Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis

Primary hepatocellular carcinoma (HCC), which comprises 90% of all malignant cancers developed in the liver, is a fatal disease that might cause death with severe complications unless treated properly [1, 2]. Many modalities such as surgical resection, percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), Y90 microspheres, external radiation therapy (RT) and transarterial chemoembolization (TACE) have been tried in the treatment for HCC [3‐8], but the optimal treatment approach remains controversial.

Stereotactic radiation therapy (SRT), for benign and malignant diseases, was initially used only for intracranial lesions. With the advent of advanced imaging techniques and robotic image-guided radiation technologies, the Cyberknife has extended highly conformal radiosurgery to extracranial SRT applications [9]. Stereotactic body radiation therapy (SBRT) is now being extended to more patients and clinical targets [10, 11]. To date, there are only a few reports in the literature that assessed the response of HCC to SBRT [12‐16]. We have employed SBRT, using the LINAC-based SBRT since 1995, with a special focus on liver tumors [17, 18]. We performed LINAC-based SBRT for 20 primary HCC patients with the result of 80% local control, thus confirming that SBRT is helpful in the treating primary HCC.

Expanding our experience further, we have attempted SBRT alone for small primary non-resectable HCC, and used the combined therapy of TACE and SBRT for advanced HCC with portal vein tumor thrombosis (PVTT). Therefore, we evaluated the response rate and toxicity of SBRT for small primary non-resectable HCC and SBRT combined with TACE for advanced HCC with PVTT.

Surgical resection has been considered a preferred modality of treatment for long-term control of some limited HCCs. However, less than 20% of patients are surgical candidates at diagnosis. In recent years, a number of alternative local modalities including PEI, TACE and RFA have been developed. These local treatments have shown local control rates of 86% after PEI [4], local control rates for liver metastasis of 70% after RFA [5] and 55% after TACE [6]. Seong JS et al. studied the combination of conformal RT with TACE for HCC and local control rates of 66% have been reported in patients [24]. As a result of our study, the local control rate was observed to be 71.9%, which is at least equivalent to the invasive local therapies. Therefore, considering the quality of life during and following treatment and the noninvasive, painless approach associated with SBRT, this technique may be a preferred treatment modality for primary HCC.

Clinically, the biologic advantage of a larger volume of potential normal tissue repair, such as that occurs with conventional RT, is of particular importance when the safety margin is small between tumor and normal tissue. If the irradiated volume is restricted to the tumor with a very small security margin, sublethal damage repair is not a first-line aim because complete cell damage is intended. SBRT can create a high-gradient dose falloff in the target tumor with a very small security margin.

Dose escalation appears to be a very important issue for local control rates. If HCC is treated with RT alone, it requires normal liver tissue-sparing radiation techniques, because the tolerance dose of the liver declines with the volume irradiated [25]. However, dose escalation with conventional RT is limited by prolonged treatment time (accelerated tumor cell repopulation) and increase of the dose to the functional liver tissue (impairment of liver function). SBRT can deliver a high dose of radiation to the target tissue with a high degree of precision within the body [26], while sparing most of the adjacent organ, resulting in potentially better local control and lower risk for RT toxicity.

Published clinical data on SBRT, especially for liver tumors, is limited [12‐16]. Blomgren et al. published the first experiences of use of stereotactic RT for liver tumors [27]. They recommend a hypofractionated RT approach with an inhomogeneous dose distribution in the target. Herfarth KK et al. used a stereotactic single dose RT approach in the treatment of liver tumors [12]. In these studies, both demonstrated high local tumor control rate and low morbidity. The present study on SBRT was attempted based on the results from the above researches, and the results of this study confirmed that SBRT is indeed helpful in the patients of small HCC.

The presence of PVTT is an extremely poor prognostic factor, because it can lead not only to, the wide dissemination of tumors throughout the liver due to the presence of arterioportal shunting, but also to marked worsening of the liver function as a result of decreased portal flow. In patients with PVTT, TACE was considered a contraindication because it could theoretically result in hepatic damage resulting from hepatic ischemia [28]. TACE is less effective in patient with PVTT, and local RT may make TACE more effective if portal vein disease can be eradicated [29]. Tazawa et al. reported a retrospective study of combined therapy (local RT + TACE) in 24 patients with PVTT [30]. In their study, the survival rate was significantly better in the responders than the non-responders. However, Yamada et al. reported 19 patients who had combined therapy (local RT + TACE) with PVTT; They found no significant difference in overall survival between the responders and non-responders [19]. However, one significant finding in this study was that on follow-up angiograms, the protrusion of PVTT into the main portal trunk decreased in all cases. Combined therapy (local RT + TACE) may prevent PVTT from spreading to the main trunk, suggesting a further benefit of TACE. Because the time frame for the RT period in this study was at least 6 weeks, in many cases, the tumor outside the RT fields continued to be enlarged after RT. A shorter fractionation schedule of SBRT like our study will be able to resolve this problem. Our policy, in combining RT with TACE, was to use SBRT solely to treat PVTT in a short treatment period, whereas intralobar HCC was treated with TACE. SBRT, for primary HCC with PVTT, has shown acceptable local control.

In our study, we observed three patients with local recurrence in tumor of left hepatic lobe of the liver. All of the local recurrence are regarded to resulting from marginal recurrence due to inaccurate treatment of a moving target and the poor breathing capacity of the patients. The magnitude of respiration-induced target motion could be as large as 2–3 cm, peak-to-peak. Various methods have been proposed to control or mitigate target motion. These include active or passive breath-holding techniques [31], respiratory gating [32] and 4 dimension or tumor tracking [33]. Breath-holding techniques, by either actively or passively suspending the patient's respiration, allow treatment during this interval. A study examining intra- and interfraction reproducibility of diaphragm position within a fraction can be reproduced satisfactorily. However, daily imaging and repositioning are still required in order to achieve any appreciable reduction in treatment margin for precise treatment. Meanwhile, we suggest to select future patients with well tolerable breathing or train patient to maintain stable breathing, in order to avoid inaccurate treatment of a moving target.

Our study shows that SBRT for small HCC and a combination of SBRT with TACE for advanced HCC with PVTT are feasible and effective treatments. Further study is necessary to define the role of dose administered as well as fractionation and side effects in selected patients with small primary HCC and advanced HCC with PVTT.