Effective Strategy of the Combination of High-Intensity Focused Ultrasound and Transarterial Chemoembolization for Improving Outcome of Unresectable and Metastatic Hepatoblastoma: a Retrospective Cohort Study1

The combination of high-intensity focused ultrasound (HIFU) and transarterial chemoembolization (TACE) has been experimentally performed in a variety ofmalignant tumors, and its validity has not yet been evaluated for hepatoblastoma (HB). We evaluated the disease-response rate, resection rate, and toxicity in children with unresectable or metastatic HB (stage III and stage IVHB) after sequential treatmentwith TACE plusHIFU in a controlled clinical trial. The 35 patientswith unresectable or metastatic HB were nonrandomly assigned to HIFU ablation (n = 12) or C5V chemotherapy (n = 23). The rates of complete resection, tumor response, and treatment toxicitywere evaluated for both regimens. Nine patients who received C5V and 10 patients who received TACE plus HIFU became operable (P = .02). The 3-year event-free survival and overall survival rates were 43.03% and 56.68% in the C5V group and 38.57% and 57.86% in the TACE plus HIFUgroup, respectively. Acutegrade3or 4 adverseevents, includingneutropenia, thrombocytopenia, andanemia,were more frequent in patients treated with C5V therapy than in patients receiving TACE plus HIFU. HIFU ablation achieved a higher rate of complete resection and a lower rate of severe complications comparedwith C5V treatment in childrenwith advanced HB (Chinese Clinical Trials Registry No. ChiCTR-PRCH-08000182). Translational Oncology (2014) 7, 788–794 Address all correspondence to:ChunbaoGuoMD, PhD,Department of PediatricGeneral Surgery and Liver Transplantation, Children’s Hospital of ChongqingMedical University, 136 Zhongshan 2nd Rd, Chongqing, 400014, PR China. E-mail: [email protected] This research was supported by the National Natural Science Foundation of China (Nos 30973440 and 30770950) and key project of Chongqing Natural Science Foundation (CSTC, 2008BA0021 and cstc2012jjA0155). No potential conflict of interest relevant to this article was reported. Author contributions: J.C. and B.C. designed and analyzed the data and prepared the manuscript. Q.L. helped with designing the experiments, analyzing the data, and evaluating the manuscript. C.G. designed the experiments, analyzed the data, and wrote the paper. These authors contributed equally to this work. Received 16 August 2014; Revised 14 September 2014; Accepted 19 September 2014 © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). 1936-5233/14 http://dx.doi.org/10.1016/j.tranon.2014.09.006 Introduction Hepatoblastoma (HB) is the most common pediatric primary liver malignancy. The curative therapy for HB requires surgical resection. However, only half of newly diagnosed patients can be treated with surgery at initial presentation [1,2]. Metastatic and unresectable disease at diagnosis portends an extremely poor prognosis, and patients rarely achieve long-term survival with chemotherapy and aggressive surgical resection of all tumor sites [3,4]. Several clinical trials have shown that systemic chemotherapy effectively improves response and survival of patients with unresectable andmetastatic HB by reducing the incidence of local recurrence and ultimately increasing tumor resectability [5,6]. However, systemic therapy increases toxicity, and systemic chemotherapy regimensmust be stopped due to adverse events such as neutropenia and nephrotoxicity [7,8]. Previous studies have shown that the eventfree survival (EFS) of patients with unresectable disease remains Figure 1. Flow diagram of the enrollment, treatment, and outcome of the 35 patients with HB. *Six patients with TACE plus HIFU ablation and four patients treated with C5V refused surgery to remove the residual tumor. Translational Oncology Vol. 7, No. 6, 2014 Combination of HIFU and TACE for hepatoblastoma Chen et al. 789 unsatisfactory at approximately 50%. The survival of patients with metastatic disease is also unsatisfactory [9,10], and the relative resistance of this neoplasm to present therapeutic regimens suggests that new treatment approaches are required. It is possible that the current strategy of treatment must be redesigned. High-intensity focused ultrasound (HIFU) is an extracorporeal method used to treat primary solid tumors and metastatic disease [11–13]. Compared with conventional therapies, HIFU significantly reduces local, regional, and systemic side effects and provides additional therapeutic options in cases when conventional therapies fail [14,15]. Extracorporeal Magnetic Resonance (MR)-guided HIFU devices have been approved by the Food and Drug Administration (FDA) in the United States for the clinical treatment of uterine fibroids, and ultrasound-guided HIFU devices have also been used in Europe to treat both benign and malignant tumors after obtaining Conformite Europeenne (CE) approval [16,17]. Transarterial chemoembolization (TACE) is a widely used treatment for patients with large-volume solid tumors. TACE is usually used in combination with ablative therapies to exterminate residual tumor cells [18]. HIFU combined with TACE has been used empirically for many years, and a small number of retrospective, uncontrolled reports suggest benefits of this therapy [19].We previously performedHIFU combined with TACE to treat unresectable disease, including HB, at our institute [19]. In the current study, chemotherapy and TACE plus HIFU regimens were nonrandomly compared in patients with stage III and stage IV HB. Herein, we report the clinical features, tumor response, adverse events, and treatment outcomes for a cohort of patients from our institute with advanced pediatric HB treated by these regimens. Materials and Methods Patients From August 2006 to November 2011, there are 45 children with stage III and stage IV HB diagnosed in our institute. The patients were eligible for study inclusion if they were younger than 5 years old at diagnosis and had biopsy-proven HB that was either unresectable or metastatic at presentation and previously untreated. Among them, 10 cases were excluded because of lost to follow-up and more than 5 years old. The remaining 35 cases were included in this study. TheTACE plus HIFU ablation in our institute was initiated in March 2009, and 12 patients received HIFU and TACE treatment protocols. For chemotherapy, 23 patients were included from August 2006 to November 2011. A determination of serum alpha-fetoprotein (AFP) concentration values was mandatory at diagnosis. Human investigations were performed after approval by the Human Investigations Committee of ChongqingMedical University and in accordance with an assurance filed with and approved by the Department of Health andHuman Services of Chongqing Medical University. Open or closed surgical biopsy was also mandatory for obtaining an accurate diagnosis before chemotherapy, except for patients inwhom the surgical risk was considered unacceptable and unequivocal clinical findings had already been obtained (HBcompatible images and an elevated AFP level). The pretreatment assessment of the primary tumor was performed using abdominal ultrasonography and computed tomography (CT) with contrast medium, magnetic resonance imaging with contrast enhancement, or both methods. The presence of lung metastases was assessed by a chest X-ray (posteroanterior and lateral views) and lung CT scan. Infants with pure fetal HB at the initial biopsy were excluded because these tumors appear to have a different biology [20]. Study Design The study design details and requirements are described in Figure 1. After the diagnosis of HB, patients initially received two cycles of a modified C5V regimen (cisplatin: 100 mg/m per dose D1; 5-fluorouracil: 600 mg/m per dose D3; vincristine: 1.5 mg/m per dose D3) at 21-day intervals. Patients were then reevaluated for response and surgical resection after two courses of chemotherapy. If the tumor was considered to be unresectable, then the patients were divided to two treatment groups: the control group (n = 23), in which further four cycles of C5V chemotherapy were performed, and the TACE plus HIFU group (n = 12), which was suggested to undergo TACE plus HIFU ablation. A detailed description of the TACE plus HIFU treatment procedure was provided by Wang et al. [19] After the TACE plus HIFU treatments were completed, four C5V cycles were administered. Thus, each patient was scheduled to receive a maximum of six cycles of the C5V regimen. TACE Procedures TACE was performed in all patients before HIFU ablation. Depending on the tumor size, location, and arterial supply and its satellite lesions, the tumor-feeding arteries were selectively embolized using a 3-F to 5-F tracker catheter. Either 100 mg/m of carboplatin (Qilu Pharmaceutical Factory, Jinan, China) or 10 to 15 mg/m of adriamycin (Pfizer, Nerviano, Italy) was mixed in 3 to 8 ml of iodized oil (Lipiodol; Huaihai Pharmaceutical Factory, Shanghai, China), and the mixed suspension was slowly injected into the tumor-feeding arteries with fluoroscopic guidance. Embolization of the feeding arteries of all tumors was performed with the use of a 1 mm × 1 mm × 10 mm gelatin sponge (Gelfoam; 3rd Pharmaceutical Factory of Nanjing, Nanjing, China) in all patients after injecting the embolization suspension.