Stereotactic body radiation therapy as an effective and safe treatment for small hepatocellular carcinoma

Hepatocelluar carcinoma (HCC) is the most common primary liver tumor and the fifth common malignant disease globally [1]. The annual diagnosis patients are over five hundred thousand [2]. According to the guideline, resection, liver transplantation and radiofrequency ablation(RFA) are the radical treatment options for small hepatocellular carcinoma(sHCC) [3]. However, only 10–30% patients who are diagnosed with sHCC are eligible for curative therapies due to several reasons [4]. Besides, for lack of donor and strict indications, liver transplantation is limited. RFA is the radical treatment option for the patients with sHCC. But if the tumor is close to bile duct or large vessels, or at deep location of the liver, or positioned at the top of the dome etc., the ablative therapy can’t be safely performed. The best treatment of sHCC remains controversial, particularly for sHCC patients who cannot be treated radically. Historically, the conventional radiotherapy for HCC has been limited due to the radiation sensitivity of normal liver, the risk of radiation-induced liver disease (RILD) after the whole liver radiation of low doses, and concern for the adjacent radiation sensitive organs such as stomach, duodenum, etc. [5]. In recent years, the advanced radiation therapy such as stereotactic body radiation therapy (SBRT) has shown high rates of local control for primary and metastatic liver cancers while avoids the risk of RILD. It is the best choice for sHCC patients who are unsuitable for resection, liver transplantation and RFA.

CyberKnife SBRT, which stands for the image guided precision radiation therapy, is the new type of stereotactic radiosurgery. The most important features of CyberKnife treatment are online position correction, respiratory synchronous tracking, real-time tracking and image guided radiotherapy, etc. Respiratory synchronous tracking system guides the accelerator to track the tumor movement, which can control the precision within 1 mm, realizing the precise therapy. Meanwhile, it enhances the dose of tumor region, reduces the dose of normal tissues nearby, and increases the therapeutic gain ratio. The aim of our study is to evaluate the curative effect and security of CyberKnife SBRT in treating sHCC in our hospital.

For patients with single lesion, especially sHCC, resection is the most effective treatment, with which the 5-year overall survival rate may run up to 60–70% [9, 10]. Sadly, merely a small part of the patients could receive the resection owing to the discompensated liver function, abnormal function of blood coagulation and the tumor positioning in the deep section of the liver, etc. [11]. Most patients cannot benefit from liver transplantation for the lack of donor and high expenses. For patients who are unsuitable for resection, percutaneous ablation therapy (RFA, anhydrous alcohol injection) are the radical procedures. The 5-year overall survival rate of sHCC patients with CPC-A who received RFA is same with the resection [12]. However, for tumors close to gallbladder, bile duct or large vessels, or near the diaphragm which is at the top of liver, the treatment is limited [13]. With the advancement of the radiation therapy, radiotherapy becomes one of the best choices for sHCC patients unsuitable for resection or RFA.

CyberKnife SBRT, featured with accurate high-dose radiotherapy, was first applied to recurrent squamous cell carcinoma of head and neck patients who have no resection options or not suitable for surgery [14]. Blomgren first applied SBRT to liver cancer patients with primary tumor or the secondary tumor who were unsuitable for surgery, TACE and RFA 20 years ago [15]. The results showed higher local control rate and lower toxicity reaction rate [16]. At present, HCC SBRT is the remedy radiotherapy for incomplete embolization of postoperative patients who received TACE, transitional therapy of preoperative transplantation of liver and the option of recurrence HCC [17, 18].

Yoon SM and his coworkers reported 93 sHCC patients treated with SBRT, whose 1-year and 3-year OS was 86 and 53.8%, respectively, tumor diameter less than 6 cm, tumor number less than three, single fraction dose 10-20Gy, total doses 30-60Gy. They considered SBRT could be served as an alternative option for the patients unsuitable for other radical treatments [19]. In our research, the 1-year OS and 3-year OS were 92.86 and 78.57%, which were higher than the results above. We consider that with single dose of 10-15Gy and total doses of 35-60Gy, SBRT is an optional choice to treat sHCC patients whose diameter of tumor is less than 3 cm.Yuan Z retrospectively analyzed and compared the treatment effect of the CyberKnife SBRT and surgical resection of Barcelona stage I HCC patients. The result showed that the 1-year, 2-year and 3-year overall survival rates of the CyberKnife SBRT were 72.7, 66.7 and 57.1%, respectively, while the surgical resection were 88.5, 73.1 and 69.2% respectively. Numerically, the OS of resection was higher than radiotherapy. However, there were no statistical differences between them. The study showed equivalent curative effect between CyberKnife treatment and resection for the early-stage HCC patients [20]. Sylvain Dewas reviewed 120 patients who received CyberKnife treatment, among which 42 were HCC patients, 72 metastatic liver cancer, 6 cholangicellular carcinoma. The median diameter was 33 mm, median GTV was 32.38cm³, and median total doses were 45Gy. The result indicated local control rates at 1-year and 2-year were 84 and 74.6%. In the meanwhile, total doses, tumor diameter and tumor volume were considered as the prognostic factors [21]. We analyzed clinical characteristics including sex, age, type of chronic hepatitis, etc., to discuss factors that may affect overall survival and local control rates. The analyzed results showed no statistical significance (Table 2). We supposed that this was caused by the small size of studied patients. We have conducted further studies by enrolling more patients to prove our conclusions.

Grade I and II hematotoxicity and hepatotoxicity were the main toxicity in our study, which was characterized with low-grade aminopherase elevation, bilirubin elevation, thrombocytopenia and aleucocytosis, and most of them could return to normal gradually after radiotherapy. Only one patient with hepatitis B liver cirrhosis suffered liver failure after 3 months of radiotherapy, who did not have liver enlargement, massive ascites and viral replication. For liver cirrhosis patients, the causes of liver function damage were complex and hard to figure out. Whereas for patients whose tumor was controlled well after radiotherapy and liver function failure wasn’t caused by tumor progress, they were more likely to suffer from serious liver injury with RILD. RILD was the major obstacles of HCC radiotherapy, and the incidence rate of liver radiotherapy was 5–10% when the dose of whole liver achieved 30-35Gy. The main inducing factors of RILD are the basic liver function, the liver cirrhosis and the PTV range [22]. Jung J predicted the RILD risk of SBRT on sHCC which cannot be resected according to dose-volume parameters, by which he discovered the risk for the cirrhosis patients with CPC-B suffering grade II hepatotoxicity was higher [23]. To evaluate liver function, indocyanine green test which is widely used in preoperation is more sensitive than CPC. However, CPC is much more important than indocyanine green test to forecast the risk of RILD [24].

CyberKnife SBRT is proved to be effective, with its main advantages being synchronous respiratory tracking, high dose delivery and low fraction [25]. Moreover, the treatment period is shorter. From the result of our study, CyberKnife SBRT was shown to be an effective and safety therapy for sHCC, which achieved higher local control rates, overall survival rates and lower toxicity reaction. The higher dose brought better local control rates but causing the risk of RILD. The optimal dose and hypofraction scheme are still controversial. Moreover, longer follow-up is required to evaluate the correlation between dose-response and potential late toxicity. SBRT achieved same effect with surgical operation. Our study had shown that nine of thirteen recurrent patients were outfield recurrence, which was the main cause of recurrence. And CyberKnife SBRT may improve curative effect when combined with chemotherapy or targeted therapy.