Oncothermia: Principles and Practices (eBook)

Contents 5
Objective of the Book 10
1 Oncology Treatments and Their Limits 13
1.1 Cancer Short History and Efforts to Cure 13
1.1.1 Historical Notes 13
1.1.2 The ''War'' Against Cancer 14
1.2 Paradigm and Challenges of Oncotherapies 19
1.3 Limitations of Oncotherapies The Quest for a Step Forward 20
1.3.1 Medical Challenge of Oncotherapies 22
1.3.2 Ethical Challenge of Oncotherapies 23
1.3.3 The Challenge of Evaluating the Results 23
2 Hyperthermia Results and Challenges 28
2.1 Hyperthermia Approach 28
2.1.1 Definition of Hyperthermia in Oncology 28
2.1.2 Basic Concepts of Oncological Hyperthermia 31
2.1.3 Technical Variations of Hyperthermia in Oncology 34
2.2 Effects of Hyperthermia 46
2.2.1 Higher Baseline Temperature 46
2.2.2 Vascular Changes 47
2.2.3 Cellular Membrane Changes 49
2.2.4 Lactic Acid Formation 50
2.2.5 ATP Depletion 50
2.2.6 Altered DNA Replication 52
2.2.7 Enhanced Immune Reaction 52
2.2.8 Pain Reduction 52
2.2.9 Selective Gain of the Heat Resistance 52
2.3 Clinical Oncological Hyperthermia 55
2.3.1 Local and Whole-Body Heating 56
2.3.2 Hyperthermia as a Complementary Method 59
2.4 Hyperthermia Successes 63
2.4.1 Brain Tumor Treatment by Hyperthermia 64
2.4.2 Pancreas Tumor Treatment by Hyperthermia 68
2.4.3 Lung and Bronchus 69
2.4.4 Hepatocellular Carcinoma and Metastatic Tumors of the Liver 72
2.4.5 Colo-Rectal Tumors 74
2.4.6 Esophagus 75
2.4.7 Head and Neck Localizations 75
2.4.8 Gastric Tumors 76
2.4.9 Breast Tumors 76
2.4.10 Other Localizations Treated by Hyperthermia 78
2.5 Hyperthermia Challenges in Oncology 83
2.5.1 Challenge of Selection and Focus 87
2.5.2 The Challenge of Temperature 88
2.5.3 Medical Challenges of Hyperthermia in Oncology 94
2.5.4 Challenge of Quality Control and Dosimetry of Hyperthermia 95
2.5.5 What We Expect? 97
2.5.6 Possible Solution: Oncothermia 98
3 Thermo-Biophysics 100
3.1 Factors of Physiology Heating 100
3.2 Biothermodynamics 103
3.2.1 Energy, Heat, and Temperature 104
3.2.2 Energy of the Chemical Bonds and Reactions 108
3.2.3 Energy Sources and Driving Forces 129
3.2.4 Energy and Structure 132
3.2.5 Energetics of Malignant Cells 133
3.2.6 -"Non-Thermal-" Effects -- The Thermodynamic Approach 144
3.3 Bioelectrodynamics 147
3.3.1 Basic Interactions 149
3.3.2 The Bioimpedance 150
3.3.3 "Non-Thermal Effects" -- The Electrodynamic Approach 156
3.3.4 "Non-Thermal Effects" -- Approach of Electric Currents 160
3.3.5 Membrane Effects 163
3.3.6 Stochastic Processes 164
3.3.7 Noises and Signals 167
3.3.8 Resonances 173
3.3.9 Modulation--Demodulation 177
3.3.10 Special Field Effects of Biosystems 182
4 Oncothermia - A New Kind of Oncologic Hyperthermia 184
4.1 Oncothermia Characteristics 184
4.1.1 Electrochemotherapy (ECT) 184
4.1.2 Concept of Oncothermia 185
4.1.3 Pennes Equation Revised 192
4.1.4 Thermal Limit Problem 197
4.1.5 Energy Transfer Through the Body Surface 198
4.1.6 Penetration Depth 200
4.1.7 Arrangement of Electrodes 201
4.1.8 Far from Equilibrium 205
4.1.9 Energy Intake and Temperature 208
4.1.10 Macroscopic Focusing on the Tumor 212
4.1.11 Heating the Extra-Cellular Electrolyte 216
4.1.12 Temperature Gradient and Heat Flow on the Membrane 219
4.1.13 Changes of the Membrane Potential 223
4.1.14 Membrane Damage by Constrained Ion Currents 224
4.1.15 Effect on Cell--Cell Connections 226
4.1.16 Oncotherm Comparison 250
4.2 Oncothermia Treatment Guidelines 251
4.2.1 Treatment Planning 254
4.2.2 Treatment Consensus 254
4.3 Complementary Applications 258
4.3.1 Complementary to Radiotherapy 258
4.3.2 Complementary to Chemotherapy 259
4.3.3 Clinical Toxicity, Safety 267
4.4 Oncothermia Case Reports 268
4.4.1 Near-Eye Treatments 268
4.4.2 Brain Cases 270
4.4.3 Gynecology Cases 276
4.4.4 Gastrointestinal Cases 277
4.4.5 Pulmonary Cases 290
4.4.6 Other Cases 297
4.5 Evaluation of Oncothermia Studies 297
4.5.1 Evaluation Conditions 299
4.5.2 Evaluation Methods 303
4.6 General Overview on a Large Patients Pool 306
4.7 Brain Studies 313
4.7.1 Brain Safety Study (Phase I) 313
4.7.2 Brain Efficacy Study (Phase II) 317
4.7.3 Hungarian Brain Glioma Study 326
4.7.4 Small Prospective, Double-Arm Brain Glioma Study 326
4.7.5 Study of Brain Gliomas with Local Clinical Responses 328
4.7.6 Brain Glioma Study with Relapses 328
4.7.7 Bicentral Brain Glioma Study 329
4.7.8 Oncothermia for Heavily Pretreated and Relapsed Brain Gliomas 333
4.7.9 Study of Metastatic Brain Tumors 333
4.7.10 Comparison of Oncothermia Brain Studies 334
4.8 Pancreas Studies 336
4.8.1 Pancreas Efficacy Study I 336
4.8.2 Pancreas Efficacy Study II (HTT) 338
4.8.3 Additional Historical Control to HTT Pancreas Study 343
4.8.4 Comparison of Pancreas Efficacy Studies I and II 344
4.8.5 Pancreas Efficacy Study III 351
4.8.6 Pancreas Efficacy Study IV 353
4.8.7 Other Oncothermia Pancreas Studies and Their Comparison 357
4.9 Lung Studies 358
4.9.1 Oncothermia Lung Study I 358
4.9.2 Oncothermia Lung Study II 362
4.9.3 Meta-Analysis of Oncothermia Lung Studies 365
4.9.4 Comparison to Historical Control 369
4.10 Liver Studies 373
4.10.1 Study of Liver Metastases of Colo-Rectal Origin 373
4.10.2 Study of Advanced Liver Metastases of Colo-Rectal Origin II 374
4.10.3 Comparison Study of Treatment Lines of Colo-Rectal Liver Metastases 375
4.10.4 Study of Platinum Derivatives with Oncothermia for Liver Metastases of Colo-Rectal Origin 378
4.10.5 Study of Liver Metastases of Rectal Origin 378
4.10.6 Study of Liver Metastases of Various Origins 378
4.10.7 Study of Very Advanced Liver Metastases of Various Origins: Comparison of Complementary Therapies 378
4.11 Comparison of Studies of Liver Metastases 381
4.12 Gynecological (Pelvic) Cancer Study 381
4.12.1 Ovary Study 381
4.12.2 Uterine Corpus Cancer 381
4.12.3 Uterine Cervix 384
4.12.4 Comparison of Oncothermia in Pelvic Gynecology 385
4.13 Breast Study 385
4.14 Esophagus Study 388
4.14.1 Esophagus Study I 388
4.14.2 Esophagus Study II 388
4.15 Stomach Study 389
4.16 Colo-Rectal Studies 391
4.16.1 Pre-Operative Oncothermia for Rectum Carcinoma 391
4.16.2 Colo-Rectal Carcinoma Study 392
4.17 Bone Studies 394
4.17.1 Refractory Bone Metastases Complementary to Radiotherapy 394
4.17.2 Monotherapy for Advanced Bone Metastases 395
4.17.3 Osteosarcoma Study 395
4.18 Kidney Study 396
4.19 Head and Neck Study 397
4.20 Urinary Bladder Malignancies 398
4.21 Soft-Tissue Malignancies 399
4.22 Prostate Study 399
4.23 Oncothermia Perspectives 401
Appendixes 404
Appendix 1: Entropy and Temperature 404
Appendix 2: Thermodynamics Onsagers Relation 410
Appendix 3: Self-Similarity and Bioscaling 411
Appendix 4: Energy Supply by Demand 413
Appendix 5: Oncogenic Growth 415
Appendix 6: Basic Bioelectromagnetics 418
Appendix 7: Bioimpedance of Cells and Tissues 420
Appendix 8: Boundary Conditions 429
Appendix 9: Direct Current Applications 433
Appendix 10: Development of Edema 437
Appendix 11: Warburg Impedance 438
Appendix 12: Cell-Membrane Permeability 440
Appendix 13: Stochastic Processes Pink Noise 442
Appendix 14: Autocorrelation 445
Appendix 15: Dissipative Systems 446
Appendix 16: Stochastic Resonance 448
Appendix 17: Resonance of enzymatic reactions 451
Appendix 18: Demodulation by Stochastic Resonance 452
Appendix 19: Non-Linear Effects of Energy Flow 455
Appendix 20: Principle of Minimal Energy-Dispersion 457
Appendix 21: Charge Inhomogeneities 458
Appendix 22: Pennes Equation 459
Appendix 23: Pennes Equation is Revised 460
Appendix 24: Self-Focusing 470
Appendix 25: Dynamism of Temperature on the Membrane 473
Appendix 26: Changes of the Membrane Potential 475
Appendix 27: Membrane Damage by Increasing Pressure 476
Appendix 28: Dynamics of Adherent Bonds 477
Appendix 29: Modulation Effect 479
Appendix 30: Components of Cell Destruction 481
Appendix 31: Experimental Conditions In Vitro 482
Appendix 32: Experimental Conditions In Vivo 484
Appendix 33: Considerations for Experimental Setup In Vivo 487
Appendix 34: Validation of Morphologic Evaluation 489
Appendix 35: Evaluation of Survival Study with Single Arm 491
Acknowledgment 508
References 510
Index 571