Hyperthermia and Thermal Ablation for Cancer Treatment PDF

Hyperthermia and Thermal Ablation for Cancer Treatment BME 229 Fall 2024 1  Hyperthermia Hyperthermia: A type of treatment in which tissue temperature is raised to damage and kill cancer cells or to make cancer cells more sensitive to other...

Hyperthermia and Thermal Ablation for Cancer Treatment BME 229 Fall 2024 1  Hyperthermia Hyperthermia: A type of treatment in which tissue temperature is raised to damage and kill cancer cells or to make cancer cells more sensitive to other treatment modalities, such as radiotherapy or chemotherapy. Historically, heat has been one of the most prominent medical therapies for almost any disease including cancer. Hippocrates, the Greek physician who is considered as “Father of Medicine (470-377 BC) stated: “Those who cannot be cured by medicine can be cured by surgery. Those who cannot be cured by surgery can be cured by fire [heat]. Those who cannot be cured by fire, they are indeed incurable!” 3  Methods of Local Tissue Heating Main clinical methods of local tissue heating: Shortwave diathermy Using high-frequency (20-30 MHz) AC current to heat up tissue (Ohmic tissue heating). Radiofrequency (RF) capacitive heating Capacitive application of RF (1-10 MHz) electric energy (Ohmic tissue heating). Microwaves Electromagnetic (EM) waves that causes dipole rotation in water molecules leading to its heating up (~75% of our body consists of water). Ultrasound High frequency (>20 kHz) sound (mechanical) waves that heat up tissue through its absorption mechanism. Laser Tissue heating through applying intense, narrow beam of light (laser beam). Etc. 4  Hyperthermia Two main types of hyperthermia: Conventional Mild temperature rise (< 50°C) during long exposure times (from a few minutes to a few hours) Thermal ablation High temperature rise (> 50°C) during short times (less than a few minutes) An example: High intensity focused ultrasound (HIFU) Temperature > 65°C, Exposure time of few seconds. 5  Cellular Response to Heat Mammalian cells are very sensitive to heat. Heat kills cells in a predictable and repeatable way. Most of studies of the effect of heat on cells have been carried out using controlled water-bath heating systems. Cell survival curves are different for temperatures below and above 43°C. For T > 43°C the curves are similar to those obtained with ionizing radiation. For T < 43°C the curves are complicated. 6  Surviving Fraction Calculation In Vitro cell culture is an established method for various studies in medicine and biology including radiobiology and hypethermia. Study of in vitro survival curves are fundamental in understanding of much of radiobiology. Number of Colonies Counted in the Active Sample Surviving Fraction = Number of Cells Seeded in the Active Sample  ( PE /100) Where PE is the Plating Efficiency defined as: Number of Colonies Counted in the Control Sample PE = 100 Number of Cells Seeded in the Control Sample NOTE: There are usually two samples used in the study Control (sham) sample Active sample (exposed to heat or radiation) 7 Surviving Fraction Example 8  Cellular Response to Heat For T > 43°C the curves are similar to those obtained for ionizing radiation where dose is replaced by exposure time. 9  43°C A Break Point Temperature for Mammalian Cells Different cells have very different sensitivities to heat Based on extensive cell survival studies 43°C is the temperature break point where most mammalian cells cytotoxicity and thermotolerance to heat dramatically change Below 43°C, cell thermotolerance can be developed gradually during the heating Above the 43°C break point, the heating time required to produce a given level of cell killing is halved for every 1°C temperature rise Below the 43°C break point, the heating time must be reduced by a factor of 4 to 6 for each 1°C temperature rise to produce a given level of cell killing These suggest that mechanisms of cell killing below and above the 43°C break point are significantly different! 12  Mechanisms of Cell Killing by Heat Heat-induced mechanisms of cell killing are completely different from ionizing radiations Primary cytotoxic heat targets in cells are proteins (specially the nuclear proteins) Heat causes protein denaturizing Possible protein targets: Structural chromosomal proteins, nuclear matrix and cytoskeleton repair enzymes, membrane protein components, etc. Different protein targets are involved in heat cytotoxicity above and below the temperature break point (43°C) 13  Heat Sensitivity and Cell Age The cell surviving fraction function for heat complements that for ionizing radiation. The phase of the cell cycle that is most resistant to ionizing radiation, i.e. late S, is most sensitive to heat! This suggests that combined radiotherapy and hyperthermia improves the cancer cell killing efficiency (synergistic effect). 14  Effects of pH and Nutrients on Sensitivity to Heat Based on cell survival studies: 1. Cells in an acid (low pH) environment appear to be more sensitive to killing by heat 2. Cells deficient in nutrients are more heat sensitive 3. Hypoxic cells are slightly more sensitive to heat (or at least have the same sensitivity as oxic cells) Cancer cells in tumors are normally in low pH environment, hypoxic, and are deficient in nutrients. All above means that cancer cells are more sensitive to heat than normal cells. Heat could be a very effective modality for cancer treatment. One major challenge in heat therapy is to find a way to effectively and uniformly distribute controlled heat inside body at the tumor location. 15  Thermotolerance Thermotolerance: The development of a transient and nonhereditary resistance to subsequent heating by an initial heat treatment. Systematic reduction in the slope of the cell survival curves for subsequent heat treatments It causes problem in fractionated hyperthermia treatments In contrast to radiotherapy, hyperthermia treatments are usually performed in one or maximum two sessions! 16 Thermotolerance and Fractionated Treatment 17  Heat Shock Proteins If cells are exposed to heat, proteins of a specific molecular weight (mass) (mainly 70 or 90 kDa) are produced. These are called Heat Shock Proteins. Heat shock protein (HSP) concentration is proportional to the degree of the cell’s thermotolerance. HSPs expression appears to be a particular cellular response to external stress. The stress could vary in nature: thermal, mechanical, or chemical (but not ionizing radiation). HSPs are identified and measured by gel electrophoresis, a technique that separates and identifies molecules based on their molecular weights. Da (Dalton) = Unit of molecular mass, very nearly equal to the mass of a hydrogen atom. It is also called Unified Atomic Mass Unit (u). 18  Heat and Tumor Vasculature Blood flow tends to act as a heat sink by carrying the heat away! Tumors in general have less organized and less efficient vasculature than most normal tissues. Heat (T > 42.5°C) appears to damage fragile vasculature of tumors more than vasculatures of normal tissues. Vessel After heating, blood flow goes down in Vessel Dilation tumors but increases in normal tissues. Damage This may result in an enhanced temperature differential between tumors and normal tissues in hyperthermia treatments (tumors get hotter than surrounding normal tissues)! 20 Heat and Tumor Vasculature Vasodilation 21 Mild Hyperthermia and Tumor Oxygenation Typical hyperthermia (T > 42.5°C) usually leads to tumor vasculature damage and therefore reduced oxygenation! But mild hyperthermia (41°C < T < 42°C) has shown to increase tumor oxygenation! Mild hyperthermia can therefore be used as an adjuvant treatment to improve the radiotherapy efficacy through increasing tumor oxygenation. 22  Thermal Dose A challenging problem in hyperthermia is to achieve uniform heat distribution in the tumor. This is mainly due to: 1. Tissue inhomogeneity that leads to non-uniform heat deposition using conventional hyperthermia methods 2. Tumor blood perfusion It has been demonstrated (both in vitro and in vivo) that hyperthermia cytotoxicity is dependent on both temperature and time The concept of thermal dose was therefore defined based on some time- integrated temperature function From experimental (empirical) results: 1. Above the transition temperature of 43°C, a 1°C rise of temperature requires reduction of exposure time by a factor of 2 to get the same rate of cell killing 2. Below 43°C, a 1°C rise of temperature requires reduction of exposure time by a factor of 4 to 6 to get the same rate of cell killing 23  Thermal Dose The concept of thermal dose was first developed by Sapareto and Dewey (1984) in the field of hyperthermia tf tf TD =  R 43−T ( t ) dt   R 43−T ( t ) t ti ti Where T(t) is the time-varying temperature in units of °C, and R = 0.5 for T  43C , and R = 0.25 for T  43C. The thermal dose definition models the cumulative effect of temperature over time. TD is expressed in minutes at 43°C 24  Thermal Dose The threshold of thermal dose that indicates an irreversible thermal damage depends on the type of tissue. For soft tissues, there are two widely-accepted experimentally verified thresholds of thermal dose to create an irreversible thermal lesion in soft tissue (coagulative necrosis lesion): TD  120 minutes at 43 °C TD  240 minutes at 43 °C For more sensitive tissues (such as nerves) the TD threshold would be lower, e.g. 60 minutes at 43 °C. 25  Thermal Dose Calculation - Example Example: Calculate the TD for the following 10-minute hyperthermia exposure. Does this exposure lead to irreversible tissue coagulation necrosis? T (°C) 49 42 37 t (min.) 0 6 10 Exposure starts Exposure ends 26 T (°C) Example Solution 49 tf  43−T ( t ) 42 TD = R dt 37 ti t (min.) R = 0.5 for T  43C 0 6 10 Exposure ends R = 0.25 for T  43C Exposure starts 27 Tissue Temperature Variation in Hyperthermia T (°C) 37 Energy ON Energy OFF t (min.) 29  Temperature Estimation Bio-Heat Transfer Equation (BHTE) A mathematical model to describe heat transport and temperature rise in perfused biological media such as tissue with blood perfusion. Where: T is the tissue temperature in C, Tb is the blood temperature in C,  is the tissue mass density in kg/m3, C is the tissue specific heat capacity in J/(kg.C), K is the tissue thermal conductivity in W/(m.C), Wb is the blood perfusion rate in kg/(m3.s), Cb is the blood specific heat capacity in J/(kg.C), 2 is the spatial Laplacian operator, and Q is the heat production rate per unit volume in W/m3. 30  Heat Production Rate (Q) in Ultrasound Hyperthermia 2 P Q  2 I I = 0 2  c0 Where: Q is the heat production rate per unit volume [W/m3] α is the ultrasound absorption coefficient [Np/m] I is the time-average ultrasound intensity [W/m2] P0 is the ultrasound pressure amplitude [Pa]  is the medium (tissue) mass density [kg/m3] c0 is the speed of ultrasound in the medium [m/s] 31  Interaction Between Heat and Radiation The interaction between heat and ionizing radiation is synergistic, i.e. the cytotoxicity achieved by combining two modalities (applying together) is greater than additive effects obtained by applying each modality alone after each other. Hyperthermia has little effect on the amount of radiation-induced DNA damage in terms of single- or double-strand breaks. Synergistic mechanisms between heat and radiation are due to the following complementary cytotoxic effects of the two modalities on cells: 1. The phase of the cell cycle with high radioresistivity (late S phase) shows low thermoresistivity. 2. Low levels of nutrients and oxygen and low pH levels in cancer cells lead to an increased thermosensitivity versus a decreased radiosensitivity. 3. Heat could inhibit repair of radiation-induced DNA damage which lead to an increase in the radiation treatment efficiency. 33  Thermal Enhancement Ratio (TER) The extent of the interaction of heat and radiation is expressed in terms of the Thermal Enhancement Ratio (TER). TER is defined as the ratio of doses of radiation to produce a given level of biological damage (e.g. cell killing) without and with the application of heat. TER depends on type of cells, type of radiation, and degree of heating. For typical X-ray radiation and temperature rises up to 43°C, values of TER could vary from 1.5 to 5 for most mammalian cells. 34 Heat and Chemotherapy Hyperthermia increases the cell-killing potential of some (but not all) chemotherapeutic agents. A few example are: Cisplatin, Bleomycin, and Doxorubicin. 35 Thermal Ablation of Tumors using Ultrasound High Intensity Focused Ultrasound (HIFU) 36 Ultrasound – An Interdisciplinary Topic Industrial Biomedical Applications Ultrasound Applications Physics + Electrical Eng. + Mechanical Eng. + Chemical and Materials Eng. NDT/NDE + Computer Eng. + Diagnosis Etc. Therapy  Ultrasound is a Wave Phenomenon What is a Wave? A wave is a disturbance or fluctuation which travels through a medium. Wave transfers energy but not matter!  Ultrasound Ultrasound is a sound energy with frequencies above human hearing threshold f0 > 20,000 Hz In Nature Dolphin Echolocation Bat Echolocation  Physics of Ultrasound Mechanical wave propagation Diffraction Absorption and attenuation Scattering Reflection and refraction Nonlinearity Wave3000® CyberLogic Inc., New York, NY Etc. Complete analysis of ultrasound wave generation and propagation in biological tissues is quite complicated!  Diagnostic Ultrasound: Pulse-Echo Imaging Fetus - 2D Image Fetus - 3D Image  Diagnostic Ultrasound: Pulse-Echo Imaging Doppler (video) 4D Imaging Non-ionizing, Inexpensive, Real-time, Portable  Ultrasound Imaging Medium Frequency High Frequency 3 - 15 MHz 20 - 100 MHz Mobile phone-based Very High Frequency (up to 2 GHz)  Therapeutic Ultrasound (1) High-power Therapeutic Ultrasound Ultrasound Hyperthermia (tissue heating for cancer cell killing and tissue/joints healing) HIFU (High Intensity Focused Ultrasound – thermal coagulation of soft tissue) Histotripsy (mechanical destruction of soft tissue using mechanical stress and cavitation) Lithotripsy (disintegration of kidney and gall bladder stones using shock waves and cavitation) (2) Low-power Therapeutic Ultrasound Sonoporation (changing permeability of cell membrane). It is used for targeted drug and gene delivery (transfecting drug molecules and therapeutic genes into cells) Sonophoresis (changing permeability of skin) Bone Healing (bone fracture healing) Wound Healing Etc. Range of Parameters Thermal Effects Mechanical Effects  Image-guided HIFU Surgery Applications in Oncology Prostate Cancer Treatment Applications in Cosmetic Surgery Wrinkle Removal and Eyebrow Lift  HIFU – A Non-Invasive Surgery Modality HIFU = High Intensity Focused Ultrasound HIFU = Bursts of focused ultrasound energy ~3 orders of magnitude more intense than diagnostic ultrasound used as a noninvasive surgery modality.  HIFU – A Non-Invasive Surgery Modality Very Well-delineated Thermal Lesions No Damage to Intervening Tissue Rapid Temperature Rise Blood Perfusion Independent Non-invasive Bloodless Surgery Thermal Lesion Induced by Heat Conduction Target Organ Focal Zone A HIFU lesion in pig’s liver HIFU Transducer HIFU Intensity Temperature Thermal Dose  HIFU – Main Features Highly Intensive: Ifocal ~ 500 – 10,000 W/cm2 Highly Focused: F-number ~ 0.7 - 2 Frequency: ~ 0.5 - 15 MHz Exposure On/Off Time: From a few ms to a few s Temperature Rise at the Focus: > 20 oC/s Focus Size: ~ 0.1-2 mm × 1-20 mm  Mechanisms of Action with Tissue Direct Mechanisms: (1) Thermal Coagulation Necrosis Conversion of mechanical energy to heat via tissue absorption (2) Non-thermal Mechanical Stress Cavitation and/or Vapor Bubbles Radiation Pressure Acoustic Streaming Indirect Mechanisms in Oncology (under investigation): Enhancing host antitumor immunity through expression of the tumor cells antigens (immunotherapy)  Image-guided HIFU Surgery Target applications: oncology, cosmetic surgery, neurosurgery, pain management, etc. Sonatherm® 600 Misonix Inc., Farmingdale, NY Sonablate® 500 Xthetix® Focus Surgery Inc., Indianapolis, IN Guided Therapy Systems LLC, Mesa, AZ Image-guided HIFU Surgery Design and Development of a Medical Device (Product Development Cycle) Requires specialties across the board Interdisciplinary Requirements R&D Clinical/Regulatory (Business, Clinical, (Design, Prototype, (FDA, CSA, CE, etc.) Technical) Test, Validate) Production Marketing (Project Management, and Sales ISO, GMP, etc.) After-sale Services A Novel Technique to Treat Prostate Cancer BME EE/CE ME/IE Prostate cancer and BPH therapies Prostate cancer has the highest cancer incidence in men and is the second leading cause of male cancer deaths Non-invasive transrectal approach CE, CSA, and JIST approved FDA approval in 2015 More than 200,000 patients have been treated to date worldwide Sonablate® 500 MD Focus Surgery Inc., Indianapolis, IN www.focus-surgery.com  HIFU Prostate Cancer Treatment Transrectal Image-guided HIFU Treatment of Prostate Video Image-guided HIFU in Cosmetic Surgery HIFU in Cosmetic Surgery and Dermatology Physician-based OTC Applications Applications Xthetix Guided Therapy Systems LLC, Mesa, AZ HIFU in Cosmetic Surgery and Dermatology The SMAS (Superficial Muscular Aponeurotic System) is a layer of tissue within the skin and subcutaneous tissue. It is one of the most important support structures for the face. The manipulation of this anatomic structure changes the appearance of the face. HIFU in Cosmetic Surgery and Dermatology Deep Probe Superficial Probe 5 mm Lesion 1 Lesion 2 z 1.2 mm z Controlled micro-lesions (injuries) in the skin Mechanisms of Action Cause collagen contraction and initiate wound healing response Induce collagen remodeling and new collagen synthesis over time  The UltraSite GT™ System – Extracorporeal Approach Ulthera Inc., Mesa, AZ Guided Therapy Systems LLC, Mesa, AZ The UltraSite GT™ System – Extracorporeal Approach Transducer Imaging / Therapy Disposables Disposable Tip Console  Regions of Facial Treatment Eyebrow lift Periorbital wrinkle reduction Smooth nasolabial fold Tighten/firm lax skin Copyright © Guided Therapy Systems LLC, Mesa, AZ  Clinical Advantages Full face treatment < 30 minutes No anesthetic required No skin cooling required No patient down time Low energy required (0.4 - 2.0 J) Safe and Effective Modality Example – Forehead Treatment Results - Eyebrow Lift in 90 Days Results - Eyebrow Lift in 90 Days Results - Forehead Wrinkles D0_Pre Results - Forehead Wrinkles D90  HIFU in Cosmetic Surgery – Conclusions Full-faced HIFU treatment Safety of the methodology has been established (no scare, no pigmentation, tolerable pain, etc.) Efficacy of the methodology has been established (for eyebrow lift) FDA clearance obtained in 2009