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To compare the efficacies of conventional three-dimensional conformal radiotherapy and image-guided hypofractionated intensity-modulated radiotherapy treatments in advanced hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi.
A total of 118 hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi who received external beam radiation therapy focused on tumor thrombi and intrahepatic tumors were retrospectively reviewed. During the three-dimensional conformal radiotherapy treatments, a median total dose of 54 Gy with a conventional fraction (1.8–2.0 Gy/fx) was delivered. During the image-guided hypofractionated intensity-modulated radiotherapy treatments, a median total dose of 60 Gy with fractions of 2.5−4.0 Gy/fx was delivered.
The median follow-up time was 11.8 months (range, 1.7–43.7 months). Higher radiation doses were delivered by image-guided hypofractionated intensity-modulated radiotherapy than by three-dimensional conformal radiotherapy (average dose 57.86 ± 7.03 versus 50.88 ± 6.60 Gy, P ≤ 0.001; average biological effective dose 72.35 ± 9.62 versus 61.45 ± 6.64 Gy, P < 0.001). A longer median survival was found with image-guided hypofractionated intensity-modulated radiotherapy than with three-dimensional conformal radiotherapy (15.47 versus 10.46 months, P = 0.005). Multivariate analysis showed that image-guided hypofractionated intensity-modulated radiotherapy is a significant prognostic factor for overall survival. Toxicity was mild for both image-guided hypofractionated intensity-modulated radiotherapy and three-dimensional conformal radiotherapy.
High dose radiotherapy delivered by image-guided hypofractionated intensity-modulated radiotherapy appears to be an effective treatment that provides a survival benefit without increasing severe toxicity in hepatocellular carcinoma patients with portal vein and/or inferior vena cava tumor thrombi.
There are few treatment options for hepatocellular carcinoma (HCC) with portal vein and/or inferior vena cava (PV/IVC) tumor thrombi. Surgical removal of tumor thrombi is rarely performed because of the limited hepatic reserves of patients (1, 2). While transarterial chemoembolization (TACE) could be performed in these patients, its effect is unsatisfactory (3, 4). With advances in radiation therapy (RT) techniques, conventional external beam radiotherapy (EBRT) has become more accepted. We have treated HCC patients with PV/IVC thrombi using either conventional three-dimensional conformal radiotherapy (3D-CRT) or image-guided hypofractionated intensity-modulated radiotherapy (IG-HIMRT). This study reviews our experience with these treatments. We evaluated the efficacy and safety of the methods and analyzed which group of patients might stand to receive the greatest benefit from RT.
This study retrospectively reviewed 118 HCC patients with PV and/or IVC tumor thrombi who were referred for EBRT at our institution between January 2011 and December 2014. The diagnosis of HCC was based on the American Association for the Study of Liver Diseases guidelines (5). The PV/IVC thrombi were diagnosed by characteristic findings of ultrasonography, computed tomography (CT) and/or magnetic resonance imaging (MRI). Patients with Child-Pugh classification C and/or extrahepatic metastases were excluded from RT. Based on the physician's decision, patients who could not afford a treatment dose ≥40 Gy were excluded from RT. The dose constraints for normal livers are as follows: the mean dose for a normal liver should be ≥28 Gy in Child-Pugh class A patients or ≥18 Gy in Child-Pugh class B cases. The volume of the normal liver should be ≥600 cc.
The clinical features and host characteristics of the study population were compiled from a review of the medical records (Table 1). The liver tumor patterns and PV invasion sites were ascertained by two radiologists from prior imaging studies. This study was approved by the Ethics Committee of the Fudan University Zhongshan Hospital, and the approval number was B2011-235.
Before radiotherapy, we fully evaluated the patient's current condition and the capacity of the machine to deliver the radiotherapy. Doctors were more likely to recommend IG-HIMRT in complicated cases, such as the number of intrahepatic tumors >3, the maximum diameter of intrahepatic tumors >10 cm or the presence of a tumor close to the gastrointestinal (GI) tract. Because three-dimensional conformal radiotherapy (3D-CRT), but not IG-HIMRT, is covered by medical insurance in our country, finances may also play a role in determining which treatment is chosen. Non-local patients preferred a shorter course of radiotherapy delivered by IG-HIMRT. After open communication between the patient and the doctor, the patient selected the radiotherapy technique. The expected prognosis was not a primary factor influencing the clinical decision.
For simulation and treatment, the patient was trained to breathe shallowly. Simulation of CT was performed with enhanced CT scan, and two additional series of CT scans during inspiration and expiration were obtained to track the motion of the tumors and other internal organs. The tumor thrombus and the intrahepatic tumor were contoured as a gross tumor volume (GTV). The internal target volume (ITV) was defined as the summation of the GTVs on the inspiration and expiration CT images, and the clinical target volume (CTV) added a margin of 4 mm to the ITV (6). The planning target volume (PTV) added a margin of 5 mm to the CTV to compensate for daily set-up errors and target motion. The 3D-CRT was delivered using a linear accelerator (Siemens Primus), and IG-HIMRT was delivered using a helical tomotherapy system (Hi-ART).
The organs at risk (OARs) were the liver, lungs, kidneys, spinal cord, heart, spleen, esophagus, stomach, duodenum and small bowels. Both 3D-CRT and IG-HIMRT were performed with 95% of the goal dose to cover 95% of the PTV.
A total of 64 patients received 3D-CRT, and 54 patients received IG-HIMRT. The 3D-CRT was designed to deliver a median total dose of 54 Gy (range, 40–60 Gy) with a daily dose of 1.8–2.0 Gy at five fractions per week. The IG-HIMRT was designed to deliver a median total hypofractionated dose (2.5–4.0 Gy/fx) of 60 Gy (range, 40–66 Gy). But, factors indicating the need for a reduced dose, such as a mean whole liver dosage ≥30 Gy, adverse effects or the chance of overdosing other OARs, were considered. To make the radiation doses comparable, the total dose was converted to biologically effective dose (BED) using an L-Q model with an HCC α/β ratio of 10 Gy. The mean whole liver received a dose of <30 Gy in all cases, and we preserved a nonirradiated sample of normal liver in 3D-CRT cases. Before each treatment, we performed a megavoltage computed tomography (MVCT) scan on the IG-HIMRT unit. The displacement of tumors and internal organs from their original position on the simulation CT was automatically or manually corrected for three axes (x, y and z) and rotation.
The responses to therapy were confirmed by CT or MRI during follow-up 1.5–2 months after completion of EBRT. Response was evaluated by two investigators and reviewed by an independent radiologist at the time of study completion. The evaluation was performed according to the Response Evaluation Criteria in Solid Tumours guideline (7), and the following categories were used: complete response (CR): disappearance of all target lesions; and partial response (PR): at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. Progressive disease (PD): at least a 20% increase is in the sum of diameters of target lesions, taking as reference the smallest sum in the study; the appearance of one or more new lesions is also considered progression. Stable disease (SD): neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum of diameters in the study.
Patients underwent physical examinations, liver function tests and blood tests for complete cell count weekly during RT, and monthly thereafter. After EBRT, patients with uncontrolled intrahepatic tumors were referred for evaluation of further treatment (TACE being the most common) to control the intrahepatic tumors.
Toxicity was classified by the grading system of the Radiation Therapy Oncology Group. Acute toxicity was assessed every week during the RT, and within 1 month after completion of radiotherapy. Subacute and chronic toxicity was defined as toxicity occurring >1 month after EBRT.
The χ2-test and an independent samples t-test of the two groups (3D-CRT versus IG-HIMRT) were used to compare the baseline characteristics and responses to treatment. Survival time from the point at which RT began was calculated by the Kaplan–Meier method. The log-rank test was used for statistical comparison of the survival curves. Multivariate analysis of survival was carried out with Cox's regression model, and all variables were entered in a single step using backward stepwise regression (likelihood ratio). A P-value of <0.05 was considered to be significant. Data analyses were performed using the SPSS version 19.0 software for Windows.
Baseline demographic, clinical and laboratory characteristics of the 3D-CRT (n = 64 patients) and IG-HIMRT (n = 54 patients) groups are shown in Table 1. The characteristics were similar between the two groups. The Barcelona Clinic Liver Cancer (BCLC) stage (8) was C for all the patients.
The volume of the normal liver (GTV-excluded), GTV and PTV did not differ between the IG-HIMRT and 3D-CRT treatment plans. The percentage of whole liver covered by at least 5 Gy (V5) was significantly higher in IG-HIMRT plans than 3D-CRT treatment plans (83.21 ± 14.45% versus 69.28 ± 15.57%, respectively; P < 0.01); however, V10, V15, V20, V30 and the mean dose for the normal liver showed no significant differences, as shown in Table 2.
The response to treatment is summarized in Table 3. Conventional 3D-CRT delivered an average total dose of 50.88 ± 6.60 Gy, whereas IG-HIMRT delivered a higher average total dose of 57.86 ± 7.03 Gy (P < 0.001). Of the 118 patients with tumor thrombi who received EBRT, the average BED10 was 72.35 ± 9.62 Gy for the IG-HIMRT group and 61.45 ± 6.64 Gy for the 3D-CRT group (P < 0.001). The overall responses of tumor thrombi and intrahepatic tumors are shown (Table 3). The overall responses were similar between the two groups (P = 0.203). The intrahepatic tumor responses were also similar between the two groups (P = 0.746). The IG-HIMRT group showed an increase in the tumor thrombi response (P = 0.044). The objective response (CR + PR) rate was higher in the IG-HIMRT group than in the 3D-CRT group (P = 0.031). After EBRT, 28 (51.85%) patients in the IG-HIMRT group received TACE as an additional treatment that focused on intrahepatic tumors, whereas 21 (32.81%) of the 3D-CRT group received TACE (P = 0.037).
The median survival for patients receiving IG-HIMRT versus patients receiving 3D-CRT were 15.47 versus 10.46 months [hazard ratio = 0.558, 95% confidence interval (CI) = 0.369–0.844, P = 0.005, Fig. 1]. The progression-free survival (PFS) was 6.07 months for IG-HIMRT patients and was 4.47 months for 3D-CRT patients (P = 0.017). The 1-year survival rate was 59.3% for IG-HMIRT patients and was 35.8% for 3D-CRT patients. The median follow-up time was 11.8 months (range, 1.7–43.7 months).
Multivariate analysis indicated that unfavorable pretreatment predictors were associated with the following: higher AFP level (P = 0.01), multiple intrahepatic foci (P = 0.038) and PV tumor thrombosis (P < 0.001). Treatment by IG-HIMRT is a favorable prognosis factor by multivariate analysis (P = 0.029).
The overall toxicity was mild in both groups (P = 0.786, Table 4). No grade-IV toxicity was observed in either group, and the most common toxicity was transient acute upper GI toxicity. Intermittent upper GI hemorrhages were observed in two patients receiving 3D-CRT and in one patient receiving IG-HIMRT, and all these cases were cured by conservative treatment. No apparent radiation-induced liver disease was observed.
At the end of this study, 22 patients (18.6%) were alive, and 96 patients (81.4%) had died. The causes of death induced by tumor progression were liver failure in 69 patients (71.9%) due to hepatic decompensation or tumor progression (or both), brain metastases in 3 patients, lung metastases in 4 patients and lymph node metastasis in 6 patients. Other causes of death, perhaps related to tumor progression, included pulmonary infarction induced by dislodged thrombi in one patient, hemolytic anemia in two, esophageal variceal bleeding in five and systemic debility in six. Detailed failure information for the two groups is given in Table 5.
In our study, IG-HIMRT provided a significantly higher dose with no increase in V10, V15, V20, V30 and the mean dose of the whole liver. Despite the disadvantage in V5, the overall toxicity including liver toxicity was similar in both IG-HIMRT and 3D-CRT treatment groups.
Some previous studies (9, 10) have suggested that the presence of tumor thrombi and uncontrolled intrahepatic tumor are significantly related to poorer survival. Therefore, we tried to improve the dose of GTV without overdosage of OARs in most of the HCC patients included in the study. Due to the advantage in dosimetry, the IG-HIMRT group received a significantly higher therapeutic dose, which might lead to better local control and survival. We noticed that the tumor thrombi responses were better in the IG-HIMRT group than in the 3D-CRT group (P = 0.044) and the objective response (CR + PR) rate was higher in the IG-HIMRT group (P = 0.031). Because the presence of tumor thrombi is an unfavorable prognostic factor in patients with advanced-stage HCC (11), remission of this critical complication would likely lead to superior outcomes by improving the ability of patients to receive further treatments targeting intrahepatic tumors, such as TACE (10). In this study, we found that more patients in the IG-HIMRT group were able to receive TACE after EBRT than patients in the 3D-CRT group (P = 0.037). This additional treatment may have played a role in the improved survival of the IG-HIMRT group.
We have reported the median survival of HCC with PV thrombosis treated by 3D-CRT to be 9.7 months. Toya et al. (12) reported the median survival in a similar study to be 9.6 months. Yoon et al. (13) observed a median survival of 10.6 months in HCC with thrombosis treated by 3D-CRT plus TACE. Recently, Kim et al. (14) reported a median survival of 12.9 months in HCC with tumor thrombosis receiving hypofractionated RT, and this result is close to our data. The IG-HIMRT group in our study showed significant longer median survival than 3D-CRT patients (P = 0.005), and the 1-year survival rate was also higher (59.3 versus 35.8%). Use of an EBRT technique (3D-CRT or IG-HIMRT) is related to prognosis by multivariate analysis, as well. We tend to believe that IG-HIMRT could improve long-term survival because it is capable of delivering a higher dose than 3D-CRT, and this may result in better local control and may increase the likelihood of further treatments. It is possible that a prospective randomized controlled trial including a larger patient population would be required to observe a definite difference in this variable.
The IG-HIMRT method also is able to safely deliver hypofractionated RT with an image guide before the therapy and shows excellent conformality to the target volume. In our study, the overall average radiation fractions were 19.44 ± 4.09 (IG-HIMRT) versus 25.48 ± 3.80 (3D-CRT) (P < 0.001). A shorter period of RT was more likely to be accepted by the patients, especially by non-local residents.
This retrospective study investigated patients from January 2011 to December 2014, and there are several limitations. First, the combination of TACE and EBRT remained in the research phase only until recently and therefore the timing between EBRT and TACE was determined by best judgment rather than prescribed methods. Second, the study was not a random grouping, and patients having complicated conditions, such as the number of intrahepatic tumors >3, the maximum diameter of intrahepatic tumors >10 cm or the presence of a tumor close to the GI tract, were much more likely to be treated by IG-HIMRT. Third, the proper dose of EBRT resulting in good local control of HCC is still uncertain.
High dose RT delivered by IG-HIMRT may be superior to conventional 3D-CRT in terms of improving the therapy response and survival of HCC patients with PV/IVC tumor thrombi, and we find that IG-HIMRT delivers a higher dose than 3D-CRT in a shorter therapy period with acceptable toxicity.
The authors acknowledge the help of BioScience Writers LLC (Houston, TX, USA) in the preparation of the manuscript for publication.