Background
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third most common cause of cancer-related death in the world [
1]. Surgical resection has been proven as the major treatment modality for HCC. However, most patients with HCC have unresectable disease at diagnosis. These patients are treated with other treatment modalities, such as percutaneous ethanol injection (PEI), radiofrequency ablation (RFA) therapy, transcatheter arterial chemoradiotherapy (TACE), or sorafenib, but the response to treatment is limited [
2‐
6].
The use of radiation therapy (RT) for the treatment of HCC was first investigated more than 40 years ago, but the early trials reported poor results due to the low tolerance of the whole liver to radiation and severe hepatic toxicity, or radiation-induced liver disease (RILD) caused by whole liver irradiation [
7,
8]. RILD, a clinical syndrome characterized by ascites, anicteric hepatomegaly, and impaired liver function, is developed in 5% of patients who received 30~33 Gy whole liver irradiation and usually occurs 2 weeks to 4 months after completion of RT. RILD usually resolves after supportive care. Unfortunately, severe RILD may develop into hepatic failure and even death [
9,
10]. The low hepatic tolerance to radiation also limits the application of higher radiation doses to the tumor. In 1991, Emami et al. reported that the TD
5/5 (the tolerance dose leading to a 5% complication rate at 5 years) for 1/3, 2/3, and the whole liver at 1.8~2 Gy/day were 50 Gy, 35 Gy, and 30 Gy, respectively [
11]. Dawson
et al used the normal tissue complication probability (NTCP) of the Lyman model to describe the relationship between irradiated liver volume and radiation dose and they demonstrated that a higher radiation dose could be delivered safely to liver tumors, with better outcomes, if only part of the liver was irradiated [
12]. As image-based treatment planning and engineering has advanced, three-dimensional conformal radiotherapy (3DCRT) was developed to irradiate the tumor accurately while minimizing the dose to the normal liver. A number of studies have demonstrated encouraging results showing that a radiation dose could be safely increased to part of the liver using 3DCRT [
13]. For example, Park et al. reported a significant relationship between the total dose to the liver tumor and the tumor response (< 40 Gy, 40-50 Gy, and > 50 Gy giving responses of 29.2%, 68.6%, and 77.1%, respectively) without significant toxicity (rate of liver toxicity: 4.2%, 5.9%, and 8.4%, respectively).
Despite improvements to 3DCRT, dose distribution remains suboptimal in some cases. In the early 2000s, the development of inverse planning systems and multileaf collimators (MLCs) culminated in a more sophisticated technique, intensity-modulated radiotherapy (IMRT). Using an inverse planning algorithm to generate multiple nonuniform-intensity beams, IMRT can potentially deliver a higher dose to the tumor while delivering a relatively lower dose to the normal liver as compared with 3DCRT. Cheng
et al. suggested that IMRT might be able to preserve acceptable target coverage and potentially reduce NTCP values (IMRT = 23.7% and 3DCRT = 36.6%,
p = 0.009) compared with 3DCRT [
14]. Fuss et al. reported that IMRT allowed a dose escalation to 60 Gy, in which range 3DCRT had to reduce the total dose to decrease the probability of RILD to acceptable levels [
15].
The RapidArc technique, developed by Varian Medical Systems about 2 years ago, is a volumetric intensity-modulated arc therapy that accurately and efficiently delivers a radiation dose to the target using a one-or two-arc gantry rotation by simultaneously modulating the MLC motion and the dose rates. RapidArc has been shown to be equivalent or superior to IMRT for some malignancies, including head and neck cancer and prostate cancer [
16‐
18], but there has been no study to determine the feasibility of using RapidArc for the treatment of primary HCC. The purpose of our study was to compare the RapidArc radiation treatment plans for patients with HCC with 3DCRT and IMRT plans using dosimetric analysis. The PTV coverage and critical organ sparing for each technique were determined using dose-volume histograms (DVH) and the NTCP model.
Discussion
Historically, the role of RT in HCC has been limited because of the risk of RILD caused by whole liver irradiation. Improved knowledge of partial liver RT has created renewed in using RT with HCC and, furthermore, technical advancements in 3DCRT have allowed higher doses to targeted to the tumors while minimizing exposure of surrounding liver tissue. Recently, more and more types of conformal RT have been developed to deliver highly conformal treatment with minimal damage to surrounding normal liver parenchyma, including IMRT, image-guided radiotherapy (IGRT) and stereotactic body radiotherapy (SBRT) [
24]. RapidArc is a novel form of volumetric intensity-modulated RT that has the advantages of a short treatment time, fewer MUs and the availability of highly conformal treatment plans. Several investigations have demonstrated the advantages of RapidArc. Verbakel
et al. demonstrated that RapidArc achieved similar PTV coverage and OAR sparing but lower MUs than IMRT in patients with head and neck cancers. Besides, double arc plans yielded better PTV coverage than single arc or IMRT [
16]. Palma
et al. reported that variable dose rate volumetric modulated arc therapy achieved better dose distribution and lower MUs than IMRT in patients with prostate cancers. This work was a pilot study to investigate the dosimetric difference of a RapidArc plan for HCC compared to 3DCRT and IMRT plans.
In our study, the homogeneity of the PTV provided by all three techniques was similar, but the RapidArc was able to achieve better conformity and hot-spot sparing of the PTV compared to IMRT or 3DCRT (p < 0.05). For OARs sparing, the three methods showed comparable results in terms of the mean dose to the stomach and kidneys and maximum dose to the spinal cord. For the normal liver, 3DCRT provided the worst dose distribution, with significantly worse Dmean, V40 Gy, V30 Gy, and NTCP values than RapidArc or IMRT. Compared with IMRT, RapidArc provided comparable V40 Gy, V30 Gy, and NTCP values for the normal liver, but RapidArc achieved significantly higher Dmean, V20 Gy and V10 Gy values for the normal liver.
The Lyman NTCP model has been widely used to predict or estimate the probability of normal tissue complication. This model supposed there is a sigmoid relationship between a uniform radiation dose given to a part of the volume in an organ and the probability of complication. More and more authors have used this model to predict RILD. Burman
et al. assigned the parameters to be as follows, n as 0.32, m as 0.15, and TD
50(1) as 40 Gy, in a model that predict the risked of RILD [
23]. Cheng
et al. applied the values of n = 0.35, m = 0.35 and TD
50(1) = 49.4 Gy in another model [
25]. Dawson
et al. further modified the parameter TD
50(1) to 39.8 Gy for hepatobiliary cancer and to 45.8 Gy for liver metastasis (n = 0.97 and m = 0.12) [
26]. Although different values for the parameters have been applied to the Lyman NTCP model by different authors, they demonstrated the feasibility of partial liver irradiation. If the TD
50 is kept constant, the NTCP value is represented as a function of partial volume. This organ demonstrates a "threshold type behavior" and the NTCP value will rise only if a certain volume is irradiated. Furthermore, the NTCP value of the partial volume depends on the dose. Therefore, we believe that the V
40 Gy and V
30 Gy influence the NTCP values of the normal liver more than V
20 Gy and V
10 Gy do. In addition, Dawson
et al. also addressed whether those who had impaired liver function might not be suitable for the Lyman NTCP model and whether a better understanding of the mechanism of RILD may improve the accuracy of Lyman model in the future.
In addition to value used for NTCP, the V
30 Gy and D
mean of the normal liver play important roles in predicting the risk of RILD. Dawson
et al. demonstrated that the D
mean of normal liver was associated with the risk of RILD [
26]. Yamada
et al. reported a deterioration in the Child-Pugh Score in 5 out of 6 patients with a V
30 Gy > 40%,
vs. 2 of 13 patients with a V
30 Gy < 40% (
p < 0.01) [
27].
Another issue that should be kept in mind is the higher low-dose irradiation to normal liver compared with 3DCRT or IMRT when RapidArc is used. Shueng
et al. published a case of cholangiocarcinoma with bone metastasis who had received palliative RT for bone pain who developed radiation pneumonitis [
28]. They demonstrated that, in this case, although the V
5 Gy of the normal lung was only 20%, this still potentially induced radiation pneumonitis. One of the possible causes is an interaction between radiation-induced inflammation within the previously irradiated field and chemotherapy. Yamashita
et al. has reported that the incidence of lung toxicity will become higher if large amount of low dose radiation is delivered [
29]. In addition to the dosimetric impact, several investigators reported that some biological factors are associated with RILD. For example, Cheng
et al. reported that the HBV carriers or cases with Child-Pugh B cirrhosis were correlated with the risk of RILD after 3D-CRT [
25]. Xu
et al. also reported that the Child-Pugh classification was associated with RILD [
30]. In the current study, the potential risk of RILD caused by low-dose irradiation is unclear, but HCC patients in Taiwan usually have hepatitis B or C infection and liver cirrhosis and they usually received TACE, PEI or targeted therapy before RT. Radiation oncologists should be aware of the potential risk of higher low-dose exposure to the normal liver when RapidArc is used.
From the view of dosimetric comparison, one of the reasons that RapidArc is not better than IMRT for liver protection may be that HCC is always surrounded by normal liver parenchyma, which is the major concern when using the volumetric RapidArc technique. In our study, we found that RapidArc increased the V10 Gy, V20 Gy and Dmean of the normal liver compared to IMRT and, therefore, we suggest that the RapidArc should be used more carefully when treating HCC cases even if both RapidArc and IMRT achieve equivalent V30 Gy for the normal liver and have similar NTCP values.
Another advantage of RapidArc over IMRT were the reduction in the number of MUs. Several studies have reported that the disadvantages of IMRT include higher MUs, longer delivery times, and more low-dose exposure of organs at risk (OARs), all of which increase the risk of a radiation-induced second malignancy. Hall reported that IMRT, as compared with 3DCRT, might double the incidence of solid cancers in long-term survivors, especially children [
31]. Zwahlen studied the cancer risk after IMRT for cervical and endometrial cancer and reported that cumulative second cancer risks (SCR) relative to 3DCRT for 6-MV and 18-MV IMRT plans were +6% and +26%, respectively [
32]. There is no sufficient data to demonstrate that the lower MUs associated with RapidArc might reduce the risk of radiation-induced second malignancy. Furthermore, radiation-induced second malignancy occurs only in those who have long-term survival after treatment. Xu
et al. reported that the 5-year survival rate for HCC patients receiving TACE plus RT was only 13% with a median survival time of 18 months [
33]. Thus this advantage of RapidArc may have little influence on the prevention of radiation-induced second malignancy for HCC patients. Verbakel WF
et al. [
16] and Wagner
et al. [
34] compared RapidArc with IMRT for different malignancies and concluded that the major advantages of RapidArc over IMRT were the lower MUs and the shorter treatment time, which can be beneficial to the reduction of intra-fractional movement, improving patient comfort, and higher patient throughput.
Although RapidArc has been demonstrated the advantages on the treatment of other kinds of malignancies, the dosimetric advantage of RapidArc in our study is not always better than IMRT. Therefore it is not convincing that IMRT should be replaced by RapidArc when treating HCC. The limitations of our study include small patient numbers, relatively coarse 5 mm-slice thickness and a lack of respiratory control or abdominal compression. These limitations would possibly cause some errors in the dose calculation and analysis. Clinical trials and long-term follow-up are required to draw more definite conclusions. Therefore, we suggest that if PTV conformity and percentages of NTCP, Dmean, V30 Gy and V10 Gy of the normal liver are acceptable, RapidArc may be selected on the basis of fewer MUs. If PTV coverage is not adequate or each of the above parameters related to liver toxicity is too high with RapidArc, then IMRT should be used.
In conclusion, RapidArc obtained favorable tumor coverage compared with IMRT and both RapidArc and IMRT achieved significantly better quality in terms of treatment plan when compared with 3DCRT. However, RapidArc is not superior to IMRT for liver protection. Nonetheless, RapidArc is a new technique, and optimization of its algorithm is still in its early stages (about 2 years of clinical experience), whereas 3DCRT and IMRT have been well-investigated and routinely used for more than 10 years. It is expected that more comprehensive planning systems for RapidArc are being developed and these might advance the optimization process in the future.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
YCK and HWY contributed significantly to study design and concept. YCK also contributed to manuscript writing and study coordinator. YMC and CWC contributed to statistical analysis. WPS and WCL contributed significantly to the acquisition of data and optimization of treatment plans. PFW and JJH contributed to final revision of manuscript. All authors read and approved the final manuscript.