Hideyuki Nishiofuku

Transcatheter Arterial Chemoembolization Using Cisplatin Powder Mixed with Degradable Starch Microspheres for Colorectal Liver Metastases after FOLFOX Failure: Results of a Phase I/II Study

PURPOSE To report the results of a phase I/II study of a transcatheter arterial chemoembolization protocol using cisplatin powder and degradable starch microspheres (DSM) for unresectable colorectal liver metastases after failure of FOLFOX (5-flourouracil, leucovorin plus oxaliplatin) chemotherapy conducted to determine the recommended dose of cisplatin powder and to assess the efficacy and safety of the protocol. MATERIALS AND METHODS A fine-powder formulation of cisplatin was mixed with DSM and administered via the hepatic artery every 4 weeks. In phase I, three cohorts of patients received escalating doses of cisplatin powder: 50 mg/m(2), 65 mg/m(2), and 80 mg/m(2). In phase II, tumor response, toxicity, and survival times were assessed. RESULTS The study enrolled 24 patients. Previously, FOLFOX had been administered to all patients, an irinotecan-containing regimen had been administered to 12 patients, and bevacizumab or cetuximab or both had been administered to 14 patients. In phase I, dose-limiting toxicity did not appear at any level, and the recommended dose of cisplatin powder was determined to be 80 mg/m(2). In phase II, a tumor response rate of 61.1% was achieved. The median hepatic progression-free survival and overall survival were 8.8 months (95% confidence interval [CI], 4.06-13.5 mo) and 21.1 months (95% CI, 8.37-33.8 mo). The following grade 3 toxicities were observed: thrombocytopenia (12.5%), aspartate transaminase elevation (33.3%), alanine transaminase elevation (12.5%), hyponatremia (8.3%), and cholecystitis (4.2%). CONCLUSIONS This study shows that transcatheter arterial chemoembolization with cisplatin powder at a dose of 80 mg/m(2) mixed with DSM is well tolerated and can produce a high response rate with a long survival time for patients with unresectable colorectal liver metastases after failure of FOLFOX.

Pharmacokinetics and Antitumor Efficacy of Chemoembolization Using 40 µm Irinotecan-Loaded Microspheres in a Rabbit Liver Tumor Model

PURPOSE To evaluate the pharmacokinetics and antitumor efficacy of 40 μm irinotecan-loaded drug-eluting microspheres (Embozene TANDEM Microspheres; CeloNova BioSciences, Inc, San Antonio, Texas) (TANDEM-IRI). MATERIALS AND METHODS The following three groups included eight VX2 rabbits each: group 1, full-loaded (50 mg irinotecan/1 mL TANDEM)/high-dose injection (1 mg irinotecan/kg); group 2, full-loaded (50 mg irinotecan/1 mL TANDEM)/low-dose injection (0.5 mg irinotecan/kg); and group 3, half-loaded (25 mg irinotecan/1 mL TANDEM)/low-dose injection (0.5 mg irinotecan/kg). Irinotecan and SN-38 in the plasma and tumors were measured within 72 hours. Histologic examinations were conducted on days 1, 3, and 7. RESULTS Serum irinotecan levels remained near the maximum concentration for 180 minutes after transarterial chemoembolization; in group 1, levels were 351.4 ng/mL at 30 minutes, 329.0 ng/mL at 60 minutes, and 333.5 ng/mL at 180 minutes. The area under the curve for 0-24 hours of irinotecan in group 1 was approximately two times higher than the same value in groups 2 and 3. High irinotecan and SN-38 concentrations in the tumors were measured at 24 hours and 72 hours. After transarterial chemoembolization, levels of liver enzymes aspartate aminotransferase and alkaline phosphatase were significantly higher in group 1 compared with groups 2 and 3. Histologic findings showed microspheres had deeply penetrated into tumors. Significantly higher tumor necrosis ratios were observed in groups 1 (86.6%-90.0%) and 3 (90.0%-100%) compared with group 2 (63.3%-70%) (P = .031 and P = .016). CONCLUSIONS Slow drug release with high drug concentration in tumors can be provided with 40 μm TANDEM-IRI. When complete arterial embolization is performed, the dose of irinotecan loaded on 40 μm TANDEM microspheres can be reduced while maintaining efficacy.

Guidelines on the use of gelatin sponge particles in embolotherapy

Gelatin sponge (GS) is one of the most widely used embolic agents in interventional procedures. There are four commercially available GS products in Japan; however, the endovascular use of Gelfoam and Spongel is off-label, and Gelpart can only be used for hepatic artery embolization and Serescue can only be used for hemostasis of arterial bleeding. GS has been used for a variety of clinical indications, mainly tumor embolization and stopping massive arterial bleeding. The optimal size and preparation procedure of GS particles differs slightly for each clinical indication. In addition, there is a risk of ischemic and/or infectious complications associated with GS embolization in various situations. Therefore, radiologists should be familiar with not only the preparation and handling of GS particles, but also the disadvantages and potential risks, in order to perform GS embolization safely and effectively.

Catheter Position for Adequate Intra-arterial Chemotherapy for Advanced Pancreatic Cancer: Evaluation with CT during Arterial Injection of Contrast Material

PURPOSE To identify the drug infusion vessel for use in obtaining the best drug distribution in arterial infusion chemotherapy for advanced pancreatic cancer. MATERIALS AND METHODS In 16 cases of advanced pancreatic cancer (pancreatic head, n = 12; pancreatic body and/or tail, n = 4), computed tomography during arterial injection of contrast material was performed at the time of angiography. The sites of catheter placement were celiac artery, superior mesenteric artery, and their branches, such as gastroduodenal artery, inferior pancreatico-duodenal artery, or dorsal pancreatic artery. RESULTS In the cases of pancreatic head cancer, all except one with hepatomesenteric vascular variation were supplied by the celiac artery and superior mesenteric artery (dual supply). In the cases of pancreatic body and/or tail cancer, two were supplied by celiac artery alone and two showed dual supply. In the cases of pancreatic head cancer, when the areas supplied by the main trunk were compared with those supplied by its branches, three of nine cases on the celiac artery side and four cases on the superior mesenteric artery side showed that the areas were not consistent, with a partial defect observed in the areas supplied by branches of the superior mesenteric artery. In the cases of pancreatic body and/or tail cancer, on both sides, one of two cases was not consistent. CONCLUSIONS To achieve optimal drug distribution in arterial infusion chemotherapy for advanced pancreatic cancer, drug infusion via both the celiac artery and superior mesenteric artery is required in the majority of cases. In many cases, optimal drug distribution is not attainable with drug infusion via a branch; therefore, drug infusion should be administered via the main trunk.

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.

Optimal indication of neoadjuvant chemoradiotherapy for pancreatic cancer.

PurposeMuch attention has been paid to preoperative treatment as a new strategy especially for borderline resectable pancreatic cancer (BRPC). The purpose of this study was to define the optimal indication of neoadjuvant chemoradiotherapy (NACRT) for pancreatic cancer.MethodsWe analyzed consecutive 184 patients who had undergone pancreatic resection in Nara Medical University Hospital. Resectability status was classified by NCCN guidelines. Full-dose gemcitabine with concurrent radiation was used as NACRT. We evaluated 85 patients treated with NACRT in comparison with 99 patients without NACRT as control.ResultsThe regimen of NACRT was well tolerated and feasible. The perioperative outcomes were almost comparable. The postoperative complications were significantly less frequent in NACRT group than non-NACRT group. The pathological effects on both resectable and borderline tumors were favorable in NACRT group compared to non-NACRT group. The overall survival of resectable pancreatic cancer was significantly better than that of BRPC regardless of whether the patients were treated with or without NACRT. The prognosis of the patients with NACRT in resectable tumors was significantly better than without, while there was no significant difference in BRPC. Furthermore, multivariate analysis of various factors in the patients with NACRT identified resectability status and completion of adjuvant chemotherapy as independent prognostic factors.ConclusionsNACRT did not improve the prognosis of the patients with BRPC, although it induced substantial pathological antitumor effect. In contrast, the prognosis of resectable pancreatic cancer treated with NACRT was favorable. Therefore, resectable pancreatic cancer may be good indication for multimodal treatment including NACRT.

Equivalent cross‐relaxation rate imaging of axillary lymph nodes in breast cancer

To determine whether equivalent cross‐relaxation rate (ECR) imaging (ECRI) is a feasible method for optimization of axillary lymph node dissection (ALND) and thereby improve quality‐of‐life (QOL).

Factors associated with failure to complete adjuvant chemotherapy in pancreatic cancer

BACKGROUND The importance of completing adjuvant chemotherapy in pancreatic cancer is becoming recognized. However, the clinicopathological factors associated with failure to complete adjuvant chemotherapy remain unclear. METHODS A total of 135 patients were analyzed to identify the factors associated with failure to complete adjuvant chemotherapy. RESULTS Ninety patients completed planned adjuvant chemotherapy, whereas 45 patients failed to complete adjuvant chemotherapy. Lower preoperative prognostic nutritional index, intraoperative blood transfusion, and organ and/or space surgical site infection, and advanced tumor stage were associated with failure to complete adjuvant chemotherapy. Neoadjuvant chemoradiotherapy was associated with significantly lower prognostic nutritional index, less incidence of organ and/or space surgical site infection, and earlier tumor stage, suggesting the conflicting effects of neoadjuvant chemoradiotherapy on completing adjuvant chemotherapy. CONCLUSIONS Several clinicopathological factors including patient conditions and perioperative events were associated with failure to complete adjuvant chemotherapy.

Pharmacokinetic Evaluation of Pancreatic Arterial Infusion Chemotherapy after Unification of the Blood Supply in an Animal Model

PURPOSE The purpose of this study was to investigate the potential pharmacokinetic advantage of pancreatic arterial infusion chemotherapy of 5-fluorouracil (5-FU) with temporary unification of the pancreatic blood supply for advanced pancreatic cancer in an animal model. MATERIALS AND METHODS Nine pigs were divided into three groups of three pigs each. 5-FU (20 mg/kg) was infused via jugular vein (group I), celiac artery (group II), and celiac artery with balloon occlusion of the superior mesenteric artery (SMA; group III). At 0, 10, 30, and 60 minutes after drug infusion, the concentrations of 5-FU were measured in plasma and tissues including the liver, pancreatic head, pancreatic uncinate process, and duodenum. Areas under the concentration-time curve (AUCs) were calculated and statistically compared. RESULTS The temporary unification of the pancreatic blood supply by converting from dual blood supply through the celiac artery and SMA into a single celiac arterial supply was confirmed by dye injection. Mean AUCs in the pancreas head and liver were significantly higher for groups II and III compared with group I (P < .05). In contrast, there were no significant differences in plasma 5-FU concentrations between groups. In addition, the AUC in the pancreatic uncinate process was significantly higher for group III compared with groups I and II (P < .05). CONCLUSIONS Pancreatic arterial infusion chemotherapy allows efficient regional drug delivery into the pancreas and liver. Importantly, the unification of the pancreatic blood supply may be required to induce maximum efficacy of arterial infusion chemotherapy for the tumor in the pancreatic uncinate process.

Unresectable Pancreatic Cancer: Arterial Embolization to Achieve a Single Blood Supply for Intraarterial Infusion of 5-Fluorouracil and Full-Dose IV Gemcitabine

OBJECTIVE Response rates to systemic chemotherapy for unresectable pancreatic cancer are low. The purposes of this phases 1 and 2 study of intraarterial therapy were to ascertain the recommended dose of intraarterial chemoinfusion and to evaluate the efficacy and safety of this therapy. SUBJECTS AND METHODS Pancreatic arteries originating from the superior mesenteric artery (the anterior and posterior inferior pancreaticoduodenal and the dorsal pancreatic) were embolized to achieve a single blood supply from the celiac artery to manage pancreatic cancer, and a catheter-port system was placed. Intraarterial 5-fluorouracil (5-FU) and IV gemcitabine (fixed dose of 1000 mg/m(2)) were administered. In phase 1, doses of 5-FU were increased from 750 to 1000 mg/m(2). In phase 2, tumor response, toxicity, and survival time were assessed. RESULTS A total of 20 patients were enrolled. In 19 patients (95%), the technique to unify the pancreatic blood supply was successful. No severe toxicity was observed with escalation of the 5-FU dose. The tumor response rate was 68.8%. The median overall survival time was 9.8 months and the progression-free survival time, 6.0 months. The grade 3 toxicities neutropenia (15.8%) and thrombocytopenia (5.3%) occurred. CONCLUSION In intraarterial administration of 5-FU at a dose of 1000 mg/m(2) combined with full-dose systemic gemcitabine for unresectable pancreatic cancer, the toxicity rate was acceptable, and response rate and survival time improved over those for treatment with gemcitabine alone.