Stereotactic ablative radiotherapy versus conventionally fractionated radiotherapy in the treatment of hepatocellular carcinoma with portal vein invasion: a retrospective analysis

After obtaining waiver of consent for this retrospective research from the institutional review board of Tri-Service General Hospital (approval number: 1–107–05-016), we identified HCC patients with PVI undergoing RT from January 2007 to December 2016. Patients with Vp3/Vp4 invasion (invading the first-order branches and/or main trunk of the portal vein), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a Child-Pugh (CP) class of A or B were eligible. Any prior interventions were allowed, except for previous RT. Those patients were considered unsuitable for standard locoregional treatment via multidisciplinary committee discussion. Given increasing evidence of the benefits of SABR for HCC patients in the past decades, our hospital practice naturally shifted from use of CFRT to use of SABR. Because SABR was not reimbursed until 2015 in Taiwan, the choice of RT technique was determined partly by the patients’ financial resources.

Diagnosis of HCC was made either by biopsy or by radiologic investigation based on characteristic imaging findings [15]. PVI was confirmed as a low-attenuation intraluminal mass that expanded the portal vein on contrast-enhanced helical computed tomography (CT) scans or on magnetic resonance imaging (MRI) scans. Pretreatment evaluation consisted of medical history, physical examination, complete blood counts, serum biochemistries, alpha-fetoprotein (AFP) level, chest film, and MRI and/or CT of the abdomen. Bone scan, positron emission tomography, or liver angiography was performed if clinically indicated.

For better delineation of the upper gastrointestinal tract, most patients were asked to take oral contrast medium before simulation. A non-contrast CT simulation with a 3 mm slice thickness was performed. During the scanning procedure, all patients were supine, and were immobilized with a vacuum cushion, with arms raised overhead. Motion management with four-dimensional CT was conducted in some patients. Breath-holding was not mandatory. Either three dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiotherapy was designated, depending on the physicians’ discretion, using the Nucletron Plato RTS v2.6.3 planning system, which was replaced by Philips Pinnacle v9.0 planning system in 2009. Instead of defining a gross target volume, the clinical target volume (CTV) was contoured directly. Contrast images registration was used to assist CTV delineation. The CTV was defined as a margin of 3–5 mm around the detectable PVI. Partial hepatic tumor was included in the CTV if the primary hepatic tumor was near to the detectable PVI or if the portal vein was invaded by the tumor directly. An example of target delineation is shown in Fig. 1. The planning target volume (PTV) was generated by expanding the CTV by 8 mm radially and by 10–15 mm craniocaudaully. Prescribed dose to the PTV was 45–54 Gy (1.8–3 Gy per fraction, five fractions per week), administered with a 15 MV photon beam. Most PTV was encompassed in the 90% isodose curve. The irradiation field contained 3–6 gantry angles. RT was delivered using an Elekta Precise or a Siemens Primus linear accelerator.

SABR was administered using the CyberKnife radiosurgery system (Accuray, Sunnyvale, CA), delivering 6 MV photons. At least one week before CT simulation, 4–6 fiducial markers were placed within or around the tumor under sonographic or CT guidance. An individually shaped vacuum pillow allowed patient immobilization in the supine position, with a vest for synchrony tracking and with abdominal compression devices to reduce respiratory motion. A contrast CT scan with a 1 mm slice thickness was obtained for treatment planning with or without MRI scan registration. The definition of CTV in SABR was the same as in the CFRT technique. The PTV was defined as the volume with a margin of 0–3 mm added to CTV for patients with fiducial implantation. If fiducial implantation failed or was unsuitable, the PTV margin was expanded to 8–20 mm craniocaudally, based on the liver motion. Margin modification was permitted for respecting normal tissue tolerance. Prior to August 2009, the MultiPlan CyberKnife treatment planning system version 1.7.0 was employed for treatment planning, and was updated to version 2.1.0 thereafter. The median total dose was 45 Gy, at 6–12.5 Gy per fraction, with 4 to 5 fractions administered on consecutive working days. The detailed dose-limiting organs and their constraints are described in our previous publication [16].

All patients were seen at least once per week during RT, 1–2 months for the first six months after RT, and every three months thereafter. Image evaluation with CT or MRI was obtained every 1–3 months. Modified Response Evaluation Criteria in Solid Tumors was used for evaluation of the PVI response [17].

Hepatic toxicity assessment consisted of Radiation-induced liver disease (RILD) and increase of CP score ≥ 2. Only patients with either adequate follow-up of three months or death and/or occurrence of toxicity within 3 months were included in the analysis. Physical examinations and blood tests conducted at every visit, were used for toxicity assessment. RILD was defined as either classic or non-classic, without intrahepatic tumor progression noted within three months after RT. Classic RILD manifested as the presence of nonmalignant ascites and the elevation of anicteric alkaline phosphatase level to at least twice the upper normal values. Non-classic RILD manifested as the elevation of transaminase levels to at least five times the upper limit of the normal or pre-treatment values.

Doses were converted to biologically effective doses (BED) with an α/β ratio of 10 for analysis. Between-group comparisons were conducted by chi-square tests or by Student’s t-tests as appropriate. OS was measured from the first day of RT until the date of death from any cause or last follow-up. In-field progression-free survival (IFPS) was measured from the first day of RT until the date of tumor recurrence or progression in irradiated field or last follow-up and patients who have received local intervention (ex, surgery or reirradiation) were censored at the date of procedure. Kaplan Meier curves were constructed for OS and IFPS, and the difference was compared using the log-rank test. The Cox Proportional Hazards model was applied to identify potential predictors of survival. A receiver operating characteristic (ROC) curve was used to define optimal cut-off points for continuous variables based on the Youden index. Given the imbalance of potential confounders between groups, propensity score-matching was used. Propensity scores were estimated from a logistic regression model that included treatment period, sex, age, prior treatment, virus infection type, performance, tumor size, tumor number, extrahepatic metastasis, PVI location, AFP level, CP class, and sorafenib use. A nearest neighbor method with a caliper width of 0.2 was used to create matched cohorts. A 2-tailed p < 0.05 was designated as statistically significant for all tests except when variables with p < 0.10 in the univariable Cox model were entered into a multivariable Cox model. SPSS (SPSS Inc. Chicago, IL, USA) version 22 and R statistical software version 3.4.3 (R Foundation, https://​www.​r-project.​org)) were used for data analysis.

Initially, 186 patients were identified by chart review. Forty-six patients were excluded owing to ineligibility, missing data or loss of follow-up after RT (Fig. 2). Finally, 140 patients were entered for data analysis. SABR was administered to 54 patients (median dose, 45 Gy; inter-quartile range [IQR], 40–48 Gy; 6–12.5 Gy per fraction), and CFRT was administered to 86 patients (median dose, 51.5; IQR, 45–54 Gy; 1.8–3 Gy per fraction). Detailed patient characteristics are listed in Table 1.

Follow-up images were available for 45 SABR patients and for 59 CFRT patients (83.3% vs. 68.6%, p = 0.052). Among evaluable patients, five complete response, 23 partial response, 15 stable disease, and two progressive disease cases were observed in the SABR group, and five complete response, 15 partial response, 27 stable disease, and 12 progressive disease cases were observed in the CFRT group. The ORR (complete and partial response) was significantly higher in the SABR group than it was in the CFRT group (62.2% vs. 33.9%, p = 0.004). Of all patients, 18 in the SABR group and 13 in the CFRT group were able to achieve either complete or partial recanalization of the invaded vein (33.3% vs. 15.1%, p = 0.012); subsequent TACE was conducted in 9 patients of the SABR group and in 11 patients of the CFRT group (16.7% vs. 12.8%, p = 0.524).

The median follow-up period was 6.2 months for all patients and 15.4 months for those alive. At the time of the analysis, nine patients in the SABR group and four patients in the CFRT group were alive. Before propensity score matching, the median survival was 10.9 months in the SABR group and 4.7 months in the CFRT group. The 1- and 2-year OS rates were 34.9% and 15.3% in the SABR group, and 15.7% and 8.0% in the CFRT group, respectively (p = 0.005, Fig. 3a). The 1- and 2-year IFPSs were also significantly higher in the SABR group compared to those in the CFRT group (69.6% vs. 39.8 and 32.2% vs. 24.2%, respectively; p = 0.007; Fig. 3b).

After propensity score-matching, 49 patients in each group were matched. (Table 2). The median survival was 10.7 months in the SABR group and 5.1 months in the CFRT group. The 1- and 2-year OS and IFPSs of the SABR group were significantly higher than those of the CFRT group (OS: 33.1% vs. 16.5% and 17.3% vs. 5.2%, p = 0.01, respectively; Fig. 4a; IFPS: 70.8% vs. 39.3% and 22.2% vs. 22.2%, p = 0.002, respectively; Fig. 4b).

Univariable analysis revealed that the presence of SABR, ECOG 0–1, CP class A, single tumor, tumor size ≤8 cm, Vp3, AFP ≤200 ng/ml, prior treatment, and BED ≥65 Gy were predictors of superior OS. No survival difference was noted between patients treated before December 31, 2011 versus after December 31, 2011. Given the presence of the high correlation between BED and the RT technique (p < 0.001), these variables were analyzed by two different Cox models to avoid collinearity. The presence of SABR and BED ≥65 Gy correlated significantly with superior OS in separate multivariable analysis models (Table 3). Furthermore, we identified that the SABR group with BED ≥65Gy showed a higher survival rate than the CFRT group with BED < 65Gy (p = 0.005) (Fig. 5).

Acute toxicities observed in the groups are shown in Table 4. Fatigue was the most common adverse event in both groups. Grade 3 abdominal pain (n = 1) in the SABR group, and grade 3 diarrhea (n = 2) in the CFRT group were recorded. One patient in CFRT group presented with a treatment-related grade 5 duodenal ulcer.

Seven patients (13%) in the SABR group and 11 patients (12.8%) in the CFRT group experienced non-classic RILD, while two patients (3.7%) in the SABR group and six patients (7%) in the CFRT group experienced classic RILD. The incidences of RILD were not different between groups, even after pooling RILD types (16.7% vs. 19.8%, p = 0.646). There were no RILD–related deaths. After excluding 23 patients with missing follow-up CP scores, 10 patients (22.2%) in the SABR group and 19 patients (26.4%) in the CFRT group experienced an increase of CP score ≥ 2, which was not statistically different between groups (p = 0.612).