Presented in part at the 93rd Scientific Assembly and Meeting of the Radiological Society of North America, Chicago, Illinois, November 25-30, 2007.
Patients with unresectable hepatocellular carcinoma (HCC) have limited treatment options. In this study, the authors investigated the feasibility, toxicity, and efficacy associated with intensity-modulated radiation therapy (IMRT) and concurrent, chronomodulated capecitabine in the treatment of unresectable HCC.
Twenty patients underwent treatment planning for HCC confined to the liver with helical tomotherapy-based IMRT. Fifty-five percent of patients had Child-Pugh Class A disease, and 45% of patients had Class B disease. Ninety-five percent of patients were prescribed 50 gray (Gy) of radiotherapy to the planning target volume delivered in 20 fractions with concurrent, chronomodulated capecitabine. Transcatheter arterial chemoembolization preceded radiotherapy in 11 patients, and 9 patients received IMRT alone because of portal vein thrombosis, esophageal varices, or tumor size.
The mean greatest tumor dimension was 9 cm (range, 1.3-17.4 cm), the mean dose to normal liver was 22.6 Gy (range, 10-29.2 Gy), and the average volume of liver that received >30 Gy (V30) was 27.2% (range, 12%-43%). Eighteen patients (90%) completed the prescribed treatment of 50 Gy. There was no increase from baseline in acute or late toxicity greater than 2 grades. Partial response or disease stability was achieved at 3 months to 6 months after treatment in 15 of 16 patients (94%). The median survival (±standard deviation) for patients who had Child-Pugh Class A and B disease was 22.5 ± 5.1 months and 8 ± 3.3 months, respectively.
The incidence of primary hepatocellular carcinoma (HCC) has increased in the United States over the last 3 decades secondary, in part, to rising hepatitis C infection rates.1 Surgical resection is considered a curative option, but only 10% to 15% of patients are candidates for curative surgery because of disease multifocality, early vascular invasion, decompensated liver disease, and poor performance status. Some alternative treatment options for these patients with advanced disease, such as percutaneous ethanol injection, radiofrequency ablation, and transcatheter arterial chemoembolization (TACE), tend to be more effective in small tumors (from <2 cm to 4 cm in greatest dimension) and have contraindications in patients with coagulopathy, portal vein thrombosis, or ascites. Other treatments, such as Y90 microspheres, frequently are used to treat diffuse tumors and retain the risks associated with invasive techniques.
External beam irradiation therapy for HCC has been used infrequently in part because of the limited tolerance of the entire liver (30 grays [Gy]), which is insufficient to control macroscopic disease. However, the increasing use of 3-dimensional (3D) treatment planning based on computed tomography (CT), in combination with advancements in liver magnetic resonance imaging (MRI) and better treatment delivery techniques with 3D conformal irradiation therapy (3D-CRT), precisely localized tumors can be irradiated at doses from >60 Gy to 90 Gy while sparing much of the normal liver.2 Partial liver CRT is associated with low toxicity, and several authors have reported achieving long-term control in patients with unresectable HCC.3-7 Increased doses >50 Gy with non-3D techniques improved tumor control marginally but were associated with a relatively high incidence of liver and gastrointestinal toxicity.8 In comparison, 3D-CRT dose distributions exhibit greater conformality and improved homogeneity, making it possible to deliver a radiation dose >65 Gy without liver toxicity. One of the newest conformal treatment approaches employs helical tomotherapy IMRT, in which a gantry 6-MV linear accelerator is rotated continuously around the patient while a multileaf collimator is positioned dynamically every 7 degrees for conformal treatment. Although this technique does not account for organ motion secondary to breathing, setup margins can be minimized because of decreased setup error obtained with daily megavoltage CT image guidance. The objectives of the current study were to review our initial experience using IMRT plus concurrent capecitabine for patients with primary HCC in the context of a multidisciplinary program, to assess the feasibility of this approach after TACE, to evaluate the early and late toxicity, and to assess tumor control patterns.
MATERIALS AND METHODS
Twenty patients with primary, unresectable HCC who were treated with IMRT and concurrent capecitabine (Xeloda; Roche Pharmaceuticals, Nutley, NJ) between October 2005 and December 2007 were studied retrospectively. In 60% of the patients, the diagnosis of HCC was confirmed by biopsy, whereas elevated α-fetoprotein (AFP) levels and a mass lesion in a cirrhotic liver were used to diagnose the remaining patients. Requirements for establishing a diagnosis of HCC on imaging included the presence of a focal lesion >2 cm in greatest dimension identified by 2 imaging modalities with hypervascularization demonstrated in at least 1 of the modalities. Specifically, the patients in this study underwent MRI or CT scans followed by angiographic liver evaluation in which contrast enhancement demonstrated the neovascularization typically associated with HCC. Tumors were considered unresectable because of extensive disease throughout the liver parenchyma, major vascular involvement by cancer with or without tumor extension into a thrombus in the portal vein, or cirrhosis and a clinical condition that precluded surgical intervention. Patients who had extrahepatic disease, Child-Pugh Class C disease, or a Karnofsky performance status <60% were not included in this study.
The mean patient age was 60.8 years, and the ratio of men to women was 17:3 (Table 1). Fifty-five percent of patients had Child-Pugh Class A cirrhosis, whereas 45% had Class B cirrhosis. Forty percent of patients had ascites before radiotherapy, and the majority of those patients (75%) required paracentesis before treatment. Two patients who had chronic ascites had frequent accumulation of fluid, and paracenteses were performed during the course of radiotherapy to improve patient setup reproducibility. One of these patients had a permanent indwelling paracentesis catheter placed 2 months before radiotherapy that was drained every other day during the course of treatment. The second patient had paracenteses on an as-needed basis (every 10-14 days) to maintain consistent abdominal girth. AFP levels were >200 ng/mL in 45% of patients, 50% of patients were positive for hepatitis C virus, and 10% of patients were positive for hepatitis B virus. The median greatest tumor dimension before radiotherapy was 9.5 cm (range, 1.3-17.4 cm). Eight patients (40%) had portal vein thrombosis, and 1 patient (5%) had portal vein compression.
Table 1. Patient Characteristics
HCC indicates hepatocellular carcinoma; AFP, α-fetoprotein; AJCC, American Joint Committee on Cancer; WNL, within normal limits; ULN, upper limit of normal; TACE, transcatheter arterial chemoembolization; RT, radiotherapy.
Total no. of patients
Diagnosis of HCC
Imaging and AFP
AJCC tumor classification
>ULN to 2.5×ULN
Serum hepatitis diagnosis
No viral markers
Portal vein thrombosis
Compressed but patent
No. of TACE procedures, range
TACE to RT interval, mo
Tumor size before RT, cm
Eleven patients underwent at least 1 TACE procedure (range, 1-3 TACE procedures) before radiotherapy planning. Those patients were referred for irradiation because they had evidence of persistent tumor blush on angiography and/or persistent elevation of AFP (3 patients), or they had abnormalities on CT or MRI images consistent with residual tumor (8 patients). The average interval between irradiation and TACE was 2.7 months. TACE was performed according to a previously published protocol using a combination of lipiodol, doxorubicin, and mitomycin-C followed by embolization with polyvinyl alcohol particles.9 Patients did not undergo radiofrequency ablation primarily because of tumor size.
External Beam Treatment Planning
CT simulation was performed for each patient using a Philips wide-bore CT scanner with 3-mm slice thickness (Phillips Healthcare, Andover, Mass). Immobilization was achieved by using a vacuum-lock body fixation device posteriorly and a vacuum-sealed cover sheet anteriorly to reduce breathing motion. The gross tumor volume (GTV) was contoured manually using a CT scan performed with either intravenous contrast or coregistration with MRI diagnostic images. A margin of 1 cm to 2 cm was added to the GTV to account for microscopic disease extension. Liver movement caused by diaphragmatic excursion and other nonspecific setup error was accounted for by adding another 0.5 cm to 1 cm radial margin and a 1.5 cm craniocaudal margin to the final planning target volume (PTV). The entire liver was contoured, and the normal liver was quantified as the total liver minus the GTV.10, 11 IMRT plans were generated using the HiArt System (TomoTherapy Inc., Madison, Wis),12, 13 and a minimum dose to the tumor of 50 Gy in 20 fractions over 4 weeks was used for 95% of plans with the optimization goal of delivering the prescription dose to 95% of the PTV. One patient who had received previous irradiation to the liver (30 Gy in 12 fractions using anterior-posterior/posterior-anterior fields) was prescribed an additional boost of 30 Gy in 12 fractions using IMRT.
Chronomodulated capecitabine was prescribed to patients on the days of radiotherapy treatment only. Capecitabine was used as a irradiation sensitizer based on the long-standing combination of 5-fluouroracil (5-FU) plus irradiation and the recent knowledge that irradiation itself can induce up-regulation of thymidine phosphorylase.14 Patients were prescribed 1 g of capecitabine in the morning and 2 g at night. The rationale for the use of this asymmetric dose schedule was based on the known circadian variation in the metabolism of 5-FU by dihydropyrimidine dehydrogenase, which is elevated at night, and the linear behavior of the activity of phosphorylase regarding the metabolism of capecitabine. These issues regarding the use of 5-FU as an irradiation sensitizer were discussed previously in detail in a review article.15
The maximum, mean, and volume of normal liver that received >30 Gy (V30) was determined from dose volume histograms. Local control was assessed by a single radiologist reviewer (K.D.H.) using either a contrast-enhanced CT or an MRI. The Response Evaluation to Criteria in Solid Tumors (RECIST) guidelines and the European Association for the Study of the Liver (EASL) were used to compare tumor size and lesion enhancement before and 3 months to 6 months after the completion of irradiation as an indicator of successful therapy.16
Overall survival was calculated from the time patients completed chemoradiation, and, in the patients who died, the probable cause of death was obtained. Acute toxicity was evaluated based on the Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE) and included fatigue, ascites, abdominal pain, fever, diarrhea, esophagitis, thrombocytopenia, and elevations in liver enzymes. Patients who had baseline symptoms were scored based on CTCAE toxicity grade both before and after radiotherapy, and the difference in grade was recorded. Data were collated and entered into a relational database (WINKS SDA; TexaSoft, Cedar Hill, Tex), which was used for data analysis, including survival and progression-free survival (assessed from the date treatment was completed) using Kaplan-Meier statistics. Institutional Review Board approval was obtained for the review of patient data, and all patients signed an institutional approved consent form for this treatment.
The average PTV volume was 634.2 cc (range, 99.9-1701.0 cc), and the average normal liver volume was 1463.4 cc (range, 871.5-2300.1 cc). On average, the PTV was 28.2% of the total liver volume (range, 8%-53%). The mean total liver volume was 2097.6 cc (range, 1371.8-3211.9 cc). The average normal liver V30 was 27.2% (range, 12%-43%). The mean dose to normal liver was 22.6 Gy (range, 8-52 Gy); and the mean doses to the small bowel, right kidney, left kidney, and right lung were 7.6 Gy, 8.3 Gy, 4 Gy, and 6.6 Gy, respectively.
Four patients, all with Class B disease, required hospitalization during treatment. Reasons for hospitalization included encephalopathy (1 of 4 patients), melena secondary to a gastric ulcer (1 of 4 patients), acute hepatitis (1 of 4 patients), and sepsis (1 of 4 patients). The patient who was hospitalized with encephalopathy had decompensated liver failure that was managed with daily lactulose. This patient was noncompliant with lactulose for several days before admission. The patient who was hospitalized with subacute bleeding from a gastric ulcer was diagnosed on endoscopy after 11 of 20 fractions (28.6 Gy). On further review, this patient had a maximum stomach dose of 52.9 Gy and a median dose of 16.9 Gy. The patient received 1 unit of blood, was started on a proton pump inhibitor, and finished the remainder of his treatment uneventfully. The 2 patients who were hospitalized for acute hepatitis and sepsis died before they completed treatment. The patient who had acute hepatitis experienced decompensated liver failure that we believed was secondary to acetaminophen toxicity and had received a cumulative radiation dose of 12.5 Gy in 5 fractions (25% of the total dose). This patient had not started on capecitabine. Another patient died of sepsis related to a permanent indwelling paracentesis catheter after receiving a dose of 35 Gy.
Four patients required a break from chemotherapy because of peripheral neuropathy (2 of 4 patients), acute hepatitis (1 of 4 patients), and sepsis (1 of 4 patients). The diagnosis of acute hepatitis was based on acutely elevated liver enzymes and/or bilirubin during radiotherapy. Grade 1 acute abdominal pain was observed in 15% of patients, 30% reported grade 1 nausea, and 5% experienced grade 2 nausea. Three patients (15%) experienced grade 1 esophagitis, and 4 patients (20%) had grade 1 diarrhea during treatment. Fatigue was the predominant symptom: Forty percent of patients experienced grade 1 fatigue, and 30% experienced grade 2 fatigue. Although 2 patients experienced a 1 grade increase in alkaline phosphatase, total bilirubin increased in 25% of patients (by 1 grade in 20% of patients and by 2 grades in 5% of patients). Twenty percent of patients experienced an increase in aspartate aminotransferase levels, and 10% had an increase in alanine aminotransferase levels. Thrombocytopenia was classified as a 1-grade change from baseline for 25% of patients and as a 2-grade change for 1 patient (5%). One patient experienced clinical symptoms of radiation pneumonitis 3 months after the completion radiotherapy and was treated with high-dose steroids for 2 weeks with full resolution of symptoms (see Fig. 1).
Eighteen patients completed the full course of irradiation, and 2 patients (10%) died before follow-up imaging was obtained. Local control, determined by contrast-enhanced CT or MRI within 3 months to 6 months after irradiation, was evaluable in 16 patients who completed the total course of treatment. According to the RECIST criteria, a partial response (a decrease >30% in the sum of the greatest dimension of target lesions) was achieved in 1 patient and was sustained for 28 months. A decrease >20% in the sum of the greatest dimension of target lesions was observed in 8 of 16 patients with post-treatment imaging (Fig. 2). Disease stability according to RECIST criteria was achieved in 14 of 16 patients, and 1 of 16 patients experienced disease progression. The average reduction in RECIST score for patients who had Child-Pugh Class A disease was 28% versus 17% for patients who had Class B disease. In patients with HCC, anatomy may not change after locoregional therapy; however, tumor vascular and cellular integrity may be disturbed. Because of this, EASL recommends evaluating enhancement on contrast-enhanced studies to determine treatment response for HCC. In the current study, a decrease in the sum of the greatest dimension of enhancing target lesions was obtained in 11 of 16 patients (69%) who were evaluated.
Eight patients (40%) had AFP levels drawn after they completed radiotherapy. Three patients (15%) did not have an initial elevation in AFP; and, in those patients, AFP levels remained stable 3 months to 6 months after treatment. Of the 5 patients who had elevated AFP levels, the majority (80%) experienced a decrease >50% in AFP after they completed radiotherapy. Of these, 75% had Child-Pugh Class A disease.
Nine of 20 patients remained alive at the time of the current report. The average survival of 18 patients who completed the entire course of radiation was 9.6 months after the conclusion of radiotherapy. The actuarial 1-year survival rate for patients with Child-Pugh Class A disease was 73% versus 11% for patients with Child-Pugh Class B disease. The median survival (±standard deviation) for patients with Child-Pugh Class A and B disease was 22.5 ± 5.1 months and 8 ± 3.3 months, respectively (Fig. 3). Disease progression occurred in 3 patients at the site of the primary tumor, and 2 patients failed in a segment of the liver (see Fig. 4) that differed from that of their treated tumor. Two other patients failed with distant metastatic disease. One patient with stable disease underwent successful orthotopic liver transplantation 8 months after completing chemoradiation.
The low liver toxicity and survival data for patients with Child-Pugh A disease observed in this study suggests that IMRT with concurrent, chronomodulated capecitabine is a treatment regimen for unresectable HCC that warrants further study. We observed no more than a 2 grade increase from baseline symptoms in acute CTCAE-graded toxicity. Furthermore, the theoretical advantages of IMRT regarding conformality and image-guided radiotherapy, compared with conventional 3D techniques, was supported by the low normal tissue toxicity related to kidney, bowel, and liver sparing. The average volume of liver that received 30 Gy was <30%, and the mean dose to normal liver was 22.6 Gy: On average, nearly a third of the total liver was included in the PTV.
Gierga et al17 reported that the inclusion of tumor motion did not lead to a significant degradation in the target dose-volume histogram when treating abdominal tumors with IMRT. Although under-dosed regions blur out as the number of treatments is increased, there is concern that larger breathing motion amplitude can result in under dosing at the ends of the target in the axis of motion.18 These concerns are minimized with IMRT when using a smaller jaw size, and Kanagaki et al determined that a 2.47-cm jaw (as used in the current study) provides adequate coverage for the small amplitudes of motion observed in the treatment of HCC with IMRT without the need of adding additional margin in the axis of longitudinal motion of the treatment volume.
Evidence for a dose-response relation for local control with chemoradiation for HCC was illustrated by Park et al,8 who demonstrated that, when using 1.8-Gy fractions, an increased total dose resulted in improved local response and overall survival. The study by Dawson et al19 also produced excellent response rates and improved survival in patients who had HCC and liver metastasis treated with radiation doses >70 Gy. Those patients also received continuous-infusion hepatic arterial fluorodeoxyuridine delivered during the first 4 weeks of radiotherapy. Similarly, Robertson et al5 applied doses up to 72.6 Gy using twice daily fractions of 1.5 Gy to 1.65 Gy and achieved an actuarial freedom from progression rate of 72% at 24 months in patients who had localized liver disease. An update of those data by Ben-Josef et al demonstrated that doses >60 Gy were associated with improved control of HCC.20 Compared with those reports, we observed low toxicity with IMRT plus the use of an irradiation-sensitizing drug like capecitabine. We used a conservative approach with a “fixed” radiation dose combined with capecitabine, because this prodrug is converted in part to 5-FU in the normal liver as well as the tumor. The long-term toxicities of grade 1 fatigue and a 1-grade elevation in total bilirubin in 2 patients also support this chemoradiation program. Daily oral capecitabine, given either according to our asymmetric dose schedule on each day of irradiation or in equally divided doses, appears to be safe, is well tolerated, and may obviate the need for the intra-arterial chemotherapy that has been popularized in initial studies of chemoradiation for HCC conducted in the United States.
Most of our patients underwent a TACE procedure before irradiation. The reason we chose this approach is based on recent historic precedent for the management of unresectable HCC with TACE, because there appears to be a survival advantage for TACE alone compared with conservative management (Table 2).21, 22 However, the benefit for chemoradiation combined with TACE in patients with progressive disease is supported by several reports of improved outcomes compared with TACE alone.6, 10, 11, 20, 23, 24 In 1 retrospective study, >200 patients underwent TACE with or without irradiation, and the partial response rate on CT images improved from 31% to 76% with the addition of irradiation.23 Likewise, the overall survival rates at 2 years and 3 years nearly doubled (26.5% and 11.1% vs 42.3% and 24%, respectively). Some authors also have combined TACE with hypofractionated 3D-CRT and have produced response rates of 55% and similar 2-year and 3-year overall survival rates (43.3% and 33.1%, respectively).24 To our knowledge, our study is the first in North America that confirms the benefit of the selected use of chemoradiation for large, unresectable HCC after TACE failure. The initial outcomes of our study are especially encouraging for patients who have Child-Pugh Class A disease. For patients who have portal vein thrombosis or large tumors, chemoradiation with IMRT and capecitabine offers a local treatment that can be integrated safely with or with out TACE. One of the advantages of using TACE in these patients is the helpful information provided by the determination of tumor extent on the angiogenic blush and by the assessment of tumor extent with the use of lipiodol, which frequently is retained in the tumor. The survival data are supported by the finding that >90% of patients exhibited a stable or partial radiographic response at 3 months to 6 months, suggesting that this regimen may be an excellent local treatment for patients who are unable to receive other invasive therapies.
Table 2. Comparison of the Literature for Transcatheter Arterial Chemoembolization and Chemoradiation in Patients With Hepatocellular Carcinoma
Currently, we also have the option of using multikinase inhibitors, such as sorafenib, for the treatment of HCC, and recent data indicated that sorafenib produced an improvement in survival by several weeks.25 One of the outcomes for our patients was the secondary development of new tumors in other areas of the liver (Fig. 3), which is a natural progression for HCC in cirrhotic patients. Adjuvant therapy for our chemoradiation patients after ablative locoregional therapy has been completed and may be used to reduce the development of new sites of disease in the liver. In the future, a combination of these approaches may improve survival and quality of life for patients with HCC.
Conflict of Interest Disclosures
Tyvin A. Rich has received honoraria from Roche and is a member of the Capecitabine Speakers' Bureau.