Review Oncology 2014;87(suppl 1):90–98 DOI: 10.1159/000368151

Published online: November 22, 2014

Multimodality Treatment Involving Radiotherapy for Advanced LiverConfined Hepatocellular Carcinoma Hong In Yoon a, b Jinsil Seong a, c a

Department of Radiation Oncology, Yonsei Cancer Center, b Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Science, and c Yonsei Liver Cancer Special Clinic, Yonsei University College of Medicine, Seoul, Korea

Abstract Background: Advanced-stage hepatocellular carcinoma (HCC) has an extremely poor prognosis although sorafenib, which is the treatment of choice, has provided survival benefits. Among advanced diseases, liver-confined HCC, which invades the vasculature without extrahepatic metastasis, requires novel therapeutic management beyond using sorafenib alone. Currently, the Korean Liver Cancer Study Group and National Comprehensive Cancer Network guidelines recommend combined radiotherapy (RT) and chemotherapy for some selected cases. For advanced liver-confined HCC, focal liver irradiation, RT technological development, and optimal selection of RT-suitable patients enable clinicians to use RT-involving multimodality treatments based on oncologic principles, such as concurrent chemoradiotherapy, which represent effective multimodality treatments for several types of malignancy. Summary: In this review, we discuss the need to develop novel therapeutic approaches for liver-confined HCC and clinical applications of

© 2014 S. Karger AG, Basel 0030–2414/14/0877–0090$39.50/0 E-Mail [email protected] www.karger.com/ocl

RT-involving multimodality treatments for advanced liverconfined HCC. Conclusion: RT-involving multimodality treatments can enhance the overall therapeutic successes for advanced liver-confined HCC and also provide potential cures to some patients via conversion to a resectable condition. © 2014 S. Karger AG, Basel

Introduction

The multimodality approach to cancer treatment, led by multidisciplinary teams, is an essential principle incorporating surgery [1, 2] and radiotherapy (RT) [3, 4] for local and regional diseases as well as chemotherapy for systemic disease. This approach is efficacious for most cancers [5–7]; however, RT-involving multimodality management has unfortunately not been successful for hepatocellular carcinoma (HCC). RT as a treatment for HCC has been overlooked because liver irradiation can induce severe hepatic toxicities at dosages below curative doses. However, recently advanced RT technologies have overcome such critical limitations to deliver high doses safely and effectively to local Prof. Jinsil Seong Department of Radiation Oncology, Yonsei Cancer Center Yonsei University College of Medicine 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752 (Korea) E-Mail jsseong @ yuhs.ac

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Key Words Hepatocelullar carcinoma · Radiotherapy · Multimodality treatment

Reappraisal of Treatment for BCLC Stage C HCC

Currently, the BCLC staging system is the most popular guideline for HCC treatment. In this system, patients are divided as follows: very early, early, intermediate, advanced, and terminal stages. Staging is determined by tumor characteristics such as size, number of nodules, portal vein thrombosis (PVT), liver function analysis (Child-Pugh score), portal hypertension, bilirubin level, performance status, and cancer-induced symptoms [15]. BCLC advanced-stage (C) disease exhibits diverse patterns such as liver-confined HCC with vascular invasion versus HCC with widespread extrahepatic disease, HCC with solitary metastasis versus multiple or multiorgan metastasis, and performance status scores of 0 versus 2. Although two randomized controlled trials demonstrated better overall survival (OS) with sorafenib [16, 17], which yielded only modest survival benefits, this broad disease spectrum indicates the need for BCLC C and asRadiotherapy for Advanced Liver-Confined HCC

sociated treatment subclassification [3]. Different prognoses have been reported for liver-confined HCC with vascular invasion and HCC with widespread extrahepatic disease. According to the TNM staging system published by the Liver Cancer Study Group of Japan, liverconfined multinodular HCC >2 cm in diameter with vascular invasion is classified as stage IVA (median survival time, 1.85 years; 5-year survival rate, 24%) and the same HCC type with widespread extrahepatic disease is classified as stage IVB (median survival time, 1.7 years; 5-year survival rate, 15%). Furthermore, depending on the extrahepatic disease, liver-confined, vascular invasive, single-nodular HCC >2 cm in diameter with extrahepatic disease can be classified as either stage III (median survival time, 3.79 years; 5-year survival rate, 41%) or stage IVB [18]. Figure 1 shows a patient who was classified as BCLC C and TNM stage IVA cancer (fig. 1a) and who received concurrent HAICCRT followed by HAIC. After treatment, the tumor markers were normalized along with a radiologic partial response (PR) (fig. 1b). This was followed by radical resection, yielding pathologic total necrosis (fig. 1c). The patient was followed up and showed no evidence of disease for >5 years after HAICCRT completion. This example supports the concept that liverconfined HCC requires a novel and differentiated therapeutic approach, including locoregional treatments.

Multimodality Treatment for HCC

Clinical Benefit of Multimodality Treatment Multimodality treatment is a basic cancer treatment principle. The main goals of radical surgery are locoregional control and a high cure rate. RT is the most effective treatment for local and regional sites that extend more broadly compared with radical surgery, especially in patients receiving neoadjuvant, adjuvant, or definitive treatment. Chemotherapy controls micrometastasis and acts as a radiosensitizer [6]. Multimodality treatment can directly enhance therapeutic outcomes. RT-involving multimodality treatments have been proven very effective for several types of advanced-stage cancers [19–21]. For rectal cancers, successful treatment outcomes have been reported with multimodality treatments involving surgery plus neoadjuvant RT or CCRT, which have become the current standard of care [22, 23]. However, RTinvolving multimodality treatment has not been used to treat HCC.

Oncology 2014;87(suppl 1):90–98 DOI: 10.1159/000368151

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tumor masses and have shown potential to improve survival without severe radiation-related toxicity [8–10]. Recently, the National Comprehensive Cancer Network (NCCN) guidelines for HCC have recommended a combination of RT and chemotherapy for patients with unresectable tumors who are not transplant candidates or if they have inoperable local disease. According to the 2009 Korean Liver Cancer Study Group (KLCSG) guidelines, RT is recommended for unresectable, locally advanced HCCs without extrahepatic metastasis [11]. Although localized concurrent chemoradiotherapy (CCRT), based on the multimodality treatment oncologic principle, yielded favorable treatment outcomes in several studies [12, 13], the efficacy of a multimodality management for HCC remains unknown because there is not sufficient evidence from phase III randomized controlled trials. In this review, we will first reassess treatments for Barcelona Clinic Liver Cancer (BCLC) stage C (advanced) HCC and the rationale for using RT-involving multimodality treatments to treat advanced liver-confined HCC. Next, we will discuss the limitations hindering the use of RT-involving multimodality treatments in HCC and strategies to overcome such limitations. Last, we will summarize the results of several studies regarding clinical applications of hepatic arterial infusion CCRT (HAICCRT) followed by hepatic arterial infusion chemotherapy (HAIC) [14] according to the multimodality treatment principle for HCC.

a

b

c

in the ipsilateral lobe. The AFP and PIVKA-II levels were elevated at 63,382.85 ng/ml and >2,000 mAU/ml, respectively (a). The patient’s disease was classified as BCLC C and TNM stage IVA. He received HAICCRT followed by HAIC, and thereafter, the tumor markers were normalized with a radiologic PR (b; AFP: 34.60 ng/

Barriers to Multimodality Treatment in HCC Several barriers have hindered the application of RTinvolving multimodality treatments for HCC, including the low radiation tolerance of the whole liver, deficits in the technology required to fulfill clinical needs, and the optimal selection of patients who would benefit from local treatment. However, these limitations have been overcome. Low Tolerance to Irradiation Is Applied to the Whole Liver rather than the Partial Liver The liver, a critical organ with various functions, is known to exhibit low radiation tolerance. Before the 1990s, whole liver irradiation was administered as a palliative treatment. After an initial report by Ingold et al. [24] demonstrated that radiation-induced liver disease (RILD) occurred in 1 of 8 patients receiving doses of 30– 35 Gy and that 12 patients (44%) received doses of >35 92

Oncology 2014;87(suppl 1):90–98 DOI: 10.1159/000368151

ml; PIVKA-II: 45 mAU/ml), and he was treated via radical liver resection (c; AFP: 14.38 ng/ml; PIVKA-II: 22 mAU/ml). In the pathologic report, the tumor size had decreased to 8 × 4.7 cm, and total necrosis with no viable tumor was reported. The patient was followed up with no evidence of disease for >5 years after the completion of HAICCRT.

Gy, several studies by the Radiation Therapy Oncology Group suggested a radiation tolerance level for the whole liver of approximately 30 Gy [25, 26]. This level does not allow the delivery of therapeutic doses to HCC. However, the liver features a parallel architecture that enables the partial liver to tolerate higher focal irradiation doses. In 1991, Emami et al. [27] reported estimated tolerance doses for 5% (TD5/5) and 50% (TD50/5) risks of liver toxicity during one-third, two-third, and whole-liver irradiation. The estimated TD5/5 for one-third liver irradiation was 50 Gy at 1.8–2 Gy/fraction. Thereafter, several studies that used a normal tissue complication probability model also demonstrated that the estimated TD5/5 risk of RILD during one-third liver irradiation ranged from 43 Gy to unlimited doses for primary liver cancers [28– 32]. Based on these findings, a group from the University of Michigan suggested that for an effective irradiated liver volume of 100 Gy could be delivered Yoon /Seong  

 

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Fig. 1. A 50-year-old male patient diagnosed with a 13.5-cm multiple HCC with PVT (arrow in a). Multiple nodules were localized

significant difference in the RILD was observed (p = 0.716). These data provide convincing evidence that advanced RT technology allows the delivery of high-dose radiation to focal liver areas.

Technological Development to Fulfill the Clinical Need for High-Dose Radiation Recent technological advancements in RT ranging from 3-dimensional conformal RT (3D-CRT) to intensity-modulated RT (IMRT), image-guided RT (IGRT), and stereotactic RT (SBRT) have allowed high-dose radiation delivery to localized tumor areas and minimal doses to the normal liver volume while avoiding RILD [34–37]. This has led to the provision of survival benefits owing to RT in HCC patients. SBRT, which comprises 3–5 fractions, expedites the delivery of higher radiation doses to tumors with pinpoint accuracy and reduces doses to the tumor-adjacent organs-at-risk. For small HCC, prospective and retrospective studies of SBRT have reported excellent local control rates leading to favorable OS and in-field progression-free survival (PFS) rates without severe toxicity [38, 39]. IMRT, which uses nonuniform beam intensity patterns to attain a superior dose distribution, skillfully controls dose distributions and can cover treatment volumes involving concave tumor shapes [40]. In a study of IMRT and 3D-CRT, Cheng et al. [41] showed that when compared with 3D-CRT, IMRT significantly reduced the normal tissue complication probability for the liver and irradiation doses to the spinal cord, kidneys, and liveradjacent stomach. Image-guided IMRT (IG-IMRT), which integrates IMRT and IGRT via kilovoltage radiography fluoroscopy, cone beam computed tomography (CT), or megavoltage CT [42] such as helical tomotherapy [43], has been performed and shown to provide better tumor volume coverage and normal organ-at-risk sparing [35, 44, 45]. Recently, Yoon et al. [10] have reported that IG-IMRT could be an effective treatment that would improve survival without increasing severe toxicity when compared with 3D-CRT for locally advanced HCC. When comparing the oncologic outcomes of 65 patients receiving IG-IMRT and 112 patients receiving 3D-CRT, IGIMRT significantly improved the 3-year OS (33.4 vs. 13.5%, p < 0.001), PFS (11.1 vs. 6.0%, p = 0.004), and infield failure-free survival (46.8 vs. 28.2%, p = 0.007) relative to 3D-CRT. The RT modality was an independent prognostic factor for OS [3D-CRT vs. IG-IMRT: hazard ratio (HR), 2.18; 95% confidence interval (CI), 1.45–3.25; p < 0.001] and PFS (3D-CRT vs. IG-IMRT: HR, 1.64; 95% CI, 1.17–2.29; p = 0.004) in a multivariate analysis. No

Clinical Benefits of RT-Involving Multimodality Treatment for HCC HAICCRT followed by HAIC for HCC is a multimodality treatment based on the oncologic principle. In 2008, Han et al. [12] demonstrated an objective response rate of 45%, a 3-year actuarial OS rate of 24.1% as well as a median survival time of 13.1 months and suggested that these findings encouraged the use of this new approach in patients with locally advanced HCC with PVT without extrahepatic metastasis. Thereafter, several studies reported the treatment outcomes of RT-involving multimodality treatments for HCC with PVT [12, 13, 52–63] (table  1). Recently, the clinical usefulness of localized HAICCRT followed by HAIC for advanced HCC with both PVT and intrahepatic metastasis has been reported [13]. Following transcatheter arterial chemoembolism (TACE) [64] for intrahepatic metastasis, localized HAICCRT followed by HAIC was administered to the main HCC with PVT in 30 patients. The median PFS and OS were 4.5 and 9.8 months, respectively. This result implies that the combination treatment of localized

Radiotherapy for Advanced Liver-Confined HCC

Oncology 2014;87(suppl 1):90–98 DOI: 10.1159/000368151

Optimal Selection of Patients Who Would Benefit from Local RT In the KLCSG guidelines, RT is recommended for cases with unresectable, locally advanced HCC without extrahepatic metastasis and with Child-Pugh A or B scores, a tumor occupying less than two thirds of the total liver volume, and

Multimodality treatment involving radiotherapy for advanced liver-confined hepatocellular carcinoma.

Advanced-stage hepatocellular carcinoma (HCC) has an extremely poor prognosis although sorafenib, which is the treatment of choice, has provided survi...
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