¹³¹I-metuximab injection (Licartin; Chengdu Hoist Hitech Co. Ltd., Chengdu, China) is an ¹³¹I-labeled HAb18 F(ab’)2 fragment of murine mAb against the HCC-associated antigen HAb18G/CD147. Before metuximab therapy, 0.5 mL of iodine solution should be taken orally tid for 3 d and continued for 7 d after treatment for thyroid protection. A vial of ¹³¹I-metuximab injection solution that had been prepared at the standard dose of 0.75 mCi/kg was removed from a lead box containing ice at a temperature of 0 °C. The thawed solution was diluted with 1 mL of saline and sucked into a 5-mL syringe for arterial injection.

One hundred and eighty-five patients (159 men and 26 women, aged 12-87 years) with advanced unresectable HCC were enrolled in this study from February 2009 to July 2011. Patients with a Karnofsky Performance Score (KPS) < 60 or severe heart, kidney of hematological disease were excluded to ensure at least a 3-mo lifespan in the enrolled patients, so as to have enough time for follow-up. Patients with a history of allergy to biological products, pregnant or breast-feeding women, or patients receiving other therapies within 4 wk of the clinical trial were also excluded. All patients in our study gave written informed consent. Patients in the test group underwent ¹³¹I-metuximab therapy and TACE while those in the control group received TACE only. The patients received local ethanol injection, microwave coagulation, resection or liver transplantation before and after TACE or ¹³¹I-metuximab therapy if needed. All tumors were diagnosed according to pathological examination or distinctive findings on computed tomography (CT), conventional angiography, magnetic resonance imaging (MRI), or serum tumor markers [α-fetoprotein (AFP)].

TACE and ¹³¹I-metuximab injection were performed through the femoral artery using the Seldinger technique with local anesthesia. Arteriography of the celiac trunk and superior mesenteric artery was performed to visualize the arterial vascularization of the liver and evaluate portal vein patency, and anticancer drugs were injected. The angiographic catheter was superselected into the hepatic artery where the target tumor was located. An embolic agent (mainly Lipiodol) was continuously injecting through the artery until the rate of blood flow to the tumor mass fell below 25%, or minimal hepatic vein appeared to protect the liver tissues around the tumor so that Licartin is more liable to stay in tumor tissues by minimizing the effect of quick or slow blood flow. Patients in the test group underwent ¹³¹I-metuximab therapy immediately after TACE. At each injection, ¹³¹I-metuximab was administered at a dose of 0.75 mCi/kg according to the patient’s weight and the intra-arterial injection usually lasted 1-2 min. Patients in the control group received TACE only. In both groups, the dose of Lipiodol, ranging from 3-20 mL, was determined according to the size and number of tumors and functional hepatic reserve. Anticancer drugs for each patient enrolled in this trial were 5-fluorouracil (800-1000 mg) and epirubicin-adriamycin (30-40 mg) according to the body surface area. Therapy for patients in both groups was repeated according to the patient’s clinical condition and the iconography exams at a 1-6-mo interval.

Clinical symptoms, blood cell counts and KPS evaluation were recorded before and after treatment. After treatment, ultrasound, CT scan or MRI was performed every 1-3 mo, with or without contrast enhancement, to evaluate the features of Lipiodol deposit and the therapeutic effect according to the Response Evaluation Criteria in Solid Tumors (RECIST). If elevated tumor marker (AFP), diminished Lipiodol, enlarged lesions or new nodules were observed, the patients were readmitted for angiography and treatment. The starting point of survival analysis was regulated as the day of initial treatment. The Kaplan-Meier method was used to analyze the survival rates in the two groups.

The primary endpoint of this study was overall survival and the secondary endpoint was short-term (1 mo) treatment response. Survival analysis was estimated by the Kaplan-Meier method. Survival probabilities were estimated using the life-table method, and between-group differences in survival rates were compared using the log-rank test. All statistical analyses were carried out with SPSS version 17.0 (SPSS, Chicago, IL, United States). All reported P values were two-sided, with P < 0.05 considered statistically significant.

The patients were divided into the test group (n = 95) with a mean age of 50.2 years (range: 22-80 years) and the control group (n = 90) with a mean age of 51.4 years (range: 12-87 years). All the patients in this trial were classified as Barcelona Clinic Liver Cancer Stage C. Both the test group and control group had a high percentage of patients (89.47% and 85.56%, respectively) with a tumor/liver volume ratio > 50%. Thus, the patients enrolled in this clinical trial had advanced HCC. Although this was a nonrandomized prospective cohort study, no significant difference was observed in baseline characteristics between the two groups (Table 1).

The patients were followed for 12 mo. At the time of analysis, 46 and 80 patients had died while 14 and zero were lost to follow-up in the test and control groups, respectively. Causes of death in the test and control groups included tumor progression in 46 and 72 patients, digestive tract hemorrhage in zero and four, tumor rupture in zero and one, acute renal failure in zero and one, and other causes in zero and two, respectively; none was possibly related to treatment.

Two hundred and forty-one (mean: 2.56 procedures) and 261 (mean: 2.90 procedures) procedures of interventional therapy were performed in the test and control groups, respectively. Arterial portal vein shunt (AVS), arterial hepatic vein shunt (APS) and/or portal vein involvement, which indicate high invasion and poor prognosis were found in 35.79% (34/95) of patients in the test group and 33.3% (30/90) of patients in the control group. No difference was observed in the time of therapy and the incidence of malignancy signs such as AVS, APS or portal vein involvement between the two groups.

The clinical symptoms were carefully recorded after treatment (Table 2). Overall, although ¹³¹I-metuximab in combination with TACE was well tolerated, the patients in the test group obviously suffered more frequent adverse events than those in the control group. The most frequent adverse event in the test group was abdominal pain. Of the 95 patients in the test group, 93 (97.89%) suffered from abdominal pain, 90 (94.74%) had fever of 37.2 °C-40 °C, which usually occurred 0.5-10 h after ¹³¹I-metuximab injection and lasted for 1-14 d, and 74 (77.89%) had anorexia and/or vomiting, which often faded away in several days. The corresponding numbers of patients in the control group were 19 (21.11%), 28 (31.11%) and 16 (17.78%) (P < 0.001). The changes in blood cell count and liver function before and 1 mo after treatment were evaluated. Statistical analysis showed that the changes in leukocytes and platelets were significant. Changes in total bilirubin, albumin, aspartate aminotransferase, alanine transaminase and hemoglobin were not significant (Table 3).

One patient in the test group had hypothyroidism and was prescribed oral thyroxin, and one sudden death occurred in the control group, possibly because of liver rupture. No human anti-murine antibody immune responses, anaphylactic reaction and changes in myocardial zymograms were observed.

The palliative rate of mass-associated pain 1 mo after treatment was 71.1% (27/38) for patients in the test group, which was higher than that in the control group (31.6%, 24/76) (P = 0.014). For changes in KPS, the patients in the test group had a greater increase than those in the control group (P < 0.001, Table 3). The therapeutic effect was evaluated following the RECIST after treatment. Rates of complete response (CR), partial response (PR), stable disease (SD) and progressive disease in the two groups are listed in Table 4. The total effective rates (CR + PR + SD) were 71.23% and 38.89% for the test group and control group, respectively. Wilcoxon rank sum test showed that the therapeutic effects in the two groups were significantly different (P < 0.001). The survival rates at 6, 9 and 12 mo after treatment were 86.42%, 74.07% and 60.49% in the test group, and 60.0%, 42.22% and 34.44% in the control group, suggesting that the survival rates for the test group were significantly higher than for the control group (P < 0.001, Figure 1).

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Figure 1 Kaplan-Meier curves of survival of patients in the test group receiving combination therapy (Licartin) and those in the control group receiving transcatheter arterial chemoembolization only (P < 0. 001). TACE: Transcatheter arterial chemoembolization.

Transcatheter arterial chemoembolization (TACE) is currently one of the widely used treatment modalities for unresectable advanced hepatocellular carcinoma (HCC). However, the long-term survival rate of such patients remains poor. At the same time, ¹³¹I-metuximab monotherapy has been shown to be effective, both in the treatment of HCC and in the prevention of HCC recurrence after orthotopic liver transplantation. However, its efficacy in combination with TACE has seldom been tested. Theoretically, TACE can enhance the antitumor effects of ¹³¹I-metuximab, because of substantially reducing blood flow to the tumor, which prolongs retention of ¹³¹I-metuximab in the tumor tissues.

¹³¹I-metuximab (Licartin) has high affinity with a target antigen highly expressed on HCC cells and has a limited area of action. The combination of ¹³¹I-metuximab and chemoembolization has a synergistic effect in the treatment of HCC. It may especially benefit patients with multiple nodules who always have a high tumor/liver volume ratio.

It is commonly accepted that HCC patients with countable nodules often have better outcome than patients with countless lesions. At present, patients with multiple lesions still have a poor prognosis and lack of efficient therapeutic modalities. However, in our trial, they managed to treat the same types of patients with ¹³¹I-metuximab combined with TACE and prolonged their lifespan significantly. This improvement was more notable than in earlier similar trials. The combination of ¹³¹I-metuximab and TACE had an extensive range of therapeutic function, especially for advanced liver cancer with wide metastasis and multiple lesions. Combination therapy may greatly improve the treatment efficacy in these patients and extend their poor life expectancy.

Radioimmunotherapy combined with TACE may provide a new concept in radiotherapy for patients with HCC.

The authors performed a study on 185 patients (159 men and 26 women) with advanced HCC. The data indicate that combination of ¹³¹I-metuximab with TACE was safe and more effective than TACE alone. The title of the paper accurately reflects the content of the article. The abstract contains a short description of the study. The abstract and article are written in accordance with the journal requirements. The introduction gives sufficient information about the research objectives. It is important that authors state their motivation to conduct this investigation. The design of the study is simple and understandable.