Cyberknife stereotactic radiosurgery for patients with primary hepatocellular carcinoma

Background: The objectives of this study was to evaluate the efficacy of Cyberknife stereotactic radiosurgery (SRS) for small non-resectable hepatocellular carcinoma (HCC) and portal vein tumor thrombosis (PVTT) in primary HCC. Methods: Thirty one patients with HCC who were treated with Cyberknife SRS were used for the study. We studied 32 HCC lesions, where 23 lesions (22 patients) were treated targeting small non-resectable primary HCC, and 9 lesions (9 patients) targeting PVTT. Tumor volume was 3.6-57.3 cc (median, 25.2 cc) and Cyberknife SRS dose was 30-39 Gy (median, 36 Gy) in 3 fractions for consecutive days for 70-85% of the planned target volume. Results: The median follow up was 10.5 months. The overall response rate was 71.9% [small HCC: 82.6% (17/23), PVTT: 44.4% (4/9)], with the complete and partial response rates of 31.3% [small HCC: 34.6% (8/23), PVTT: 22.2% (2/9)], and 40.6% [small HCC: 47.8% (11/23), PVTT: 22.2% (2/9)], respectively. No patient experienced Grade 4 toxicity. Conclusion: Cyberknife SRS provides a feasible treatment modality with minimal side effects in selected patients with medically inoperable primary HCC. Background Primary hepatocellular carcinoma (HCC), which comprises 90% of all malignant cancers developed in the liver, is a fatal disease that causes death within a few months unless treated properly [1,2]. Many modalities such as surgical resection, percutaneous ethanol injection (PEI), radiofrequency ablation (RFA), external radiation therapy (RT) and transarterial chemoembolization (TACE) have been tried in the treatment for HCC [3-7], but the optimal treatment approach remains controversial. Currently, the conventional RT has a limited role for the treatment of HCC, because of the low efficacy of radiation for tumor control as well as the low tolerance of the liver to RT of tumoricidal dose [8]. With the conventional RT, it is not possible to deliver a high radiation dose to a treatment volume in a short time, without also irradiating some normal hepatic tissue. On the contrary, hypofractionated stereotactic radiosurgery (SRS) is a modality that can deliver a high dose of radiation in a short time to well defined hepatic tumor sites, and there is a rapid dose fall off gradient encompassing tumors. SRS, for benign and malignant diseases, was initially used only for intracranial lesions. With the advent of advanced imaging techniques and robotic imageguided radiation technologies, the Cyberknife has extended highly conformal radiosurgery to extracranial SRS applications [9]. Cyberknife SRS 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 SRS [12-14]. We have employed extracranial stereotactic RT, using the LINAC-based radiosurgery system since 1995, with a special focus on liver tumors [15,16]. Expanding our experience further, we have attempted Cyberknife SRS alone for small primary non-resectable HCC, and used the combined therapy of TACE and SRS for advanced HCC with portal vein tumor thrombosis (PVTT). Therefore, we evaluated the response rate and toxicity of Cyberknife SRS for both small primary non-resectable HCC and advanced HCC with PVTT. Methods Patients eligibility From March 2004 to March 2005, 31 patients participated in a retrospective study at the Cyberknife center, Catholic University. We treated 32 HCC lesions with the Cyberknife (Accuray Inc, Sunnyvale, CA) SRS, where 23 lesions (22 patients) were treated, targeting small non-resectable primary HCC, and 9 lesions (9 patients) targeting PVTT. The criteria for patients to be included in the study were as follows: (1) patients with histologically proven primary HCC, (2) patients not showing extrahepatic metastasis, (3) patients with tumor size (maximal diameter) ≤ 5 cm, (4) age < 75, (5) patients with HCC that did not develop within the transplanted liver, (6) patients who had ECOG score ≤ 3, (7) patients with no previous experience of radiotherapy and (8) patients with leukocytes ≥ 4,000/ , platelet ≥ 50,000/ . Written informed consent was obtained from all patients before therapy. Treatment and dose prescription In terms of previous treatment before SRS, 17 of our patients had received TACE, 3 patients PEI, 6 patients RFA, and 5 patients had not received any previous treatment. TACE (range: 1 4 times, median: 2 times) was performed after SRS in patients with PVTT, whereas the patients in small HCC were treated with SRS alone. The interval between TACE and SRS was at least 2 weeks. Stereotactic radiosurgery treatment was administered using the Cyberknife image guided radiosurgery system. The radiation dose was prescribed at the isodose line that could completely cover the hepatic tumor. Gross tumor volume (GTV) was defined as the tumor volume, which enhanced contrast at computer tomography (CT) scan, and planned target volume (PTV) included GTV with a 0.5 cm-margin. The total doses administered were 30-39 Gy (median, 36 Gy) with the prescription isodose level range of 70-85% (median, 80%) in 3 fractions over three consecutive days. Cyberknife SRS procedure and breath-holding technique Frameless extracranial radiosurgery was carried out at our institution using the Cyberknife SRS system. Liver parenchyma around the tumor was implanted with four gold markers, which acted as radiographic landmarks for the image guidance system. The fiducials were 1 × 3 mm gold seeds, which were implanted percutaneously using an 18-gauge needle under ultraonography guidance. In image-guided radiosurgery, the tumor position during treatment is always defined relative to the abdominal CT. Patients were positioned supine on the table. Images were taken in the spiral mode using 2 mm slice thickness. The CT image was taken when breathing from the patient reached the maximum expiration. The Cyberknife SRS On-target treatment planning system (version 3.3) provided a wide range of treatment options, including the ability to use forward or inverse treatment planning associated with single-isocenter, multipleisocenter, or conformal shape non-isocentric algorithms. In this study, the conformal shape inverse planning was used. Treatment was delivered in the step, image and shoot sequence. First, the robot positioned the linear accelerator at a fixed beam-pointing position. Then, the patient took a breath and held it while the imaging system acquired the targeting data. The patient then took a resting breath, followed by an RT breath-hold, during which the treatment beam was turned on. Anywhere from 10 to 50 monitor units of RT were delivered at each beam position, broken up into breath-holding periods of 10-15 sec, depending on the pulmonary capacity of the patient. Once the complete dose for a particular beam direction had been delivered, the robot advanced the LINAC to the next beam position and the imaging/treatment cycle was repeated. The beam pointing during each RT breath-hold was based on the tumor position observed during the most recent prior imaging during a breathhold. All patients were treated using the breath holding techniques as follows: the initial time from ‘breath-hold: inhale or exhale’ to ‘image acquisition for target localization purposes’ is 15 sec. The patient then breathes normally for 15-20 sec for ‘breath-hold: inhale or exhale’ and ‘SRS beam on’, followed by a third 15-20 sec for ‘breath-hold: inhale or exhale’, ‘a skin marker check’ and finally ‘Cyberknife beam on’. The position of the internal fiducials is then correlated with the movement of the chest wall and the robot retargets the linear accelerator accordingly in real time. Dose limitation to normal tissues The liver, stomach, duodenum, intestine, kidney, and spinal cords were contoured during the planning process and dose-volume histograms (DVH) were used to ensure that normal tissue tolerances were not exceeded. Liver Doses of 30-35 Gy with conventional fractionation are often considered to be the limit of liver tolerance. Kazunari Yamada et al. reported that the volume of the liver receiving a dose in excess of 30 Gy, with conventional fractionation, could be used as a predictive test for damage in liver function [17]. A V30 of < 50% is similar to the surgical criteria for lobectomy [18]. We evaluated V20 as a predictor for liver damage accrued from the SRS treatment in our study: in the α/β ratio of 3, 30 35 Gy with conventional fractionation is equivalent to a dose of 3 x 6 Gy (total, 18 Gy). The V20 was limited so as not to exceed 50% of the functional liver tissue. Stomach, duodenum and intestine Due to the lack of clinical data on the effect of very high fraction doses exceeding 8 Gy, the dose of 7 Gy was chosen based on the experience in brachytherapy [19]. Therefore, the maximum dose to the stomach, duodenum, small or large bowel was limited to below 7 Gy per fraction (total, 21 Gy) to avoid serious side effects. Kidney Emani et al. suggested 23 Gy for TD5/5 for whole-kidney irradiation [20]. Cassady reported that a threshold dose of 15 Gy delivered with conventional fractionation appeared reasonable [21]. As renal toxicities are usually related to the total volume of treated kidney, DVH are essential to predict renal toxicities. In this study, at least 2/3 of the right kidney was limited to receive a dose of less than 5 Gy per fraction (total, 15 Gy): in the α/β ratio of 3, 23 Gy with conventional fractionation is equivalent to a dose of 3 x 5 Gy (total 15 Gy). Spinal cord The maximum dose to the spinal cord was limited to below the 7 Gy per fraction from the linear-quadratic formula of Withers et al : for an α/β ratio of 3, 42 Gy with conventional fractionation is equivalent to a dose of 3 x 7 Gy (total, 21 Gy) [22]. Response and toxicity evaluation The tumor response was based on the change in the maximum tumor size on the abdominal CT scans 1 month after completion of SRS, and then tumor response was checked at 2–3-month intervals. A complete disappearance of the tumor was defined as complete response (CR), a decrease of more than 50% of the tumor size as partial response (PR), a decrease of less than 50% of the tumor size or no change as stable disease (SD), and in-field progression with a tumor size increase of more than 25% as progressive disease (PD). Toxicity was evaluated according to the NCI common toxicity criteria (CTC 2.0 version) [23].