Abstract
Background/Aim: This study compared the dose distributions of carbon ion radiotherapy (C-ion RT) and intensity-modulated radiotherapy (IMRT) in patients with locally advanced hepatocellular carcinoma (LAHCC). Patients and Methods: A retrospective analysis was conducted in 10 consecutive patients with LAHCC who had undergone C-ion RT. The dose-volume histogram parameters of clinical plans using C-ion RT at 60 Gy and simulated plans using IMRT at 60 Gy and 50 Gy were compared. We measured the percentage of the normal liver volume that received at least 5 Gy (V5), 10 Gy (V10), 20 Gy (V20), 30 Gy (V30), 40 Gy (V40), and 50 Gy (V50). Results: The V5, V10, V20, and the mean liver dose were significantly lower in patients who received 60 Gy of C-ion RT than in those who received 50 or 60 Gy of IMRT. Conclusion: C-ion RT exhibits a better liver dose distribution than IMRT in patients with LAHCC.
Hepatocellular carcinoma (HCC) involving a major branch of the portal or hepatic vein, including portal vein tumor thrombosis (PVTT) or inferior vena cava tumor thrombosis (IVCTT), are locally advanced-stage tumors that are difficult to treat despite the availability of multidisciplinary therapies. In a randomized controlled trial, Yoon et al. found that the clinical outcomes of patients with locally advanced HCC (LAHCC) who underwent transarterial chemoembolization (TACE) combined with X-ray radiotherapy (RT) were more favorable than those of patients only treated with sorafenib (1), and that TACE combined with X-ray RT improved survival compared to sorafenib alone. Accordingly, TACE combined with X-ray RT could potentially be a standard treatment for patients with LAHCC.
Conventional X-ray RT is of limited use owing to the poor radiation tolerance of the liver; therefore, a curative dose to the tumor is usually not feasible. More recently, stereotactic body RT (SBRT) and intensity-modulated RT (IMRT), which can deliver high radiation doses to the target with much better precision, have become widely used to treat patients with HCC (2-4). Particle therapy has since improved radiation dose distributions further still (5, 6). In particular, carbon ion RT (C-ion RT) has produced favorable clinical outcomes for patients with HCC (7-11), as this modality reduces the dose to the liver while ensuring good target coverage (12, 13) owing to its physical characteristics that include distal tail-off because of a high and narrow Bragg Peak as well as a sharp lateral penumbra (14). Abe et al.'s dosimetric comparison between C-ion RT and SBRT for HCC treatment found that the former has better sparing of the liver (5). However, their study investigated patients with HCC that exhibited no macroscopic vascular invasion; there have been no studies comparing the dose distributions of C-ion RT and IMRT in patients with LAHCC. Nevertheless, it is important to compare the dose distributions of C-ion RT and IMRT for patients with LAHCC (which have large and/or irregular shapes), as the dose to the liver may increase for the patients with LAHCC than the patients with HCC who have no macroscopic vascular invasion. As such, we conducted a simulation analysis to compare the dose distributions of C-ion RT and IMRT in patients with LAHCC.
Patients and Methods
Patients. Data from patients with HCC who had undergone C-ion RT at Gunma University Heavy Ion Medical Center between June 2010 and November 2018 were retrospectively collected. A total of 210 HCC patients received C-ion RT during the study period; 10 patients with LAHCC (i.e., HCC involving a major branch of the portal or hepatic vein, including the PVTT or IVCTT) were investigated. The diagnoses of all patients were confirmed by the presence of typical hallmarks of HCC using four-phase multi-detector-row computed tomography (CT) or dynamic contrast-enhanced magnetic resonance imaging. This study complied with the standards set forth in the Declaration of Helsinki and current ethical guidelines, and was reviewed and approved by our Institutional Review Board (approval number1608).
Target delineation. Treatment-planning CT with respiratory-gated CT, as well as four-dimensional CT images were acquired. Treatment-planning and contrast-enhanced CT images were merged to precisely delineate the gross tumor volume (GTV). The clinical target volume (CTV) was defined as the GTV plus at least a 5 mm margin in all directions to encompass any microscopic disease progression. The internal target volume (ITV) was defined as the sum of CTV from the four-dimensional CT images. The planning target volume (PTV) was defined as the sum of the ITV and an additional margin for patient setup discrepancies (8).
C-ion RT. At our facility, the C-ion RT dose distribution was calculated using the XiO-N, software, which is based on the XiO treatment planning system (Elekta, Stockholm, Sweden) and incorporates an ion beam RT dose engine (K2 dose) developed by the National Institute of Radiological Sciences (15) as well as a source management tool developed by Mitsubishi Electric (Tokyo, Japan). C-ion RT doses were expressed in Gy [relative biological effectiveness (RBE)], which was defined as the physical dose multiplied by the RBE of C-ions (16). The heavy ion accelerator at our facility generated C-ion beams; the passive scattering technique was applied for the treatment of HCC. The beam energy selections were 290 MeV/u, 380 MeV/u, or 400 MeV/u depending on the depth of the tumor. Prescribed doses were 60 Gy (RBE), with the aim of covering the PTV with at least 95% of this dose. C-ion RT plans used two or three coplanar ports to avoid the gastrointestinal (GI) tract. The maximum dose to 1 ml (D1cc) was <40 Gy (RBE) administered to the GI tract (8). Figure 1 shows the typical dose distribution of C-ion RT; all treatment plans were made by medical physicists.
IMRT. IMRT treatment plans were calculated using the X-ray RT treatment-planning system (Eclipse, Varian Medical Systems, Inc., CA, USA). All IMRT treatment plans were simulated using the treatment-planning CT images of patients who received C-ion RT; moreover, all the contours were the same as those used for C-ion RT. The prescribed doses were 60 and 50 Gy; the aim was to cover the PTV with at least 95% of the prescribed dose. IMRT plans used five or six coplanar 6 MV X-rays with gantry angles to avoid the GI tract and spinal cord. The dose constraints were D1cc<40 Gy administered to the GI tract. The weights of each field were also arranged to cover the PTV with at least 95% of the prescribed dose while minimizing the dose to the liver and GI tract. Figure 2 shows the typical IMRT dose distribution in the same patient as that shown in Figure 1; again, all IMRT treatment plans were made by medical physicists.
Dose-volume histogram (DVH) parameters and statistical analyses. We assessed the percentage of the minimum dose that covered 95% of the target volume (D95) based on the DVH for the PTV. To compare normal tissue sparing achieved with C-ion RT versus IMRT, we assessed the mean liver dose (MLD) as well as the percentage of the normal liver volume that received at least 5, 10, 20, 30, 40, and 50 Gy using both C-ion RT (RBE) and IMRT (the V5, V10, V20, V30, V40, and V50, respectively) for the normal liver (i.e., total liver volume minus GTV). Additionally, we defined patients at high risk for developing radiation-induced liver disease (RILD) as those with MLD >23 Gy and V30 values >28% (17).
The DVH parameters when using both modalities were analyzed. Normal distributions were compared using t-tests (the V5, V10, V20, V30, V40, V50, and MLD), and non-normal distributions were compared using Wilcoxon's test (PTV D95), after testing for normality with the Shapiro–Wilk test. Statistical significance was defined as a p-value less than 0.05. All statistical analyses were performed using the SPSS 22.2.0 software (IBM Corp, Armonk, NY, USA).
Results
Patient characteristics. The median tumor size was 53 mm (range=27-119 mm). The median PTV and liver volume were 363.2 cm3 (range=77.1-1331.2 cm3) and 1113.3 cm3 (range=782.6-1854.6 cm3), respectively.
DVH parameters. Table I shows the DVH parameters used in the clinical plans of C-ion RT [60 Gy (RBE)] versus those used in the simulated IMRT using 60 Gy, while Table II shows the same C-ion RT plan compared to the simulated IMRT using 50 Gy.
There was no significant difference in the PTV D95 between 60 Gy (RBE) with C-ion RT and 60 Gy with IMRT (p=0.24). In contrast, the difference in the PTV D95 between 60 Gy (RBE) with C-ion RT and 50 Gy with IMRT was significant (p<0.01).
There were also significant differences in the liver V5, V10, and V20 between the 60 Gy (RBE) C-ion RT plan and each of the 60 Gy and 50 Gy IMRT plans (p<0.05 for both comparisons). In contrast, there were no significant differences in the V30, V40, and V50, values, indicating high-dose areas. Thus, the median MLD was also significantly different between C-ion RT at 60 Gy (RBE) and IMRT at 60 Gy.
The numbers of patients who exceeded an MLD of 23 Gy and V30 of 28% in the C-ion RT 60 Gy (RBE) group were 1 and 4, respectively, those in the IMRT 60 Gy group were 7 and 8, respectively, and those in the IMRT 50 Gy group were 6 and 7, respectively. Therefore, the numbers of patients at high risk of developing RILD in the three groups were 1, 7, and 6, respectively. Scatterplots of the MLD and tumor sizes when comparing these modalities are shown in Figure 3.
Axial computed tomography images of a locally advanced hepatocellular carcinoma. The dose distribution is shown, when treated with 60 Gy [relative biologic effectiveness (RBE)] of carbon-ion radiotherapy. The area within the red outline is the gross target volume. Highlighted are the 95% (red), 90% (yellow), 70% (light green), 50% (green), 30% (light blue), 10% (blue) isodose curves [100% was 60 Gy (RBE)].
Axial computed tomography images of a locally advanced hepatocellular carcinoma. The dose distribution is shown, when treated with 60 Gy with IMRT. The area within the red outline is the gross target volume. Highlighted are the 95% (red), 90% (yellow), 70% (light green), 50% (green), 30% (light blue), 10% (blue) isodose curves (100% was 60 Gy). The tumor is from the same patient as that shown in Figure 1.
Discussion
Our study demonstrated that C-ion RT has a more favorable dose distribution than IMRT when treating LAHCC, and also produces a lower dose to the liver. Additionally, there was a significant difference in PTV dose coverage between C-ion RT at 60 Gy (REB) and IMRT at 50 Gy.
A number of studies have investigated the relationship between liver DVH parameters and RILD given that this organ has poor tolerance for radiation. One such study found that an MLD >23 Gy and V30 >28% were risk factors for RILD (17). In the present study, 70-80% of patients would be difficult to treat with IMRT at 60 Gy owing to the high risk of developing RILD. Moreover, 60-70% of patients risked developing RILD even with IMRT at 50 Gy. Lowering the prescribed dose would decrease the target D95, which would likely worsen the local control rate. In contrast, when administering 60 Gy (RBE) of C-ion RT, 10% of patients exceeded an MLD of 23 Gy and 40% exceeded a V30 of 28%; the D95 of the dose coverage to the PTV using this method was significantly better than that when using 50 Gy of IMRT. These data indicate that C-ion RT ought to be preferable to IMRT in terms of delivering a sufficient radiation dose to the LAHCC, while simultaneously avoiding the risk of RILD. Additionally, adopting C-ion RT created the possibility of treating patients with LAHCC who were ineligible for IMRT, thereby expanding the treatment indication for LAHCC.
DVH parameters of C-ion RT [60 Gy (RBE)] and simulated IMRT (60 Gy).
DVH parameters of C-ion RT [60 Gy (RBE)] and simulated IMRT (50 Gy).
There was no significant difference in the PTV D95 between the C-ion RT at 60 Gy (RBE) and IMRT at 60 Gy groups. However, the lowest PTV D95 among the patients who received C-ion RT was 49.1 Gy (RBE), which was below the lowest PTV D95 observed in the simulated IMRT at 60 Gy. This may be because C-ion RT plans used fewer ports than did IMRT plans. In the present study, C-ion RT treatment plans made by a maximum of three ports to avoid the GI tract maintain the planned constraints while irradiating the PTV to the greatest extent possible, especially when the PTV is surrounded by the GI tract. As such, the dose distribution with C-ion RT could be further improved with the use of additional ports (as is done with IMRT).
Liver functional status is a critical prognostic factor (18, 19). A higher radiation dose-concentration directed at the tumor might maintain liver function status and consequently survival. Yoon et al. reported that TACE combined with X-ray RT resulted in improved overall and progression-free survival than did sorafenib treatment in patients with LAHCC. Hence, TACE combined with C-ion RT might further improve survival over TACE combined with X-ray RT, particularly as C-ion RT can help maintain liver function.
Scatter plots of the mean liver dose (MLD) and tumor size. (A) Comparing 60 Gy [relative biological effectiveness (RBE)] of carbon-ion radiotherapy (C-ion RT) and 60 Gy of intensity-modulated radiotherapy (IMRT). (B) Comparing 60 Gy (RBE) of C-ion RT and 50 Gy of IMRT.
There were some limitations in our study. First, we performed a retrospective simulation with a small number of patients. Second, the dose of C-ion RT to the liver [Gy (RBE)] might not be equal to that of IMRT (Gy). Because Gy (RBE) is calculated based on the survival response of human salivary gland cells after C-ion beam irradiation, and not of liver cells, a direct comparison between Gy (RBE) and Gy for the liver can be problematic. Moreover, the dose constraints of C-ion RT and those of IMRT for the liver might be different. However, the dose constraints of C-ion RT for the liver used in our study are considered safe, as previous clinical studies of C-ion RT used the same dose constraints, and no severe toxicities were observed (7-11).
In conclusion, we demonstrated that C-ion RT for treating LAHCC provides a better dose distribution than IMRT; a clinical-use dose of 60 Gy (RBE) using C-ion RT showed a superior dose distribution to the PTV and liver than did 50 Gy of IMRT. Additionally, our results suggest that adopting C-ion RT may enable the treatment of patients with LAHCC who cannot be treated with IMRT owing to the high risk of RILD; hence, C-ion RT may expand the treatment indication of LAHCC.
Acknowledgements
The Authors wish to thank all the patients involved in this study and our colleagues at the Department of Radiation Oncology, Gunma University Graduate School of Medicine.
Footnotes
Authors' Contributions
S.S., K.S., M.K., T.N. and T.O. made substantial contributions to the conception and design of the study. S.S., K.S., N.O., T.K., Y.K., and T.O. treated and followed the patients. S.S., K.S, N.O., and T.O. collected the data. S.S., K.S., M.K., and T.O. drafted the manuscript and performed the statistical analysis. N.O., T.K., M.O., Y.K., and T.N. were involved in revising the manuscript critically for important intellectual content. S.S., K.S., and T.O. participated in the acquisition and interpretation of the data. All Authors read and approved the final manuscript.
This article is freely accessible online.
Conflicts of Interest
The Authors have no conflicts of interest to declare.
- Received December 3, 2019.
- Revision received December 10, 2019.
- Accepted December 11, 2019.
- Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
