Takeshi Aramaki

Radiologic placement of side-hole catheter with tip fixation for hepatic arterial infusion chemotherapy.

PURPOSE To investigate the technical outcome of radiologic catheter placement with use of a side-hole catheter with distal fixation for hepatic arterial infusion chemotherapy. MATERIALS AND METHODS Between January 1993 and September 1999, 426 patients were referred to our department to undergo intraarterial infusion chemotherapy for unresectable malignant liver tumors. A subclavian artery was exposed under local anesthesia and a catheter was inserted. After inserting the tip of the side-hole catheter into the gastroduodenal artery, splenic artery, or peripheral branch of the hepatic artery, the catheter tip was fixed to the vessel with use of coils and a mixture of n-butyl cyanoacrylate (NBCA) and iodized oil. The proximal end of the catheter was connected to an implanted port, and the port system was embedded subcutaneously. RESULTS Placement was successful in 425 of 426 patients (99.8%) in a mean time of 76 minutes. Catheter dislodgement was noted in 12 patients (2.8%). Cumulative patency rates of the hepatic artery calculated according to the Kaplan-Meier method for the entire group were 91.0%, 81.4%, and 58.1% at 6 months and 1 and 2 years, respectively. Complications related to catheter placement were observed in nine cases and included dysfunction of the implanted system (n = 3), significant bleeding around the implanted port (n = 2), improper infusion of NBCA and iodized oil (n = 2), and cerebral infarction (n = 2). CONCLUSION Radiologic catheter placement via a subclavian artery with side-hole catheter placement with distal fixation for hepatic arterial infusion chemotherapy is a highly successful procedure with a reduced risk of catheter dislodgment and arterial occlusion.

Right Gastric Artery Embolization to Prevent Acute Gastric Mucosal Lesions in Patients Undergoing Repeat Hepatic Arterial Infusion Chemotherapy

PURPOSE The purpose of the study was to investigate the technical outcome and clinical effect of right gastric artery (RGA) embolization to prevent acute gastric mucosal lesions caused by influx of anticancer agents into the RGA in patients undergoing repeat hepatic arterial infusion chemotherapy (HAIC). MATERIALS AND METHODS In 217 patients with malignant hepatic tumors, we attempted RGA embolization with use of metallic coils and/or a mixture of n-butyl cyanoacrylate (n-BCA) and iodized oil, along with the embolization of the gastroduodenal artery. After this procedure, an infusion catheter was placed radiologically and HAIC was performed. We then evaluated the technical outcome and clinical effect of RGA embolization. RESULTS RGA embolization was technically successful in 201 of 217 patients (93%). Major complications--nausea, epigastric pain, and fever--were noted in 12%, 4%, and 2% of successful cases, respectively, and were treated conservatively. Recanalization occurred in 4% (nine of 201) of the patients. Eventually, sufficient RGA embolization was achieved in 192 patients. The incidence of acute gastric mucosal lesions confirmed endoscopically was only 3% (five of 192) in patients with sufficient RGA embolization, whereas it was 36% (nine of 25) in patients without sufficient RGA embolization, with a significant difference (P <.01). CONCLUSION RGA embolization is a highly feasible procedure that can reduce the incidence of acute gastric mucosal lesions associated with HAIC.

Prospective Study of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: An Asian Cooperative Study between Japan and Korea

PURPOSE To evaluate the safety and efficacy of transcatheter arterial chemoembolization used for the treatment of unresectable hepatocellular carcinoma (HCC) with an Asian cooperative prospective study between Japan and Korea. MATERIALS AND METHODS Patients with unresectable HCC unsuitable for curative treatment or with no prior therapy for HCC were enrolled. The patients underwent transcatheter arterial chemoembolization with emulsion of Lipiodol and anthracycline agent, followed by embolization with gelatin sponge particles, which was repeated on an as-needed basis. The primary endpoint was 2-year survival rate, and the secondary endpoints were adverse events and response rate. RESULTS The 2-year survival rate of 99 patients was 75.0% (95% confidence interval, 65.2%-82.8%). The median time-to-progression was 7.8 months, and the median overall survival period was 3.1 years. Of 99 patients, 42 (42%) achieved a complete response, and 31 (31%) had a partial response. The response rate was 73% using modified Response Evaluation Criteria in Solid Tumors. The grade 3-4 toxicities included increased alanine aminotransferase level in 36%, increased aspartate aminotransferase level in 35%, thrombocytopenia in 12%, and abdominal pain in 4% of patients. All other toxicities were generally transient. CONCLUSIONS Asian transcatheter arterial chemoembolization demonstrated sufficient safety and reasonable efficacy as a standard treatment for unresectable HCC. These results could be useful as reference data for future trials of transcatheter arterial chemoembolization.

A randomised phase II study of TSU-68 in patients with hepatocellular carcinoma treated by transarterial chemoembolisation.

BACKGROUND TSU-68 is an antitumour drug that acts by inhibiting angiogenesis. We evaluated the efficacy and safety of TSU-68 in combination with transarterial chemoembolisation (TACE) in patients with intermediate-stage hepatocellular carcinoma (HCC). PATIENTS AND METHODS In this multicenter, open-label phase II study, we randomised patients with HCC who had been treated with a single session of TACE to receive either 200mg TSU-68 twice daily or no medication. The primary end-point was progression-free survival (PFS). RESULTS A total of 103 patients were enrolled. Median PFS was 157.0days (95% confidence interval [CI], 124.0-230.0days) in the TSU-68 group and 122.0days (95% CI, 73.0-170.0days) in the control group. The hazard ratio was 0.699 (95% CI, 0.450-1.088). Fatigue, elevated aspartate aminotransferase (AST), elevated alkaline phosphatase, oedema and anorexia were more frequent in the TSU-68 group than in the control group. The most frequent grade 3/4 adverse events were AST elevation (46% of patients in the TSU-68 group and 12% of controls) and alanine aminotransferase elevation (26% of patients in the TSU-68 group and 8% of controls). Two deaths, grade 5 hepatic failure and melena were noted in the TSU-68 group. CONCLUSION This exploratory study shows a trend towards prolonged PFS with TSU-68 treatment after a single session of TACE, but this observation was not statistically significant. The two deaths were related to the study treatment. These results suggest that further examination of the study design is necessary to determine whether TSU-68 has any clinical benefits when combined with TACE.

Phase I study of tivantinib in Japanese patients with advanced hepatocellular carcinoma: Distinctive pharmacokinetic profiles from other solid tumors.

A c‐Met inhibitor tivantinib is a candidate anticancer agent for patients with hepatocellular carcinoma (HCC), and CYP2C19 is the key metabolic enzyme for tivantinib. Previous Japanese phase I studies in patients with solid tumors (except HCC) recommend 360 mg twice daily (BID) and 240 mg BID for CYP2C19 extensive metabolizers (EM) and poor metabolizers (PM), respectively. In this study, Japanese patients with HCC in whom sorafenib treatment has failed were enrolled to evaluate the safety, tolerability and pharmacokinetics of oral tivantinib as a single agent. The dose was escalated separately in EM and PM, from 120 mg BID to 240 mg BID, in both capsule and tablet formulations. A total of 28 patients (EM: 21, PM: 7) received tivantinib. At a dose of 120 mg BID, dose‐limiting toxicities (DLT) did not develop in 12 EM (capsule: 6, tablet: 6) and 7 PM (capsule: 4, tablet: 3) during the DLT‐observation period (for 29 days after first dosing). At this dose, the pharmacokinetic profiles of tivantinib (AUC0–12 and Cmax) did not remarkably differ between EM and PM. When treated with 240 mg BID, 5 of 9 EM (capsule: 4 of 6, tablet: 1 of 3) developed neutropenia‐related DLT accompanying plasma tivantinib concentration higher than expected from the previous studies. Consequently, PM did not receive 240 mg BID. In conclusion, 120 mg BID of tivantinib is recommended among Japanese patients with HCC regardless of CYP2C19 phenotype.

Hepatic Arterial Infusion of 5-Fluorouracil for Patients With Liver Metastases From Colorectal Cancer Refractory to Standard Systemic Chemotherapy: A Multicenter, Retrospective Analysis

INTRODUCTION This retrospective study evaluated the safety and efficacy of hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU) for patients with liver metastases from colorectal cancer refractory to standard systemic chemotherapy. PATIENTS AND METHODS Fifty-five patients who had shown disease progression during the prior standard systemic chemotherapy with oxaliplatin, irinotecan, and 5-FU were enrolled. The treatment was weekly HAIC with 5-FU 1000 mg/m2/5 hours through an indwelling catheter-port system. RESULTS No major adverse reaction was observed other than grade 3 leukocytopenia (3.6%) and hyperbilirubinemia (1.8%). The overall response rate and disease control rate were 18.2% and 70.9%, respectively. The median progression-free survival and median overall survival (OS) were 2.8 months, and 6.7 months, respectively. The initial sites of disease progression were liver in 14, other than liver in 27, and both in 6. Multivariate analysis identified Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1 and number of extrahepatic metastatic sites (NMS) ≤ 1 as favorable prognostic factors for OS (hazard ratio [HR], 8.277; 95% CI, 3.60-19.0; P = .000 for ECOG PS; and HR, 2.456; 95% CI, 1.30-4.61; P = .005 for NMS). CONCLUSION HAIC with 5-FU may be a safe and effective treatment for patients with colorectal liver metastases refractory to standard systemic chemotherapy.

Phase I/II Study of Radiologic Hepatic Arterial Infusion of Fluorouracil Plus Systemic Irinotecan for Unresectable Hepatic Metastases from Colorectal Cancer: Japan Clinical Oncology Group Trial 0208-DI

PURPOSE Treatment of patients who have metastatic colorectal cancer (CRC) by using a combination of hepatic arterial infusion chemotherapy (HAIC) and systemic chemotherapy has resulted in promising clinical outcomes. Additionally, image-guided HAIC is reported to be less invasive and distribute drugs more accurately than surgical HAIC. The purpose of this study was to assess the combination of image-guided delivery of fluorouracil through HAIC and systemic irinotecan in a multicenter phase I/II study. MATERIALS AND METHODS Twenty-five patients with unresectable liver metastases from CRC were fitted with hepatic arterial catheter and port systems by using image-guided methods. Intraarterial fluorouracil (1,000 mg/m(2)) was administered on days 1, 8, and 15 of each treatment cycle. The dose of systemic irinotecan on days 1 and 15 was escalated from 75 mg/m(2). RESULTS No dose-limiting toxicity was encountered during phase I, and the recommended dose of irinotecan was set at 150 mg/m(2). Grade 3 or higher adverse events included hyperglycemia (15%), elevated γ-glutamyl transpeptidase levels (15%), and neutropenia (9%). The response rate and median survival time were 72% and 49.8 months (95% CI, 27.5-78.1 mo), respectively. CONCLUSIONS The combination of image-guided delivery of fluorouracil through HAIC and systemic irinotecan yielded favorable safety, response rate, and survival results. This combination should be evaluated in a large study.

Comparison of epirubicin hydrochloride and miriplatin hydrate as anticancer agents for transcatheter arterial chemoembolization of hepatocellular carcinoma.

The aim of this retrospective study was to compare the local control effects of transcatheter arterial chemoembolization (TACE) using epirubicin (EPIR) and that using miriplatin (MPT) for hepatocellular carcinoma (HCC).

Phase I/II Multicenter Study of Transarterial Chemoembolization with a Cisplatin Fine Powder and Porous Gelatin Particles for Unresectable Hepatocellular Carcinoma: Japan Interventional Radiology in Oncology Study Group Study 0401

PURPOSE A multicenter phase I/II study of transarterial chemoembolization with a fine cisplatin powder and gelatin particles (GPs) for multifocal hepatocellular carcinoma (HCC) was conducted. Primary endpoints were dose-limiting toxicity (DLT) and recommended dose (RD). Secondary endpoints were the incidence and severity of adverse events and tumor response. MATERIALS AND METHODS Nonselective transarterial chemoembolization was performed until all tumor enhancement disappeared. Lipiodol was not used. In the phase I study, the cisplatin dose was escalated from 35 mg/m(2) to 65 mg/m(2) in 15-mg/m(2) increments to determine DLT and RD. In the phase II study, 40 patients were treated with the RD. Toxicity was assessed by Common Toxicity Criteria for Adverse Effects (version 3.0), and tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST; version 1.0) and European Association for the Study of the Liver (EASL) criteria. RESULTS A total of 46 patients were enrolled. As no DLT occurred at any dose level in the phase I study, RD was determined as 65 mg/m(2). In the phase II study, the treatment was discontinued in one patient as a result of vasovagal response. Toxicities of grade 3 or higher included nausea (2.2%), pancreatitis (2.2%), cholecystitis (2.2%), thrombocytopenia (8.7%), hyperbilirubinemia (2.2%), and increased aspartate aminotransferase (28.3%) and alanine aminotransferase (21.7%) levels. Tumor response rates under RD were 25.6% and 64.1% by RECIST and EASL criteria, respectively. CONCLUSIONS Nonselective transarterial chemoembolization with fine cisplatin powder and GPs was well tolerated and effective in patients with multifocal HCC at the RD of 65 mg/m(2).

Transcatheter arterial embolization for external iliac artery hemorrhage associated with infection in postoperative pelvic malignancy

Transcatheter arterial embolization was attempted for external iliac artery (EIA) hemorrhage in five patients with wound infection after pelvic malignant tumor surgery. To prevent distal migration of coils and to preserve distal branches of the EIA, the entire weakened artery was occluded with use of coils via a bilateral femoral artery approach with balloon occlusion of the distal side. The success rate was 100%. No limb loss was observed immediately after embolization. This method can prevent distal migration of coils and preserve branches that can be collaterals to the femoral artery, and as such it can be used to embolize an adequate portion of the affected artery.