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Journal of Thermal Biology 58 (2016) 80–90

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Journal of Thermal Biology
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Thermal analysis of induced damage to the healthy cell during RFA of
breast tumor
Sundeep Singh a, Arka Bhowmik b, Ramjee Repaka a,n
Department of Mechanical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
Mechanical and Aerospace Engineering Dept., University of California, 420 Westwood Plaza, Engineering IV, Los Angeles, CA 90095, USA

art ic l e i nf o a b s t r a c t

Article history: Effective pre-clinical computational modeling strategies have been demonstrated in this article to enable
Received 27 July 2015 risk free clinical application of radiofrequency ablation (RFA) of breast tumor. The present study
Received in revised form (a) determines various optimal regulating parameters required for RFA of tumor and (b) introduces an
6 January 2016
essential clinical monitoring scheme to minimize the extent of damage to the healthy cell during RFA of
Accepted 7 April 2016
tumor. The therapeutic capabilities offered by RFA of breast tumor, viz., the rise in local temperature and
Available online 20 April 2016
induced thermal damage have been predicted by integrating the bioheat transfer model, the electric field
Keywords: distribution model and the thermal damage model. The mathematical model has been validated with the
Pre-clinical modeling experimental results available in the literature. The results revealed that, the effective damage of tumor
Radiofrequency ablation
volume sparing healthy tissue essentially depends on the voltage, the exposure time, the local heat
Breast cancer
distribution, the tumor stage and the electrode geometric configuration. It has been confirmed that, the
Finite element analysis
Bioheat equation assessment of damage front can accurately determine the extent of damage as compared to the thermal
front. The study further evaluates the damaged healthy and tumor volumes due to RFA of different stages
of breast cancer. The assessment of cell survival and damage fractions discloses the propensity of re-
appearance/healing of tumor cells after treatment.
& 2016 Elsevier Ltd. All rights reserved.

1. Introduction Liu, 2004) for irreversible cellular damage. Out of all these treat-
ment modalities, RFA has received much attention as a minimally
Breast cancer is one of the common types of cancer found invasive strategy for the treatment of unresectable primary he-
among the female all over the world (DeSantis et al., 2011). At patic tumors (Tungjitkusolmun et al., 2002), and promising results
present, commonly used breast cancer treatment techniques are have also been obtained in treating tumors in lung, bone, brain,
surgery, chemotherapy, radiation therapy, hormonal therapy, tar- kidney, prostate gland, pancreas, breast, coronary vascular dis-
geted cancer therapy, etc. The surgical procedures are complex, eases (Mirza et al., 2001; Fornage et al., 2004; Morady et al., 1993),
time consuming and relatively expensive with poor cosmetic re- etc.
sults, while radiation therapy and chemotherapy lead to major Breast is an ideal case for RF application because of its super-
health related side effects. Thus, in recent times new treatment ficial location on the thorax and the absence of intervening organs.
modalities have been developed by scientists which are relatively First clinical application of RFA for the treatment of human breast
fast, having less health related side effects and comparatively in- cancer was performed by Jeffrey et al., (1999), on 5 women (aged
expensive with better cosmesis. The newly developed techniques 38–66 years) with locally advanced (stage III) invasive breast
are either based on rising the temperature, viz., laser (Megan et al., cancer (tumor size 4–7 cm). The study reported zero complications
2008; Bhowmik et al., 2015a), focused ultrasound (Bhowmik et al., with success in 4 out of 5 patients. Subsequently, few more studies
2015a), radiofrequency (Haemmerich et al., 2003; Ng and Jamil, explored the feasibility of RFA for the treatment of breast cancer
2014; Jamil and Ng, 2015), microwave (Wu et al., 2015) and such as Fornage et al., (2004), Burak et al., (2003), and Hayashi
magnetic field (Jordan et al., 2001) assisted thermal ablation et al., (2003). Especially, the application of RF technique in patients
methods, or lowering the temperature, i.e., cryotherapy (Deng and with early/small breast carcinoma seems to be an appealing
treatment method with improved cosmesis, and hence a compe-
titive method compared to other conventional and new treatment
Correspondence to: Department of Mechanical Engineering, Indian Institute of
Technology Ropar, Nangal Road, Rupnagar-140001, Punjab, India.
methods (Grotenhuis et al., 2013). Thus, the present study is fo-
Tel.: þ 91 1881 242159; fax: þ91 1881 223395. cused on the application of RF technique for the thermal ablation
E-mail address: (R. Repaka). of small/early and localized breast cancers.
0306-4565/& 2016 Elsevier Ltd. All rights reserved.
S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90 81

Nomenclature ωb blood perfusion (m3 s  1 m  3 tissue)
Ω thermal damage parameter
A frequency factor (s  1) τ necrosis time (s)
c specific heat (J kg  1 K  1)
C concentration of damaged/undamaged cell Subscripts
d diameter of electrode and trocar (mm)
D diameter of tumor (mm/cm) a arterial blood
E electric field (V m  1) b blood
Ea activation energy (J mol  1) c core
f radiofrequency (Hz) D damaged
h depth (mm/cm) e electrode tip
J current density (A m  2) f final value
k thermal conductivity (W m  1 K  1) s tissue/trocar base surface
Q ‴m metabolic heat generation (W m  3) t tissue
Q ‴ext external power source (W m  3) tb trocar base
R universal gas constant (¼ 8.314 J mol  1 K  1) tt trocar tip
t time (s) UD undamaged
T temperature 0 initial value
V electric potential (V)/volume (mm3)
x, y, z position/coordinates Abbreviations

Greek symbols AJCCS America joint committee of cancer staging
PBE Pennes bioheat equation
α thermal diffusivity RFA radiofrequency ablation
ρ density (kg m  3)
s electrical conductivity (S m  1)

In an RF technique an electrode is inserted into the tissue by a 2002; Ekstrand et al., 2005; Quaranta et al., 2007). In addition, a
guiding mechanism and separate grounding pads are used on the few studies focused on estimating the optimal input configuration
outer surface of the ablation domain to establish an electric circuit. during RFA, viz., voltage and frequency, and predicted the outcome
Once the electrode tips are accurately placed in the ablation zone of induced damage due to combinations of various (a) thermo-
of the tumor and the circuit is closed, alternating current (in the physical properties of tumor and healthy tissues (Jamil and Ng,
frequency range of 375–500 kHz) is supplied to the electrode. The 2013b) or (b) geometric configurations (Jamil and Ng, 2013c,
established electric fields between the electrode tips and the 2013d). Jamil and Ng (2013b) employed Taguchi design of ex-
grounding pads cause the conduction of current from the elec- periments, involving the Analysis of Variance (ANOVA) on the data
trode tip to the tissue. The oscillating electric and magnetic fields obtained from experiments to quantify the effect of two input
at the frequency of the radio waves cause the ions within the tunable parameters, voltage and frequency and four thermo-phy-
tissue to agitate due to a change in the direction of current. The sical properties, the metabolic heating rate in healthy tissue and
agitation of ions results in the frictional/resistive heating of tissues, tumor, the blood perfusion rate in healthy tissue and tumor. The
since, biological tissues are poor conductors with high impedance study suggested that the voltage and frequency were crucial
value. Due to the large value of tissue impedance, the resistive parameters that had a direct effect on the treatment outcome.
heating is dominant within few millimeters of tissue surrounding Thus, RFA of tissue entails to proper treatment plan, including
the electrode. But, the actual thermal ablation zone within the careful consideration of voltage and frequency. Similarly, Jamil and
tumor is mainly due to thermal conduction of heat to the per- Ng (2013d) also employed ANOVA on experimental data to
ipheral tissue. The rise in local temperature of tumor tissue above quantify the effect of voltage and frequency, along with four
the threshold value for a certain exposure time causes irreversible geometric parameters, viz., tumor size, tumor location, electrode
cellular damage (i.e., damage integral, Ω Z1). In general, the size and relative position of the electrodes with respect to the
coagulation (i.e., the initial phase of damage) begins when the tumor. The study by Jamil and Ng (2013d) revealed that the reli-
temperature of tissue rises to 43–45 °C but, the desired damage able treatment during RFA largely depends on (a) the optimum
(Ω Z1) of the entire ablation zone can be achieved at a higher configuration of input and geometric parameters, and (b) the
temperature, i.e., above 50 °C. The rapid heating or excessive precision with which thermal damage is imparted to the tumor
heating above 100 °C causes boiling, vaporization and carboniza- and migrating cells within the normal tissue. More recently, Ng
tion which reduces the ability of nearby tissue to conduct elec- and Jamil (2014) evaluated the efficacy of RFA due to varying
tricity due to the rise in impedance and limits the thermal diffu- electrical conductivity, thermal conductivity, and blood perfusion
sion process. To avoid high ablation temperature within the tumor, rate corresponding to different types of tissues. The sensitivity of
protocols like increasing the electrode surface area and pulsing the such variation was tested using Taguchi's design of experimental
input power have been found to be efficient. Further, the strategy method. Particularly, for temperature controlled mode the thermal
of permeating saline solution in the ablation zone improves the conductivity had an additive effect on the ablation volume. While,
effective electrical conductivity. At the same time, it increases the the blood perfusion and electrical conductivity had an inverse
probability of irregular necrotic zones. effect on the ablation volume. Overall, the computer simulations
Due to the associated complication during RFA of tumor, many facilitated the researchers to make a predictive assessment of as-
studies in the recent time used computational simulation to pre- sociated queries regarding RFA of tumor based on the hypothesis
dict the outcome of the ablation process (Tungjitkusolmun et al., of unforeseeable events.
82 S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90

In this work, the performance of the single tip electrode for RFA 2. Problem definition and mathematical modeling
of small cancerous tumor within the breast have been predicted,
since earlier in-vivo studies have clarified that RFA fails to ablate 2.1. Problem definition
large tumor volume completely. In spite of the tunable parameters
discussed in the literature survey, the exposure time also needed The problem considers a three dimensional model of breast
(Fig. 1(a)), which has been constructed based on the anatomical
to be optimized to determine the efficacy of thermal damage. The
details (Ng and Sudharsan, 2001) available in the literature. Elec-
same was lacking in earlier investigations. Thus, this study de-
trical, thermal and thermo-physical properties of different mate-
termined the optimal exposure time along with voltage for dif-
rials (Ekstrand et al., 2005; Ng and Sudharsan , 2001; Bhowmik
ferent sizes of tumors during RFA. In addition, the study also
et al., 2014; Bezerra et al., 2013; Jossinet, 1996; Andreuccetti et al.,
showed the possibility of connecting the damage parameter of the
1997; e-funda, 2014; Teflon, 2014) have been depicted in Table 1.
radial tumor-healthy junction with that of the electrode-tip tem-
Electrical properties of tissue presented in Table 1 have been
perature with the intention to quantify the accuracy of damage considered at a radio-frequency of 500 kHz. The dielectric con-
based on the monitoring parameter, e.g., electrode-tip tempera- stant, i.e., εr (relative permittivity) has been neglected, since the
ture. The correlations that link the radial damage front with the dielectric losses caused by rotation of molecules in the electric
electrode-tip temperature is a part of our extended work on the field are negligible for frequency below 1 MHz (Ekstrand et al.,
RFA of breast tumor. The same will be presented in the imminent 2005). The study considered stainless steel properties for trocar
publication. Overall, the objectives of the present study are of electrode as well as connecting shaft (e-funda, 2014), and Teflon
three folds, viz., (a) introducing an effective pre-clinical modeling properties for the insulating material (Teflon, 2014). The three
strategy for the hassle free RFA procedure, (b) defining essential dimensional model for trocar (Ekstrand et al., 2005) with one
regulating parameters for preferential thermal damage of tumor mono-polar electrode has been shown in Fig. 1(b). Since the ab-
volume sparing healthy tissue, and (c) revealing the role of mon- lation regime/size of tumors are small, thus, the study considered
itoring the electrode tip temperature to optimize the extent of a trocar with one mono-polar electrode instead of multi-tined
damage. Due to lack of any experimental data (or rise in tem- electrodes or bipolar electrodes.
perature profile) in the literature for RFA of breast tumor, the study Different sizes of early tumor volume within the breast (Fig. 1
validated the present mathematical model with the results avail- (a)) have been modeled based on the staging guidelines given by
able on RFA of bovine liver tissue (Sethuraman et al., 2014). American Joint Committee for Cancer Staging (AJCCS) (Greene
et al., 2006). Breast cancer is mostly originated at the upper outer


Fig. 1. (a) Breast model with tumor stages and (b) trocar model with mono-polar electrode.
S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90 83

Table 1
Electrical as well as thermal properties of breast tissue, tumor, electrode and trocar insulator and thermo-physical properties of breast tissue and tumor (Ekstrand et al.,
2005; Ng and Sudharsan, 2001; Bhowmik et al., 2014; Bezerra et al., 2013; Jossinet, 1996; Andreuccetti et al., 1997; e-funda, 2014; Teflon, 2014).

Tissue/electrode Electrical properties Thermo-physical properties

Properties s (S m  1) c (J kg  1 K  1) k (W m  1 K  1) ρ (kg m  3) ωb (m3 s  1 m  3) Q ‴m (W m  3)

Breast fata 0.0560b 3000c 0.21d 920c 0.1796  10  3d 400d
Glandular tissuea 0.4274b 3000e 0.48d 1080e 5.3908  10  4gvnd 700d
Musclea 0.4459f 3800g 0.48d 1085g 5.3908  10  4gnd 700d
Tumora 0.4386b 3500d 0.48d 1080e 0.011h 1400h
Electrode (stainless steel) 9.804  105bmi 500i 36.7i 8100i – –
Trocar tip (stainless steel) 9.804  105i 500i 36.7i 8100i – –
Trocar base (Teflon) 1.0  10  16j 1010j 0.23j 2190j – –

Electrical properties of tissue obtained at 500 kHz.
Jossinet (1996).
Ekstrand et al. (2005).
Ng and Sudharshan (2001).
Bezerra et al. (2013).
Andreuccetti et al. (1997).
Bhowmik et al. (2014).
e-funda (2014).
Teflon (2014).

portion of the breast within the glandular tissue (Greene et al., ∂Tt ρ cb ωb ⎡ Q ‴m Q ‴ext
= αt ∇2Tt − b ⎣ Tt − Ta ⎤⎦ + +
2006). Therefore, the present study has modeled different stages ∂t ρt ct ρt ct ρt ct (1)
of breast tumor volume within the upper outer portion of the
breast in the glandular tissue (Fig. 1(a)). The tumor diameter (D) where ρt, ct and αt are the density, the specific heat and the
has been varied within the range given for three stages, viz., T1mic thermal diffusivity of the tissue, respectively, αt is expressed as kt
(D r0.1 cm), T1a (0.1 cm oDr 0.5 cm) and T1b /ρtct,ωb, ρb and cb are the perfusion rate, the density and the
(0.5 cm oDr 1 cm) as suggested by AJCCS (Greene et al., 2006). specific heat of the blood, respectively, Q ‴m is the volumetric heat
According to earlier studies (Ng and Sudharsan, 2001; Vaupel, generation due to metabolism, Q ‴ext is the volumetric heating due
1998), the blood flow in breast tumor has been found to be in the to external power source, Ta is the arterial blood temperature
range of 8–80 ml/100 g per min. Therefore, the study considered (¼37 °C), Tt is the unknown local tissue temperature, t is the time,
the blood perfusion within the tumor to be 60 ml of blood/100 g of subscripts t and b represent tissue and blood, respectively. It is
the tissue per min (Ng and Sudharsan, 2001). In order to obtain worth-noting here that, the Pennes perfusion based model is
the equivalent blood flow/perfusion in the tumor in m3 of blood capable to estimate the temperature distribution accurately in
per m3 of tissue per second, the unit 1 ml of blood/100 g of tissue vascularized tissue with thermally insignificant vessels. However,
per min is converted to 1 m3 of blood/m3 of tissue per second by this model overestimates the local temperature for a relatively
using the density of tumor tissue given in Table 1. Therefore, 60 ml large diameter vessels (Bhowmik et al., 2013). Therefore, the effect
blood/100 g tissue per min will be equivalent to blood perfusion of of vascular flow should not be ignored while estimating the local
0.011 m3 of blood/m3 of tissue per second. The metabolic heat temperature of tumor near large diameter vessels. As discussed
generation per m3 of tumor volume has been assumed twice that earlier, in the present work large diameter vessels have been
of the healthy cell (i.e., glandular tissue). This is mainly due to the considered to be far from the small volume breast tumor. In such a
fact that the considered tumor volume is small in size, i.e., not case, the only interstitial perfusion effect of blood is dominant,
more than 1 cm diameter. Metabolic heat generation of breast which can be accurately modeled using Pennes bioheat model.
tumor size more than 1 cm diameter can be evaluated using the Pennes bioheat model has been used in a wide range of applica-
relation suggested in (Ng and Sudharsan, 2001). The model as- tions to accurately estimate the heat transport phenomenon in
sesses early/small melanoma volume within the breast, and perfused biological tissues and organs, viz., RF hyperthermia
therefore the sink effect due to blood vessels is assumed to be (Tungjitkusolmun et al., 2002; Jamil and Ng, 2015), laser-tissue
negligibly small. Since, early melanoma volumes are nutrient de- ablation (Megan et al., 2008; Paul et al., 2014; Bhowmik et al.,
ficient (Frangioni, 2008) as the supply blood vessels fails to extend 2015a), thermal response due to fat thickening (Bhowmik et al.,
to the tumor from chest wall. However, for relatively larger de- 2015b), whole body thermoregulation under non-anesthetized
velopment stages, the presence of nearby blood vessels causes a condition (Vallez et al., 2016), characterization of tumor (Mitra and
significant reduction in the local temperature and formation of Balaji, 2010; Jamil and Ng, 2013a, 2013b, 2013c, 2013d; Ng and
unwanted hot spots/non-uniformity (Tungjitkusolmun et al., Jamil, 2014; Das and Mishra, 2015), optimization of treatment
2002). The consideration of heterogeneous vascular architecture parameters (Jamil and Ng, 2013b, 2013c, 2013d), etc.
and its effect on tissue temperature distribution during RFA had During RFA, volumetric heating of local tissue is mainly due to
been reported by Tungjitkusolmun et al. (2002); Singh et al. the conduction losses (resistive heating) caused by applied electric
(2015). fields to the resistive material, i.e., tissue. Therefore, the absorbed
power density or the external power source due to resistive
2.2. Mathematical modeling heating can be written as (Ekstrand et al., 2005)

Q ‴ext = J⋅E = σ⋅E2 (2)
The Pennes bioheat equation (PBE) has been considered for
evaluating the change in temperature within the breast during where J is the current density (A m  2), E is the electric field
RFA. The PBE for perfused tissue domain can be written as (Pennes, (V m  1) and s is the electrical conductivity (Sm  1). The current
1998) density (J) and the electric field (E) are the vector quantities.
84 S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90

Further, it has been assumed that the real part admittance (i.e., here that, induced thermal damage is zero for τ r0.
electrical conductivity) is contributing to the resistive heating, The concentration/volume of undamaged (CUD) and damaged
since, the imaginary part has negligible effect. (CD) cells over time can be evaluated from the knowledge of
A quasi-static electrical model has been used to demonstrate thermal damage. The concentration of undamaged cells (CUD) over
the electric field distribution within the tissue due to the applied time can be determined using the relation
voltage, and can be given by Laplace equation as (Ekstrand et al.,
CUD (t )
2005) = exp [−Ω(t )]
C0 (7)
∇⋅(σ ∇V ) = 0 (3)
where CUD (t) is the concentration of remaining undamaged cells
where V is the electric potential (V). The electric field (E) and the over time, C0 is the concentration of undamaged cells before the
current density (J) generated within the tissue can be written as onset of ablation, i.e., τ r 0. All cells within the tissue before the
onset of ablation have been assumed to be undamaged, i.e., 100%
E = − ∇V ; J = σ E (4)
concentration (or C0 ¼1.0). Thus, the concentration of damaged
In the above mentioned equations, the electrical conductivity cells (CD) over time can be easily determined using the relation
(s) has been considered to be independent of temperature, since, CD (t )
peak temperatures of the tissue in the study have been found to be = 1 − exp [−Ω(t )]
C0 (8)
well below the charring temperature ( 100 °C). Since, earlier
study (Chang, 2003) has revealed that, the difference in computed where CD (t) is the concentration of damaged cells over time. From
temperature with and without the temperature dependent elec- Eqs. (8), Ω ¼ 1.0 means  63% of the tissue molecules are damaged,
trical conductivity is approximately 5–8%, below the charring which is assumed to produce desired damage as suggested by
temperature. (Henriques, 1947). The damage integral, Ω¼1.0 or 63% of induced
It is a well-known fact that, the blood perfusion (ωb) within the thermal damage to tissue molecules is sufficient to restrict any
tumor is more than the surrounding healthy tissue and varies with reversible change and to initiate natural death of cells.
size. The increase in blood perfusion within the tumor causes a
greater cooling effect as can be interpreted from Eq. (1). Hence, the 2.3. Boundary and initial conditions
ablation temperature and the time required for ablating tumor is
considerably more compared to the healthy tissues. The threshold The initial voltage of the entire tissue domain before the appli-
temperature at which the onset of cellular damage manifests cation of RF energy has been considered to be zero. The electrical
within the tumor and within the healthy tissue has been con- boundary condition for the outside surface of breast has been set to
sidered to be at 45 °C, but the desired damage (Ω Z1) of the entire be V¼0, since the outside surface is grounded using a grounding
tumor takes place at relatively higher temperature. Further, during pad. An electrical insulation boundary condition (n  j ¼ 0) has been
the ablation blood perfusion changes due to gradual necrosis of set for the portion of insulated trocar base inside and outside the
cells with time and is mainly due to leftover undamaged cells. The tissue domain. The electrode potential Ve and trocar tip potential Vtt
perfusion is assumed to be increasing initially due to vasodilation have been set to the constant source potential V ( = P *Zref ). Here,
of capillaries caused by heating of perfused tissue (Abraham and P refers to the supplied power and Zref is the reference impedance
Sparrow, 2007) and later decreases with time/induced damage profile of RFA device. The effect of external radiation on the current
given as within the electrode is negligible at 500 kHz radio frequency.
⎧ Therefore, it has been assumed that the current within the elec-
ωb,0 for Ω(t ) ≤ 0

⎪ trode is fully balanced (Ekstrand et al., 2005). The outer surface of
ωb (t ) = ⎨ ωb,0 ⎡⎣ 1 + 25Ω (t ) − 260Ω (t )2⎤⎦ for 0 < Ω(t ) ≤ 0.1 breast and trocar base (outside the tissue domain) have been as-

⎩ ωb,0 exp [−Ω (t )] for Ω(t ) > 0.1 sumed to be subjected to natural convection, i.e., qconv
¼hconv(Ts–T1), where hconv and T1 are considered as
where ωb,0 is the constant blood perfusion of tissue (given in Ta- 10 W m  2 K  1 and 22.4 °C, respectively. The initial temperature of
ble 1) and Ω(t) is the induced thermal damage. The first relation in breast tissue has been considered to be same as that of the core
Eq. (5) suggests that, all cells in the tissue are undamaged and body temperature, i.e., Tc (¼37 °C), and the initial temperature of
perfusion remains same. The second relation exhibits a small in- the electrode, trocar tip as well as trocar base has been set to 25 °C.
crease in perfusion during the initial damage due to vasodilation of At present, different modes of controlling unit (source) are used
capillaries caused by heating of perfused tissue. The third relation to control the power delivered to the tissues, such as power-con-
represents ceasing of perfusion within the tissue in an exponential trolled mode, temperature-controlled mode and impedance-con-
manner. It is worth-noting here that, perfusion ceases at a com- trolled mode. The present study modeled the case of manual
paratively large value of Ω, i.e., higher than 1. temperature control mode instead of programmed adjusted tem-
The induced thermal damage field, Ω(t), within the tissue is perature control mode. In the manual control mode, the usual
equivalent to the rate of protein denaturation for a period of ex- practice is to apply a constant voltage in the active electrode/trocar
posed time above the threshold temperature for cellular damage, tip by maintaining the tip sensor temperature below the preset
which can be expressed using first-order Arrhenius rate target temperature (Tungjitkusolmun et al., 2002). In this study,
equation (Henriques, 1947) as the preset target temperature has been set to 70 °C, and the
t manual adjustment of voltage has been achieved by trial-and-er-
Ω (t ) = ∫τ= 0 A exp ⎡⎣ −Ea/RT (τ ) ⎤⎦ dτ for τ ( =t − tT ) > 0
(6) ror method. For numerical simulations, the specific heat and
density of blood have been considered to be 4200 J kg  1 K  1 and
where τ is the necrosis time (i.e., t–tT), tT is the ablation onset/ 1060 kg m  3, respectively.
threshold temperature, A is the frequency factor, Ea is the activa-
tion energy and R is the universal gas constant 2.4. Numerical procedure
(¼ 8.314 J mol  1 K  1). In the present study, A and Ea for the bulk
tissue domain have been considered as 1.8  1051 s  1 and The spatial and temporal temperature distributions during RFA
327,000 J mol  1, respectively (Jia et al., 2007). It should be noted of cancerous breast tumor have been obtained by solving the
S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90 85

coupled electric field distribution equation (Eq. (3)), energy 80
equation for perfused tissue domain (Eq. (1)) and rate equation for Measured (Sethuraman et al., 2014)

Rise in temperature, T ( C)
tissue damage (Eq. (6)) using a commercially available finite ele-

ment software, COMSOL Multiphysics 5.0. The present work used Present FEM model
the version 5.0 of the coupled solver that was developed by
COMSOL AB, Stockholm, Sweden.
The meshing of physical domain has been done using fine tet-
rahedral mesh elements, i.e., 4,31,486 tetrahedral elements. The
maximum element sizes of muscle, gland, fat and the tumor have
been considered to be 0.3 cm, 0.3 cm, 0.3 cm, 0.05 cm, respectively. 40
Similarly, the maximum element sizes of electrode, trocar tip and
trocar base have been considered to be 0.05 cm, 0.055 cm and Electrode Tip location:
0.1 cm, respectively. The above mesh element sizes have been de- 3 cm from top surface of bovine liver
termined after several runs with varying number of mesh elements 20
and identical properties to attain a grid independent solution. The P=6W
relative tolerance for the electric field interface and heat transfer tf = 15 min
interface has been set to 0.0001. The numerical convergence has
been found to be taking place below the pre-specified relative tol- 0
erance of the solvers. A direct linear solver, MUMPS (MUltifrontal 0 250 500 750 1000
Massively Parallel sparse direct Solver) with default preordering Time (s)
algorithm has been used for solving the electric field. Whereas,
Fig. 2. Comparison between the measured electrode tip temperature values (Se-
iterative conjugate gradient method has been used with geometric
thuraman et al., 2014) and predicted temperature values (from the present FEM
multi grid pre-smoothers for solving the temperature field. The model) at the electrode tip location 3 cm from the top surface of bovine liver tissue
Backward Difference Formula (BDF) has been used for time during RFA of bovine liver at 6 W constant power input (P) and exposure time (tf) of
marching, and care has been taken to store the data at each step by 15 min.
assigning strict steps for the solvers. The Newton-Raphson algo-
rithm has been used for iteration in both direct and iterative solvers. Table 2
Electrical and thermal properties of bovine liver tissue and electrode (Haemmerich
et al., 2003; Sethuraman et al., 2014).

3. Results and discussion Tissue/electrode Electrical Thermal properties
3.1. Model validation Properties s (S m  1) c (J kg  1 K  1) k (W m  1 K  1) ρ (kg m  3)

Bovine liver 0.18a 3600b 0.65a 1060b
In order to verify the model fidelity, the elevation of electrode tip
Active probe tip 108 840 18 6450
temperature above the measured temperature at ambient room (Ni–Ti)
condition (¼20 °C) during the ex vivo study of RFA on bovine liver Probe shaft 10  5 1045 0.026 70
tissue (Sethuraman et al., 2014), has been compared with the pre- (Polyurethane)b
dictions made by the present FEM model (considering similar a
Sethuraman et al. (2014).
geometry, electrode configuration and boundary conditions), as can b
Haemmerich et al. (2003).
be seen from Fig. 2. For validation, the electrical and the thermal
properties of bovine liver tissue and electrode have been obtained
from Haemmerich et al. (2003), Sethuraman et al. (2014) (refer heating time, electrode placement within the tumor, etc. Out of all
Table 2). The blood perfusion and the metabolic heat generation these factors, exposure time and applied voltage play a critical
effects have been neglected for ex vivo study (Sethuraman et al., role, which needed to be optimized for different stages of breast
2014). The electrode has been modeled within the liver up to an cancers, in ensuring risk free clinical application of RFA. The
insertion depth of 3 cm from the top surface of liver model. The thermal efficacy of tumor damage has been assessed based on the
bovine liver model has been heated using a constant power P of thermal damage field (Ω Z1.0) and the required exposure time (t)
6 W for 15 min similar to the operational details opted by Se- instead of isothermal field. Since, isothermal fields overestimate
thuraman et al. (2014). Here, the applied constant input electric the amount of tissue injury and produces under heating of tumor
potential V of the electrode was  17.30 V (i. e. , V = P *Zref ) cor- if heating is stopped earlier. To evaluate the optimal voltage and
responding to the reference impedance Zref profile around 50 Ω. desired time for thermal damage (Ω Z1), detail sensitivity study
The prediction of rise in temperature using the present model has been performed by varying the applied voltages for different
(Fig. 2) has been found to be in satisfactory agreement with the tumor diameters, as can be seen from Fig. 3(a) and (b). The study
measured value presented in Sethuraman et al., (2014). Henceforth, considered the manual adjustment of voltages by trial-and-error
the thermal analysis of RFA of breast tumor has been carried out method, and by keeping the tip temperature below the target
using the same model, except few input configurations for tumor temperature (70 °C). The applied voltages and exposure time for
ablation have been modified, since the tissue properties of human various stages of tumor have been found to be different, since the
breast tumor differs from that of the bovine tissue. thermal capacity (ρcV) varies with the tumor volume (V), as can be
seen from Fig. 3(a) and (b). Hence, for a given tumor volume a
3.2. Estimation of optimal regulating parameters for RFA of breast trade-off has been attained between exposure time and voltage. In
tumor this work, the optimal regulating parameters, viz., voltage and
exposure time (Fig. 3(c)) have been determined based on various
It is well-known from the earlier study (Ekstrand et al., 2005) interdependent factors such as (a) maintaining mild temperature
that, the preferential heating of tumor volume depends on mul- range for tumor ablation, (b) maintaining the tip temperature
tiple factors, viz., tissue properties, tumor shape, applied voltage, below the target temperature, and (c) maintaining the exposure
86 S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90


Fig. 3. Variation of (a) time to reach the threshold temperature (t45 °C) and (b) necrosis time (τ) for different tumor diameters (D) with applied voltage (V), and (c) the
temperature front (at T ¼ 45 °C) and thermal damage front (Ω ¼1.0) of different tumor sizes for the associated optimized regulating parameters.

time reasonably longer (preferably in minutes) to attain a better depending on the type of tissue and electrode.
control during the clinical procedure. Fig. 3(a) and (b) illustrate the
variation of time required to reach the threshold temperature 3.3. Assessment of sensitivity of clinically relevant monitoring
(t45 °C) and necrosis time (τ), respectively, with applied voltage for parameter
different stages of breast tumor. The necrosis time (τ
(¼ tf-t45 °C)4 t45 °C). Where, tf is the total time. Fig. 4(a) represents various temperature measurement loca-
The associated threshold temperature front and damage front tions during RFA, viz., electrode tip, P1 and P4 (tumor-gland
due to optimal regulating parameters, viz., voltage and exposure junctions), P2 and P5 (0.5 mm away from the tumor) and P3 and P6
time, for different tumor development stages have been shown in (1.0 mm away from the tumor). For all the tumor diameters, rise in
Fig. 3(c). It is worth-noting from Fig. 3(c) that, the entire tumor temperature above the core body temperature ( ¼37 °C) is max-
reaches the threshold temperature quite earlier (i.e., t450C) than the imum at the tumor-electrode tip junction, as can be seen Fig. 4(b).
necrosis time (τ). Thus, there is a possibility of under heating if the For illustration purpose only two stages, viz., T1a (0.5 cm) and T1b
temperature is monitored during the thermal ablation. In the (1.0 cm) are presented in Fig. 4(b). The electrode tip position P4 has
present analysis, the heating of tumor volume has been dis- been adjusted for different tumor diameters by trial-and-error
continued as soon as the entire tumor volume reaches the desired method to ensure damage front spread beyond P4 is minimum. In
damage value (ΩZ1), i.e. equivalent to the time (tf). case of all tumor sizes (Fig. 4(b)), tumor-gland junctions (P1 and
The safe/required damage, while minimizing excess heating P4) are above the threshold temperature, and are exposed for time
and attaining a good control of RFA in clinical practices, can be (tf) to attain the desired thermal damage (Ω Z1).
achieved by employing mild voltage and by increasing the ex- During clinical RFA procedure (in case of temperature con-
posure time reasonably. The considered optimal exposure time (tf) trolled system), voltage is adjusted either manually or using au-
and voltage (V) for different tumor volumes are less than 10 min tomated program by monitoring the in-vivo electrode tip tem-
(i.e., necrosis time, τ o4 min) and not more than 10 V, respec- perature with a temperature sensor placed at the electrode tip
tively, as can be seen from Fig. 3(c). These values are chosen in casing (Hayashi et al., 2003). It is worth-noting that, RF electrode is
such a manner that, the clinical practitioners have reasonable time not directly heated by the RF current due to the low intrinsic
to damage the tumor, and stop the electric supply. It is worth impedance of material, instead it is heated by the surrounding
noting that, the optimal values of regulating parameters may differ tissue. Thus, the measurable in-vivo electrode tip temperature
S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90 87

Fig. 4. (a) Schematic diagram representing different temperature measurement locations during RFA and (b) variation of rise in temperature profiles above the core
temperature (¼ 37 °C) for two tumor stages at different locations (viz., electrode tip, tumor-glandular junction and healthy glandular tissue) with exposure time (the
optimized regulating parameter are same as in Fig. 3(c)).

could be the useful data to know the rise in peri-electrode tumor time as well as the temperature difference between the electrode
temperature. In view of this, the present work relates the electrode tip and the peripheral tumor-healthy junctions from the pre-
tip temperature with that of the induced damage due to rise in clinical modeling would be resourceful to achieve a better in-vivo
entire tumor temperature (Fig. 4(b)). Further, the present study control of clinical RFA (simply by monitoring the electrode tip
proposes that, the pre-clinical modeling would be useful to temperature). It can be clearly seen from Fig. 4(b) that, the asso-
(a) quantify the accurate tumor damage/exposure time to mini- ciated exposure time (tf) as well as the temperature difference
mize the damage of peripheral healthy tissues and (b) facilitate the between the tip and the peripheral junction of tumor can certainly
estimation of the associated temperature rise of the entire tumor estimate the extent of damage (based on the tip temperature at
based on the tip temperature. The knowledge of ablation/exposure the end of necrosis time, τ). The tip temperature, associated

Voltage = 8 V T (0C) Voltage = 10 V
T (0C) Ω t = 551 s Ω
57.46 t = 385 s 69.69
-5 -4 -3 -2 -1 0 1 2 3 4 5 73.1 -6 -4 -2 0 2 4 6 5684.4
1.0 1.0
56 41.0
T = 45 0 C Ω = 0.7 38.0 0.9 T = 45 0 C Ω = 0.7 0.9
54 65 40.0
37.0 0.8 39.0 0.8
52 36.0 Ω > 1.0 38.0
0.7 60 0.7
50 35.0 37.0
T = 48 0 C 0.6 36.0 0.6
48 34.0 55 T = 50 0 C
Ω > 1.0 35.0
0.5 34.0 0.5
46 33.0
0.4 50 33.0 0.4
44 T = 50 0 C 32.0 32.0
31.0 0.3 31.0 0.3
42 45
30.0 0.2 30.0 0.2
40 T = 55 0 C 29.0
29.0 0.1 T = 60 0 C
38 40 28.0 0.1
0 27.0
37 0
Tumor (D = 0.5 cm Tumor (D = 1 cm
(a) (b)
Fig. 5. Thermal and damage field distributions/maps of two tumor sizes during RFA due to optimal regulating parameters shown in Fig. 3(c); (a) D ¼0.5 cm, and (b)
D ¼1.0 cm.
88 S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90

temperature difference and the exposure time at the end of tumor heat deposited inside the tumor conducts further towards the
necrosis for two different breast cancer stages, viz., T1a (0.5 cm) healthy breast tissues. On the other hand, if the tumor diameter (in
and T1b (1.0 cm) have been shown in Fig. 4(b), which will provide the longitudinal direction) is less than the length of electrode then,
a priori information about the controlling constraints (i.e., the a greater portion of the healthy tissue is exposed to the outer
applied voltage, target electrode tip temperature and the total surface of the electrode. It is evident from Fig. 6(b) that, extent of
exposure time) for clinical application of RFA. damage to the healthy volume during RFA of small/large volume
The variation in thermal and damage field distributions/maps tumor is relatively small in magnitude, i.e., o0.22 cm3, if the
of two different tumor development stages (i.e., T1a and T1b) at electric supply is discontinued after reaching the exposure time.
the end of exposure time have been presented in Fig. 5. It is evi- However, in practice a significant amount of surrounding healthy
dent from Fig. 5 that, the isothermal contours (on the left hand tissue is subjected to post-treatment damage due to thermal dif-
side) overestimate the tumor damage front from that of the actual fusion, and is considered to be desirable in clinical practice to limit
damage front (on the right hand side). Although, the onset of tu- the migrating cancer cells within the healthy tissues.
mor damage starts at 45 °C but the desired damage of the entire Fig. 7 illustrates the cell survival fraction and cell damage
tumor, i.e., Ω Z1, takes place at a relatively higher temperature fraction due to the rise in tissue temperature and induced thermal
(T 445 °C). damage during RFA of breast tumor. In Fig. 7, left and right por-
tions of the electrode tip represent the concentration of cell sur-
3.4. Effect of induced thermal damage on healthy cell volume, tumor vival fraction and cell damage fraction, respectively. It is apparent
cell volume and blood perfusion from Fig. 7 that, the cell damage fraction increases with the ex-
posure time. Whereas, the cell survival fraction decreases with the
The thermal damage of tumor and healthy tissue volumes have increase in exposure time. It can be concluded from the above
been calculated by subtracting (a) the portion of the trocar volume results that, the thermal degradation of cell is a gradual process
from the original volume of tumor before the trocar is inserted, and complete death of cell takes place at a relatively large value of
and (b) the entire portion of trocar volume and tumor volume induced damage. In practice, the desired damage of tumor cells
from the volume of damage front, respectively, as shown in Fig. 6 can be attained at Ω ¼1.0, i.e., the threshold cell damage fraction
(a). Fig. 6(b) depicts the variation of damaged volume for both to be CD/C0 Z63.20% and cell survival fraction to be CUD/C0
healthy and tumor tissues with the increase in tumor diameter for r36.80%. The cell survival fraction greater than the threshold
the chosen optimal regulating parameters (Fig. 3(c)) during RFA of value, and the cell damage fraction less than the threshold value
breast tumor. For relatively smaller tumor diameters (i.e., upto may cause reappearance/possible healing of tumor cells after the
5 mm or so), the damaged volume of healthy tissue is more treatment. It can be further noted that, the tumor cells near the
compared to the tumor tissue. Whereas, opposite trend has been electrode tip suffers maximum damage fraction (i.e., CD/C0 490%)
noticed for the tumor having diameter greater than 7 mm. This and least cell survival fraction (i.e., CUD/C0 o10%).
situation arises because trocar geometry has been kept unchanged
for all tumor diameters, though trocar tip from tumor bottom 3.5. Outline of pre-clinical modeling strategy
surface has been adjusted. If the diameter of electrode is com-
parable with the tumor diameter (in the lateral direction), then the The pre-clinical computational modeling could play a crucial


500 Healthy tissue
Damaged volume (mm )

Tumor tissue




1 mm 3 mm 5 mm 7 mm 10 mm
Tumor diameter, D

Fig. 6. (a) Schematic diagram of damage front (Ω ¼ 1) representing the calculation of damaged tumor and healthy volumes due to RFA, and (b) variation of damaged healthy
and tumor volumes during RFA of different tumor sizes.
S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90 89

Fig. 7. Cell survival fraction (CUD/C0) and cell damage fraction (CD/C0) maps/distributions of two different tumor development stages (D ¼0.5 cm and 1.0 cm) during RFA due
to optimal regulating parameters.

role to understand the complicacies/risks of RFA before its clinical 4. Conclusion
implementation. The gained knowledge could be useful for the
development of strategies or shall provide a route to minimize the The present article demonstrates the role of predictive pre-
complications. The mathematical models may serve as a predictive clinical computational modeling strategies towards an effective
tool and notify the clinical practitioners about the possible out- and risk free thermal ablation of breast tumor using RF technique.
In other words, the article laid down certain clinically relevant
come. Therefore, based on the results discussed in the previous
outlines (a) to minimize the extent of thermal damage to the
sections, the present study outlined a few essential strategies;
healthy volume by optimizing the regulating parameters, (b) to
avoid healing of tumor by ensuring sufficient thermal damage to
(1) Initially, the induced thermal damage to healthy tissue needs
the tumor volume and (c) to enable better control of in-vivo
to be minimized for different development stages of tumor by
thermal damages by monitoring the measurable clinical para-
establishing an optimal input configuration (viz., voltage, ex-
meters. The study adopted systematic modeling steps to predict
posure time, and electrode-tip temperature) of the RFA tech-
the induced damages to the healthy cells during RF ablation of
nique by performing a parametric study.
different development stages of breast tumor. Based on the com-
(2) After establishing the optimal input configuration, the relation
puter simulations, it has been verified that the thermal damage
(i.e., the difference in temperatures at the end of necrosis
field provides a better estimation of tissue-injury compared to the
time) between the essential monitoring parameters (elec-
isothermal field. The optimization of regulating parameters reveals
trode-tip temperature) and tumor-healthy junction needs to
that, the undesirable thermal injury can be minimized by achiev-
be extracted from the numerical results to enable a better in-
ing a good control during clinical RFA by employing mild voltages
vivo control of clinical RFA.
and reasonably longer exposure time. The study further proposes
(3) The electrode position within the tumor for all development
that the measurable quantities, viz., electrode tip temperature and
stages needs to be adjusted and electrode geometry needs to
exposure time shall act as potential monitoring parameters in
be configured reasonably to impose sufficient damage to the
clinical practices. Thus, a priori knowledge of change in tempera-
tumor volume sparing healthy tissue. If the electrode position
ture between the electrode tip and peripheral tumor-healthy
is adjusted, earlier steps {steps (a) and (b)} shall be repeated.
junctions as well as the desired exposure time at the end of tumor
(4) Finally, the possibility of reappearance/healing of damaged
necrosis from computational study shall allow better control of in-
tumor cells and healthy cells after the completion of RFA
vivo damages. It has been evaluated that, the thermal degradation
needs to be confirmed numerically by quantifying the cell
of cell is a gradual process and therefore it is possible that tumor
survival and cell damage fractions.
may heal after the treatment due to insufficient damage of tumor
volume. The insufficient damage of tumor volume has been
All the above mentioned essential strategies have been devel-
quantified based on the cell survival and cell damage fractions.
oped using a viable computational model. The obtained results/
input data after following the essential modeling strategies, if used
to assist clinical application of RFA would lead to maximum da- Acknowledgements
mage to the tumor tissue and minimum damage to the healthy
tissue. Authors would like to acknowledge Science and Engineering
90 S. Singh et al. / Journal of Thermal Biology 58 (2016) 80–90

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