calculation
		20.3.2	 Treatment Angiography
		20.3.3	 Posttreatment Imaging
	20.4	 Efficacy and?Safety
		20.4.1	 Clinical Outcome
		20.4.2	 Future Perspectives
	References
21: Holmium-166 Radioembolization in?NET Patients
	21.1	 Introduction
	21.2	 Clinical Workflow
		21.2.1	 Pre-treatment Evaluation/Planning
		21.2.2	 Treatment and?Follow-Up
	21.3	 Radiation Safety
	21.4	 Imaging
	21.5	 166Ho Radioembolization for?Neuroendocrine Tumors
		21.5.1	 Clinical Case
	21.6	 Future Perspectives
	References
22: Complications and?Side Effects on?the?Course of?Liver Radio-Infusions with?111In-Octreotide
	22.1	 Introduction
	22.2	 Side Effects
		22.2.1	 Acute Side Effects
			22.2.1.1	 Carcinoid Crisis
		22.2.2	 Chronic Side Effects
			22.2.2.1	 Renal Toxicity
			22.2.2.2	 Bone Marrow Toxicity
			22.2.2.3	 Endocrine Organs
	22.3	 Radiobiological Properties
	References
23: Progression-Free Survival and?Response Rate in?Neuroendocrine Liver-Metastasized Patients, Treated with?111In-Octreotide
	23.1	 Introduction
	23.2	 Response Rate and?Progression-Free Survival
		23.2.1	 Response Rate
		23.2.2	 Progression-Free Survival (PFS) and?Overall Survival?(OS)
	23.3	 Conclusions
	References
24: Therapy Response vs. Variability of?Tumor Size, Absorbed Dose, and?Ki-67 Index After 111In-Octreotide Intra-arterial Infusions
	24.1	 Introduction
	24.2	 Tumor Size, Absorbed Dose, and?Ki-67 Index
		24.2.1	 Tumor Size
		24.2.2	 Absorbed Dose
		24.2.3	 Ki-67 Proliferation Index
	References