Consideration of role of radiotherapy for lymph node metastases in patients with HCC: Retrospective analysis for prognostic factors from 125 patients

Objectives: To evaluate the role of radiotherapy (RT) for hepatocellular carcinoma (HCC) patients with abdominal lymph node (LN) metastasis at our institution in the past 7 years.

Methods and Materials: We identified 125 patients with HCC metastasis to regional LNs treated with or without external beam RT (EBRT) between 1998 and 2004. Clinical characteristics collected included α-fetoprotein status, γ-glutamyltransferase, status of intrahepatic tumors (size and number), previous therapy for intrahepatic tumors, metastatic LN status (location, number, and size), tumor thrombi, and Child-Pugh classification. Of the 125 patients, 62 received local limited EBRT and were classified as the EBRT group. They received locoregional LN irradiation. The tumor dose ranged from 40 to 60 Gy in daily 2.0-Gy fractions, 5 times weekly. Another 63 patients, who did not receive EBRT, were selected from hospitalized patients in the same period and were classified as the non-EBRT group. The parameters studied included survival rates and tumor response to EBRT both as demonstrated by clinical symptoms and as seen on CT. The Kaplan-Meier method was used to evaluate the survival rates, and the Cox regression model was used to identify predictors of outcome.

Results: After EBRT, partial responses and complete responses were observed in 37.1% and 59.7% of patients, respectively. The median survival was 9.4 months (95% confidence interval 5.8–13.0) for the EBRT group and 3.3 months (95% confidence interval, 2.7–3.9) for the non-EBRT group (p < 0.001). Multivariate analysis showed that multiple intrahepatic primary tumors, occurrence of tumor thrombi, no therapy for intrahepatic tumors, and greater Child-Pugh classification were related to a poorer prognosis in all patients. In the EBRT group, the survival periods decreased as the distance of LN involvement from the liver increased (following the natural flow of lymph) and was also associated with the intrahepatic primary tumor size. The incidence of death resulting from LN-related complications was lower in the EBRT group.

Conclusion: Lymph node metastasis from HCC is sensitive to EBRT. EBRT with 25 fractions of 2 Gy is an effective palliative treatment for patients with LN metastases from HCC presenting with good performance status and may prolong overall survival.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although most prevalent in Southeast Asia and Africa, its incidence in Western countries is increasing (1). Surgical resection has been considered the treatment of choice for long-term control of the disease. However, <20% of patients are surgical candidates at diagnosis (2). Nonsurgical treatments, such as transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection therapy, have achieved a survival benefit for unresectable HCC (3). The aim of palliative treatments for patients with unresectable HCC is to prolong survival and relieve symptoms.

Most HCCs are restricted to the liver. The spread of most HCCs is hematogenous, and regional lymph node (LN) metastasis is uncommon. The incidence of LN involvement in patients with HCC was reportedly between 1.6% and 5.9% during treatment (4, 5), but the incidence was as great as 25.5% and 32.9% in autopsy cases (6, 7). Because LN involvement is not rare in autopsy cases, in patients with unresectable disease, the LN status has generally been neglected. Also, death resulting from LN involvement is usually caused by local mechanical obstruction, which is difficult to distinguish from liver failure caused by intrahepatic tumor. Figure 1 presents four common lethal patterns of metastatic LNs from HCC as summarized from our institute. Jaundice is often induced by biliary obstruction, pyloric (or duodenal) obstruction results in abdominal pain, and inferior vena cava obstruction is usually followed by ascites and edema of the lower extremities. HCC patients occasionally develop motility (paralysis) intestinal obstruction, the cause of which is probably compression of the celiac nerve plexus.

Lymph node metastasis is a rare clinical situation but may be more frequent in the future with the development of diagnostic imaging, the increasing incidence of HCC, and more effective local treatments, such as surgical resection, TACE, and percutaneous ethanol injection. These therapies lead to prolonging survival (8).

The patients with LN metastasis from HCC have a poor prognosis, even if they undergo radical resection by experienced surgeons (9, 10, 11). The survival in patients treated with resection was quite variable, ranging from 2 to 87 months (10). This is because LN involvement is generally not the limiting factor in determining symptoms or survival in HCC patients—both of which relate more to hepatic parenchymal involvement or distant metastatic diseases. TACE and percutaneous ethanol injection are not suitable for HCC patients with LN involvement. Some patients undergo palliative therapy, such as biliary decompression using self-expanding metal stents, to relieve obstructive jaundice, but obstruction commonly recurs in ≤6 months because of tumor ingrowth and biliary sludge (12). External beam radiotherapy (EBRT) has been attempted for these patients, but only 4 HCC patients with abdominal LN involvement were treated with EBRT in two reports (13, 14), which were published 10 years apart. The role of radiotherapy for LN metastasis from HCC and its prognostic factors are unclear. Therefore, we decided to evaluate the role of RT for HCC with abdominal LN metastasis at our institution in the past 7 years.

We report the preliminary results for 62 HCC patients with abdominal LN metastasis who received EBRT and compare them with 63 HCC patients with abdominal LN metastasis treated without EBRT in the same period. We also provide dose–response information regarding EBRT use in HCC patients.