Radiotherapy for Hepatocellular Carcinoma With Tumor Vascular Thrombus: Ready for Prime Time?

Radiation therapy has been studied for decades in virtually every upper GI cancer, but only recently has this modality been actively studied as an ablative modality in liver tumors. Although the routine use of radiation therapy is undergoing re-evaluation in many other locally advanced GI cancers, the use of radiation therapy in hepatocellular carcinoma (HCC) is rapidly increasing. The reason for this increasing use of radiation therapy lies in the unique paradox that HCC presents to treating clinicians: although the majority of patients have disease that is confined to the liver, only a minority of these patients are candidates for potentially curable, liverdirected therapy. Liver-confined HCC is often associated with large size, vascular invasion, or multifocality. Adding to the complexity, the tumor typically resides in a functionally compromised liver as a result of the common risk factors of hepatitis B, hepatitis C, alcohol, and cirrhosis. The advanced locoregional presentation and underlying liver disease limit the application of curative options such as liver transplantation, partial hepatectomy, or radiofrequency ablation (RFA). Historically, the use of radiation therapy for liver tumors was similarly limited because of the technical inability to deliver ablative doses without incurring a significant risk of radiation-induced liver disease (RILD). The risk of RILD is primarily mediated by two treatment-related factors: the dose of radiation that the liver receives and the volume of liver irradiated. This association between toxicity and the volume of liver irradiated hampered the development of effective radiation strategies for liver tumors when radiation planning was primarily performed with plain film x-rays (two-dimensional treatment planning). Two-dimensional treatment planning necessitated larger volumes to avoid missing tumors as a result of lack of imaging to guide radiation port designs. Additionally, it was difficult to establish volume-based radiation dose–toxicity data without the use of cross-sectional imaging in treatment planning. The advent of computed tomography–based treatment planning was a critical developmental step, given that it allowed for the more accurate definition of tumor volumes. More importantly, computed tomography– based treatment planning allowed investigators to identify the liver and the radiation dose that the liver received. This ability facilitated an era of prospective trials that defined the liver radiation dose–volume relationship of RILD and established treatment planning parameters that could be used to safely treat liver tumors. Additional advances in radiation treatment delivery allowed greater conformality of the radiation dose cloud around liver tumors while maximizing the sparing of the liver. Strides were also made in the management of respiratory motion, immobilization, and image guidance during radiation treatments, which permitted further reduction of the planning target volume and correspondingly reduced the volume of normal liver irradiated. These advances permitted the development of stereotactic body radiotherapy (SBRT), a potentially ablative radiation strategy of high-dose radiation given in five or fewer fractions, for liver tumors. In the article that accompanies this editorial, Bujold et al formally evaluate SBRT from two sequential prospective trials of individualized-dose SBRT in patients with HCC who were not candidates for surgery, transarterial chemoembolization, or RFA. In these two trials, 101 patients were treated with SBRT. These patients were generally high risk: more than half of the patients had a Cancer of the Liver Italian Program score of 2 to 4, and 55% of the patients had tumor vascular thrombus. Additionally, more than 60% of the patients had multiple lesions, with a median sum of largest diameter of almost 10 cm and a median largest lesion size of 7.2 cm. Despite the large representation of high-risk patients, SBRT demonstrated an impressive local control at 1 year of 87%, with a median time to local progression that was not reached. The median overall survival was 17 months. SBRT was well tolerated, with a low rate of grade 3 or greater toxicity; the majority of toxicities were transient aminotransferase or platelet abnormalities. As the authors mention in their discussion, these results compare favorably to best supportive care or sorafenib, the only other standard options in this group of patients. The article by Bujold et al adds to the growing body of evidence that liver tumors can be treated with durable local control with radiation. However, the question of where radiation fits into the armamentarium of therapies for HCC remains. Clearly surgery, be it transplantation or partial hepatectomy, remains the gold standard for localized disease. However, only a small minority of patients who are diagnosed with liver-confined HCC meet the tumor-specific and medical criteria for an operation. RFA has a well-established track record of outstanding local control for tumors that are smaller than 3 cm, but the efficacy is more limited for larger tumors and for tumors in anatomically challenging locations. Transarterial chemoembolization is an effective regional therapy for multifocal disease, but its efficacy in patients with extensive vascular involvement or in tumors larger than 10 cm is limited. Sorafenib has an important and significant benefit in disease control in unresectable HCC, but the clinical activity is modest and carries significant adverse effects. Radiation represents a potentially ablative liver-directed therapy that is complementary to the existing options. A tumor that is located in the dome of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 13 MAY 1 2013