Patient and tumor characteristics in ten studies on radiofrequency ablation for breast cancer
Globally, breast cancer is the most common type of cancer among women, which comprises 23% of all female cancers that are newly diagnosed in more than 1.1 million women each year. Over 411 000 deaths result from breast cancer annually; this accounts for over 1.6% of female deaths from all causes. Hyperthermia also called thermal therapy or thermotherapy is a type of cancer treatment in which body tissue is exposed to high temperatures. Research has shown that high temperatures can damage and kill cancer cells, usually with minimal injury to normal tissues. Otherwise, ablation or high temperature hyperthermia is defined as the direct application of chemical or thermal therapies to a tumor to achieve eradication or substantial tumor destruction. Many ablation modalities have been used, including cryoablation, ethanol ablation, laser ablation, and radiofrequency ablation. The most recent development has been the use of microwave ablation in tumors. Furthermore, The use of breast cancer mammography screening has allowed detecting a greater number of small carcinomas and this has facilitated treatment by minimally invasive techniques. Currently, physicians test minimally invasive ablation techniques to determine if they will be acceptable substitutes for surgical removal of primary breast tumors. Therefore, numerical electromagnetic and thermal simulations are used to optimize the antenna design and predict heating patterns. A review of different hyperthermia ablative therapies, for breast cancer treatment is summarized in this work. Otherwise, advanced computer modeling in high hyperthermia treatment and experimental model validation will be referred to in this chapter.
1.1. Tumor ablation
Tumor ablation is defined as the direct application of chemical or thermal therapies to a tumor to achieve eradication or substantial tumor destruction. The aim of tumor ablation is to destroy an entire tumor by using heat to kill the malignant cells in a minimally invasive fashion together with a sufficient margin of healthy tissue, to prevent local recurrence. Many ablation modalities have been used, including cryoablation, ethanol ablation, laser ablation, and radiofrequency ablation (RFA). The most recent development has been the use of microwave ablation (MWA) in tumors .
Nevertheless the local application of heat to treat patients with malignant tumors is not a novel concept. The Edwin Smith papyrus describes the topical application of hot oil or heated metallic implements that were used approximately 5000 years ago to treat patients with tumors . The use of an electrical current to produce thermal tissue necrosis in patients with breast carcinoma also is not new: Metallic or clay-insulated electrodes were inserted into locally advanced breast tumors in the late 19th century to shrink the tumor and reduce pain and bleeding .
1.2. Principles of tissue damage
1.2.1. Radiofrequency ablation
This therapy works by converting radiofrequency waves into heat through ionic vibration. Alternating current passing from an electrode into the surrounding tissue causes ions to vibrate in an attempt to follow the change in the direction of the rapidly alternating current. It is the ionic friction that generates the heat within the tissue and not the electrode itself. The higher the current, the more vigorous the motion of the ions and the higher the temperature reached over a certain time, eventually leading to coagulation necrosis and cell death. The ability to efficiently and predictably create an ablation is based on the energy balance between the heat conduction of localized radiofrequency energy and the heat convection from the circulation of blood, lymph, or extra and intracellular fluid . The amount of radiofrequency produced heat is directly related to the current density dropping precipitously away from the electrodes, thus resulting in lower periphery temperatures. It can be approximated that the heat generated in a region at distance d from the electrode drops as 1/d4. The goal of radiofrequency ablation is to achieve local temperatures that are lethal to the targeted tissue. Generally, thermal damage to cells begins at 42°C; and once above 60°C, intracellular proteins are denatured, the lipid bilayer melts, and irreversible cell death occurs .
1.2.2. Microwave ablation
Water molecules are polar, that is, the electric charges on the molecules are asymmetric. The alignment and the charges on the atoms are such that the hydrogen side of the molecule has a positive charge, and the oxygen side has a negative charge. When an oscillating electric charge from radiation interacts with a water molecule, it causes the molecule to flip. Microwave radiation is specially tuned to the natural frequency of water molecules to maximize this interaction. Temperature is a measure of how fast molecules move in a substance, and the vigorous movement of water molecules raises the temperature of water. Therefore, electromagnetic microwaves heat matter by agitating water molecules in the surrounding tissue, producing friction and heat, thus inducing cellular death via coagulation necrosis .
1.3. Ablative devices
1.3.1. Radiofrequency ablation
The different manufacturers employed various strategies to obtain larger ablation zones ; there are currently three different manufacturers that offer commercial radiofrequency tumor ablation devices in the USA (Boston Scientific, Rita Medical and Valleylab) and an additional one in Europe (Celon). Two manufacturers (Boston Scientific and Rita Medical) employ multitined electrodes, to increase electrode surface area and volume of tissue heating. For multitined electrodes typically an incremental deployment of the tines in stages is used, with ablation at each deployment stage for a certain amount of time or until the target temperature is achieved to ensure complete ablation of the target volume. Two manufacturers use internal electrode cooling via circulation of water or saline to increase ablation zone size (Valleylab and Celon). By cooling the electrode, the tissue surrounding the electrode is also cooled. The location of maximum temperature is ‘pushed’ further into the tissue, resulting in a larger ablation zone size. A similar effect is obtained by infusing saline into the tissue via ports in the electrode this method is used by the Starburst Xli™ electrode .
1.3.2. Microwave ablation
A variety of probes have been proposed for use in MWA, with the majority being based on a coaxial structure due to the deep-seated location of many tumors and the angular symmetry of the tumor. Initial antennas based upon a coaxial waveguide structure include designs, such as the monopole, dipole and slot antennas, often encased in a polytetrafluoroethylene (PTFE) catheter to minimize adhesion of the probe to desiccated ablated tissue. A number of challenges, characteristics and trade-offs have been identified in the design of MWA probes. Challenges include the reduction of backward heating, minimization of probe diameter and impedance matching of the antenna to the surrounding tissue. Trade-offs in design involve probe diameter versus maximum application of power and ablation power versus ablation time. Early coaxial antennas developed for MWA yielded ablation zones resembling a ‘tear drop’, as opposed to the desired spherical shape . More recent MWA probes were designed to minimize probe size, maximize ablation zone size, minimize detrimental heating of the feedline and yield more spherical lesions, by minimizing impedance mismatch [10-12].
2. Clinical applications
2.1. Radiofrequency ablation
The first RFA clinical report was published in 1999, Jeffrey
Currently Takayuki 
|Authors||Patients||Age range||Tumor Size (cm)|
|Medina||25||42-89||0.9 - 3.8|
|Jeffrey||15-g multineedle LeVeen||RF-2000 Radio Therapeutics|
|Izzo||15-g multineedle LeVeen||RF-2000 Radio Therapeutics|
|Burak||2 cm array probe|
|Hayashi||15-g, 7 cm array|
|Fornage||7-array / 15-g, 9 cm array Starburst RITA||RITA-500 / RITA-1500|
|Marcy||1.5 mm · 1.1 mm non-isolated tip Elektrotom||Elektrotom 104HF|
|Susini||18-G Cool tip RF Radionics||Not mentioned|
|Oura||3 cm Cool-tip uninsulated Valleylab||Not mentioned|
|Medina||17-g Elektrotom 106, Germany||Monopolar 200 W|
|Takayuki||17-g Valleylab RF Ablation System with Cool-tip||Monopolar 200 W|
|Jeffrey||480-kHz||Impedance||46.8 - 70.0||Ultrasound|
|Burak||460 kHz||Impedance||Not mentioned||Ultrasound|
|Fornage||461 KHz||NO||90 and 95||Ultrasound & Doppler|
|Marcy||500 kHz||NO||Not mentioned||Ultrasound|
|Oura||Not mentioned||Impedance||"/> 60||Ultrasound|
|Medina||500 KHz||NO||70 - 80||Ultrasound|
|Takayuki||500 KHz||Impedance||Not mentioned||Ultrasound|
2.2. Microwave ablation
Three studies on microwave ablation have been published [23-25]. A pilot safety (phase I) study included ten patients with core needle biopsy-proven invasive breast carcinoma (T1–T3 tumors) . Of the eight patients who responded, 82–97% tumor cell kill was found, confirmed by M30 immunohistochemistry. Image guidance was performed using US. Five to 27 days after treatment patients underwent mastectomy. The same group also published another article in which 21 patients with T1–T2 invasive breast carcinoma underwent microwave ablation . In 68% of the patients, histologic evidence of tumor necrosis was present. Finally, this group published a dose-escalation study .
Twenty-five patients with core needle biopsy-proven invasive breast carcinoma (T1–T2 tumors) were included. US provided image guidance; there was no correlation between clinical/ultrasonographic size changes and pathologic tumor response. In 68% of the cases there was evidence of pathologic response using H&E staining. In two cases complete ablation was reached; these patients received the highest temperature dose. Complications mentioned were mild pain during treatment, skin burn, and short-lived erythema of the skin.
In RFA several different devices from different manufacturers were used in different ways for varying periods of time and varied protocols, so not surprisingly, they reported quite heterogeneous results. Nevertheless successful cases for different protocols were obtained for smaller tumors with a low failures and complication rate. In addition the clinical MWA is limited to external techniques and currently the greatest amount of interstitial research was conducted in the liver tissue. The generation of an appropriately sized ablation zone, long treatment times, insufficient interoperative imaging modalities and performance in the vicinity of vascular structures are limitations of current devices. An ideal ablative technology would ensure complete destruction of all malignant cells with no significant side effects or complications.
3. Advanced computer modeling in breast cancer hyperthermia treatment
In this section, we present a computer modeling for microwave high hyperthermia in breast cancer treatment. Computational electromagnetic (CEM) or electromagnetic modeling employs numerical methods to describe propagation of electromagnetic waves. It typically involves the formulation of discrete solutions using computationally efficient approximations to Maxwell's equations. There are three techniques of CEM: the finite-difference time-domain (FDTD), the method of moments (MOM), and the finite element method (FEM), which has been extensively used in simulations of cardiac and hepatic radiofrequency (RF) ablation . A FEM model was used in this work because it can provide users with quick, accurate solutions to multiple systems of differential equations and therefore, they are well suited to solve heat transfer problems like ablation . Numerous MWA antenna designs speciﬁcally targeted for MWA cardiac and hepatic applications have been reported [20-24], but they have not been used to treat breast cancer. These designs have been focused largely on thin, coaxial-based interstitial antennas , which are minimally invasive and capable of delivering a large amount of electromagnetic power. These antennas can usually be classified as one of three types (dipole, slot, or monopole) based on their physical features and radiation properties . On the other hand, several researchers are investigating non-invasive microwave hyperthermia for treatment of breast cancer .
The frequency-dependent reflection coefficient can be expressed logarithmically as:
where, Pin is the input power and Pr indicates the reflected power (W). SAR represents the amount of time average power deposited per unit mass of tissue (W/kg) at any position. It can be expressed mathematically as:
where, σ is tissue conductivity (S/m), ρ is tissue density (kg/m3) and E is the electric field . The SAR takes a value proportional to the square of the electric field generated around the antenna and is equivalent to the heating source created by the electric field in the tissue. The SAR pattern of an antenna causes the tissue temperature to rise, but does not determine the final tissue temperature distribution directly. The tissue temperature increment results from both power and time. MW heating thermal effects can be roughly described by Pennes’ Bioheat equation :
where k is the tissue thermal conductivity (W/m°K), ρb is the blood density (Kg/m3), Cb is the blood specific heat (J/Kg°K), ωb is the blood perfusion rate (1/s). Tb is the temperature of the blood and T is the final temperature. Qmet is the heat source from metabolism and Qext an external heat source. The major physical phenomena considered in the equation are microwave heating and tissue heat conduction. The temperature of the blood is approximated as the core temperature of the body. Moreover, in ex vivo samples, ωb and Qmet can be neglected since no perfusion or metabolism exists. The external heat source is equal to the resistive heat generated by the electromagnetic field.
3.2. Material properties
The computer antenna model used in this work is based on a 50Ω UT-085 semirigid coaxial cable. The entire outer conductor is copper, in which a small ring slot of width is cut close to the short-circuited distal tip of the antenna to allow electromagnetic wave propagation into the tissue. The inner conductor is made from silver-plated copper wire (SPCW) and the coaxial dielectric is a low-loss polytetraﬂuoroethylene (PTFE). The length of the antenna also affects the power reﬂection and shape of the SAR pattern. Furthermore, the antenna is encased in a PTFE catheter to prevent adhesion of the antenna to desiccated ablated tissue. Dimensions and thermal properties of the materials and breast tissue, which were taken from the literature , are listed in Table 5 and 6.
|Center conductor diameter||0.51 mm|
|Dielectric diameter||1.68 mm|
|Outer conductor diameter||2.20 mm|
|Diameter of catheter||2.58 mm|
|Electrical Conductivity of breast||0.137 S/m|
|Thermal conductivity of breast||0.42 W/m K|
|Specific heat of blood||3639 J/Kg/k|
|Blood perfusion rate||0.0036 s-1|
|Electrical conductivity of tumor||3 S/m|
|Thermal conductivity of tumor||0.5 W/m K|
|Inner dielectric oft he coaxial cable||2.03|
Figure 1 shows the axial schematics of each section of the antenna and the interior diameters.
A finite element method computer models were developed using COMSOL Multiphysics 4.0 commercial software. One of the models assumed that the coaxial slot antenna was immersed only in homogeneous breast tissue; the other model assumed that the antenna was immersed only in breast cancer. The coaxial slot antenna exhibits rotational symmetry around the longitudinal axis; therefore axisymmetric models, which minimized the computation time, were used. The inner and outer conductors of the antenna were modeled using perfect electric conductor boundary conditions and boundaries along the z axis were set with axial symmetry.
All boundaries of conductors were set to perfect electric conductor (PEC). Boundaries along the
Figure 3 shows the temperature distribution in normal adipose-dominated tissue . The reflection coefficient calculated for the frequency at 2.45 GHz was -2.82 dB, the maximum temperature was 116.03 ºC, and the ablation zone radius was 53 mm. The isotherm was considered at 60 ºC because ablation is produced above this temperature . Figure 4 shows the temperature distribution in breast cancer tissue. The reflection coefficient calculated for the frequency at 2.45 GHz was -6.38 dB, the maximum temperature was 125.96 ºC, and the ablation zone radius was 92 mm.
In RFA for high temperature hyperthermia therapy in breast cancer several devices from different manufacturers were used in diverse ways for varying periods of time and assorted protocols, therefore exist heterogeneous results. Nevertheless successful cases for were obtained for smaller tumors with a low failures and complication rate. On the other hand the effect of MWA on malignant and normal adipose-dominated tissues of the breast was simulated using an axisymmetric electromagnetic model. This model can analyze the heating patterns using the bioheat equation. The results from computer modeling demonstrated that, effectively, the difference in dielectrical properties and thermal parameters between the malign and normal adipose-dominated tissue could cause the preferential heating on tumor during MWA. Even though electromagnetic high temperature hyperthermia requires further research, it is a promising minimally invasive modality for the local treatment of breast cancer.
The project described was supported by Instituto de Ciencia y Tecnología del Distrito Federal. Project Name: “Desarrollo de un sistema automatizado de determinación volumétrica por imágenes ultrasónicas para cuantificar el efecto de la energía térmica aplicada en la ablación del cáncer. Number: PICCO10-78. Agreement: ICYTDF; 340/2010.