Review Article Dig Dis 2014;32:755–763 DOI: 10.1159/000368018
Considerations for Radiation Therapy in Hepatocellular Carcinoma: The Radiation Oncologists’ Perspective Jeong Il Yu Hee Chul Park Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Abstract Although the Barcelona Clinic Liver Cancer staging system does not recommend radiation therapy (RT) as a locoregional modality in hepatocellular carcinoma (HCC), many prospective and retrospective studies have reported excellent local control with favorable survival rates after RT using modern techniques. Additionally, there have been several comparative or meta-analysis results reporting the superiority of RT in unresectable HCC. Therefore, it might be more reasonable to apply RT in unresectable HCC as an alternative locoregional modality to improve local control in HCC. However, several considerations for the application of RT in HCC exist. The considerations for RT in HCC are purpose, combination treatment and technique. The purpose of RT should be based on baseline liver status as well as tumor extent and location. There are several reasonable advantages in local, intrahepatic and extrahepatic control when combined with other modalities, but it could lead to overtreatment in some cases. The technical considerations according to the purpose and combination modality are the final step. For the
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application of RT in HCC, the purpose of RT, combination strategy and technical considerations should be taken into account. © 2014 S. Karger AG, Basel
Introduction
In the management of hepatocellular carcinoma (HCC), both disease extent and the status of the surrounding normal liver are important factors for decisionmaking. The Barcelona Clinic Liver Cancer (BCLC) staging system based on these two major determinants is the most widely used system to select the optimal treatment modality and to predict survival outcomes [1]. Curative treatment options in HCC include hepatic resection [2, 3], radiofrequency ablation (RFA) [4] and liver transplantation [5–8]; however, these modalities are not indicated in more than two-thirds of HCC cases even at the time of diagnosis [9]. Transcatheter arterial chemoembolization (TACE) [10] is usually selected as a secondary option based on evidence from randomized trials and meta-analyses [1]. TACE, however, showed insufficient local control rates in large tumors [11] and even in small hypovascular tumors. Hee Chul Park, MD, PhD Department of Radiation Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine 50 Irwon-dong, Gangnam-gu, Seoul 135-710 (Korea) E-Mail hee.ro.park @ samsung.com
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Key Words Hepatocellular carcinoma · Radiation therapy · Considerations
External Beam Radiation Therapy
Radiation therapy (RT) is one of the most validated and verified modalities in the oncology field along with surgery and chemotherapy. The effectiveness of RT in prolongation of survival as well as improvement in locoregional control has long been recognized in many sites of the body, including the head and neck, central nervous system, thorax and sarcomas. It can be used as a radical treatment for organ preservation without surgery or for unresectable lesions, adjunct treatment after surgery or palliative therapy. Historically, however, RT has played a very limited role in the management of HCC, used only in some extrahepatic lesions for palliative intent. The most important reason for the abandonment of RT in HCC management was low RT tolerance of the surrounding normal liver [14]. The dreaded complication, radiation-induced liver disease, was reported even after administration of limited doses to control HCC in early studies. When taking into account that the most important priority in HCC management is liver function preservation, it was natural to restrict the role of RT. However, the recent development of RT techniques such as three-dimensional conformal RT (3D-CRT), image-guided RT (IGRT), stereotactic ablative body RT (SABR) and/or particle beam RT is changing previous results of RT regarding complications, local control rate and even survival rate. These modalities are techniques that commonly permit clear and steeper dose delivery to target the tumor distinct from the surrounding normal organ when compared to previous RT techniques. Based on these advantages of new techniques, RT is expected to have a greater role than before in an unsolved area of HCC management [15, 16] such as unresectable tumors and/or those that have failed or are refractory to TACE. 756
Dig Dis 2014;32:755–763 DOI: 10.1159/000368018
Rationale of RT Application in HCC
The necessity of achieving local control in the management of HCC cannot be emphasized enough. HCC is curable only after obtaining successful local control, and TACE is not generally accepted as a curative modality because of the relatively low local control probability [1]. Therefore, the combination of TACE with another modality, like RFA, is used as an alternative modality to enhance local control in HCC. High-precision RT, like 3D-CRT or SABR, is one of the reasonable alternatives available to achieve sufficient local control with or without TACE. Table 1 displays evidence of the effectiveness of RT in HCC. There have been some comparative studies evaluating the efficacy of 3D-CRT [17–19]. Eun et al. [18] reported a retrospective cohort study comparing results between RT and best supportive care in advanced HCC, and survival was significantly different (45.9 months for RT vs. 4.8 months for best supportive care). Tang et al. [19] compared results of surgical resection with 3D-CRT in 371 resectable HCC cases with portal vein tumor thrombosis (PVTT), and 3D-CRT showed a median 2.3-month survival gain when compared to resection (p = 0.03). Additionally, Cho et al. [17] reported a comparison study of TACE plus 3D-CRT and sorafenib, which is the current standard management in advanced HCC, and survival was significantly different between the two groups not only in all cohorts (14.1 months for 3D-CRT vs. 3.3 months for sorafenib) but also in the propensity score-matched cohort (6.7 months for 3D-CRT vs. 3.1 months for sorafenib). There were other meta-analyses examining the effect of RT in HCC from randomized and non-randomized trials [20, 21]. A meta-analysis based on five randomized controlled trials showed a higher response rate (odds ratio 3.61, 95% confidence interval [CI] 2.05–6.37) and 1-year survival rate (odds ratio 2.68, 95% CI 1.69–4.26) for the TACE and RT combination compared to TACE alone [21]. Another recent meta-analysis of 10 randomized trials and 18 observational studies re-affirmed the survival advantage (relative risk 1.37, 95% CI 1.11–1.70 at 1 year and relative risk 2.32, 95% CI 1.44–3.75 at 3 years) of TACE plus RT combination compared to TACE alone [20].
Considerations for RT Application
There are some considerations that should be taken into account when applying RT in HCC. The first and most important step is to determine the objective RT purpose according to clinical indications, Yu/Park
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If TACE does not work, sorafenib [12], an oral multikinase inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor and Raf, is the only remaining treatment option based on the survival advantage from a randomized trial [13]. The benefit of overall survival prolongation, however, is modest (approx. 2.5 months), and the response rate is very limited even including stable disease. Therefore, other reliable local modalities to improve outcomes in HCC management while preserving adequate liver function are needed.
Table 1. Evidence of RT effectiveness in HCC
Comparative study
Subject
Study aim
n
Survival, months
Eun et al. [18] Tang et al. [19] Cho et al. [17]
BCLC C/D HCC with PVTT BCLC C
RT vs. BSC RT vs. surgery TACE + RT vs. sorafenib
29 vs. 18 185 vs. 186 67 vs. 49
45.9 vs. 4.8 12.3 vs. 10.0 14.1 vs. 3.3
Meta-analysis
Subject
Study aim
n
Odds ratio at 1 year
Meng et al. [21] Liao et al. [20]
5 RCTs, 12 CCTs 10 RCTs, 18 observations
TACE + RT vs. TACE TACE + RT vs. TACE
1,370 1,223
2.23 1.48
p
