Effect of secondary electron generation on dose enhancement in Lipiodol with and without a flattening filter

Abstract Purpose Lipiodol, which was used in transcatheter arterial chemoembolization before liver stereotactic body radiation therapy (SBRT), remains in SBRT. Previous we reported the dose enhancement in Lipiodol using 10 MV (10×) FFF beam. In this study, we compared the dose enhancement in Lipiodol and evaluated the probability of electron generation (PEG) for the dose enhancement using flattening filter (FF) and flattening filter free (FFF) beams. Methods FF and FFF for 6 MV (6×) and 10× beams were delivered by TrueBeam. The dose enhancement factor (DEF), energy spectrum, and PEG was calculated using Monte Carlo (MC) code BEAMnrc and heavy ion transport code system (PHITS). Results DEFs for FF and FFF 6× beams were 7.0% and 17.0% at the center of Lipiodol (depth, 6.5 cm). DEFs for FF and FFF 10× beams were 8.2% and 10.5% at the center of Lipiodol. Spectral analysis revealed that the FFF beams contained more low‐energy (0–0.3 MeV) electrons than the FF beams, and the FF beams contained more high‐energy (>0.3 MeV) electrons than the FFF beams in Lipiodol. The difference between FFF and FF beam DEFs was larger for 6× than for 10×. This occurred because the 10× beams contained more high‐energy electrons. The PEGs for photoelectric absorption and Compton scattering for the FFF beams were higher than those for the FF beams. The PEG for the photoelectric absorption was higher than that for Compton scattering. Conclusions FFF beam contained more low‐energy photons and it contributed to the dose enhancement. Energy spectra and PEGs are useful for analyzing the mechanisms of dose enhancement.


| INTRODUCTION
In stereotactic body radiation therapy (SBRT) of liver cancer, highdose radiation delivered using hypo-fractionation increases the probability of tumor control and patient survival. 1,2 Accurate daily localization of the treatment target is very important owing to a large irradiation dose delivered in a short period of time. 3,4 In liver SBRT, Lipiodol has been used as an embolic agent and for tumor seeking in transarterial chemoembolization (TACE). Lipiodol is ethiodized oil, is a poppyseed oil used by injection as a radioopaque contrast agent. Several institutions have recently reported promising responses in patients with unrespectable hepatocellular carcinoma treated with TACE followed by radiation therapy. 5,6 Our previous study reported that MC calculation demonstrated a large dose enhancement in the Lipiodol region using a virtual phantom and clinical patient CT. 7 However, we only used 10 MV (109) flattening filter free (FFF) beam and the factor of the dose enhancement was not revealed.
Recently, medical linear accelerators capable of generating flattening filter free (FFF) beams were developed. FFF beam offer increasing the dose delivery efficiency of state of the art radiotherapy techniques such as intensity modulated radiotherapy and SBRT. 8,9 While FFF beams are advantageous for radiation dose delivery, the removal of the flattening filter largely decreases the beam attenuation and increases the photon spectrum. Thus, it also affects the photon energy distribution or the beam quality. 10,11 For a FFF beam, these low-energy photons are part of the beam and contribute to the dose deposition in the photon beam buildup region close to the patient's body surface. Compared with FF beams, FFF beams exhibit less head scatter and leakage; however, measurements and Monte Carlo (MC) simulations suggest that irradiation by FFF beams results in higher surface doses compared with FF beams. 12,13 This suggests that low-energy photons may play an important role in the surface dose enhancement by FFF beams. Therefore, there is a possible that the difference of the energy spectrum such as FF and FFF beams also affect the dose enhancement.
In this study, we compared the dose enhancements in Lipiodol and evaluated the probability of electron generation (PEG) which present the factor of the dose enhancement, for FF and FFF beams.

2.A | MC calculations
A TrueBeam linear accelerator (Varian Medical Systems, Palo Alto, USA) that generated FFF and FF beams with 6 MV (69) and 109 was used in this study. The MC code BEAMnrc was used to model the TrueBeam linear accelerator (linac). [14][15][16][17] The components of the TrueBeam accelerator's head are proprietary and not available to the public for direct simulations; however, Varian provides IAEA-compliant phase-space files, which were simulated using the GEANT4 MC code, located just above the secondary X/Y collimator. The phase space was scored onto the surface of a cylinder located above the secondary collimator. Therefore, the phase-space files below the secondary collimator were modeled using Beamnrc. The phase-space data scored at a source-to-surface distance (SSD) of 70 cm were used as input data for an inhomogeneity virtual phantom. Dose calculation, and photon and electron energy spectra acquisitions were performed using the MC code PHITS. Although BEAMnrc can easily create the linac model, BEAMnrc cannot analyze the energy spectrum in the phantom. PHITS can deal with the transport of nearly all particles, including neutrons, protons, heavy ions, photons, and electrons, over wide energy ranges using several nuclear reaction models and nuclear data libraries. 18 The dose calculation grid size was 2.0 mm. The cutoff energies for photons and electrons were set to 0.01 MeV. The number of photon histories in Beamnrc and PHITS was 2.0 9 10 8 and 2.0 9 10 9 , respectively. In our previous study, the MC calculation accuracy was validated by comparing its results with the percent depth dose (PDD) and off axis ratio measured with water equivalent phantom that contained Lipiodol. 7 It showed that the measured data and the MC results agreed within 3%.

2.B | DEF and the energy spectral variations of photons and electrons for a virtual phantom
The dose enhancement factor (DEF) was defined as a ratio of the average deposited dose to the volume, both with and without the presence of Lipiodol, after the MC simulation. We considered a virtual inhomogeneity phantom, with Lipiodol (3 9 3 9 3 cm 3 ) located at a depth of 5.0 cm in a water-equivalent phantom (20 9 20 9 20 cm 3 ) (Fig. 1). The size of the Lipiodol was determined by the report of John, et al. 19 They measured the size of the liver tumor size and it was approximately 3 cm. A 5 9 5 cm 2 field was used for irradiating at the SSD = 90 cm. The PDD was measured and normalized to the calculated dose at D max . Lipiodol, ethiodized oil injection, is a sterile injectable radio-opaque diagnostic agent. Each milliliter contains 480 mg of Iodine organically combined with ethyl esters of fatty acids of poppyseed oil. The mass density of Lipiodol was set to 1.28 g/cm 3 .
The energy spectral variations of photons and electrons were investigated using the same beam and virtual phantom (this section).
The number of bins in each spectrum was set to 50, with energy F I G . 1. A geometric scheme of Lipiodol was located at depth of 5.0 cm in a water-equivalent phantom (20 9 20 9 20 cm 3 ).
ranging from 0 MeV to 20 MeV. The energy spectrum was analyzed at 6.5 cm depth that was the center of the Lipiodol with and without the Lipiodol and the energy spectrum was normalized at the dose per MU with FF and FFF beams for 69 and 109 (Fig. 2).     Figure 7 shows the total PEG with FF and FFF beams for 69 and 109. Comparing the results for the FF and FFF beams, the total PEG for the FFF beam was larger than that FF beam (<1.5 MeV) for 69, and the total PEG for the FFF beam was larger than that FF beam (<2.5 Mev) for 109 with and without Lipiodol.  Therefore, the PEG owing to the Compton scattering was higher than that owing to the photoelectric effect in the case of water, while the PEG owing to the photoelectric effect was higher than that owing to the Compton scattering in the Lipiodol. From the results in Fig. 7, the total PEG for Lipiodol was higher than that for water. Thus, it is concluded that the PEG owing to the photoelectric effect is a primary determinant of the dose enhancement.

| DISCUSSION
A previous study investigated the surface dose difference across FFF and FF beams. 12 That study reported that FFF beams yield a modestly higher surface dose in the buildup region compared with FF beams for field sizes ≤10 9 10 cm 2 . In addition, FFF beams contained more low-energy photons in the buildup region. In our study, the same trend was observed; the FFF beams contained more low-energy photons (0-0.3 MeV) at a depth of 8.5 cm in water, as shown in Fig. 5. Thus, the PEG owing to the photoelectric effect and Compton scattering was higher at low energies, and it was dominant for the total PEG. Moreover, the DEF deviation with FF and FFF beams for 69 was larger than 109 beams. This also occurred because the 69 beams contained more low-energy photons than the 109 beams, which predominantly determined the total PEG. There the difference of output factor with FF and FFF beams was within 2% and the difference of the total scatter factor with and without MLC was within 1% for small field. 23,24 We revealed the factor of the dose enhancement with the analysis of energy spectrum and PEG with FF and FFF beams for 69 and 109. DEF was larger with FF beam than FFF beam in the Lipiodol.
FFF beam shortened beam delivery time and it contribute to higher dose enhancement. Considering the balance of tumor coverage and skin sparing, there is a possibility that FFF beam would be useful for liver SBRT who Lipiodol was remained in the tumor.

| CONCLUSION
The difference of DEFs with FF and FFF were 10.0% and 2.3% at the center of Lipiodol for 69 and 109, respectively. The photons at