Preoperative percutaneous needle indigo carmine and lipiodol mixture marking in lung segmentectomy.

OBJECTIVES: For successful nodule localization and appropriate surgical margin distances in pulmonary segmentectomy for patients with lung malignancies, the effectiveness and feasibility of preoperative marking using an indigo carmine and lipiodol mixture remain unclear. METHODS: Patients who underwent thoracoscopic pulmonary segmentectomy with (marking group, n = 69) and without (non-marking group, n = 265) preoperative marking at our institution from January 2013 to March 2020 were retrospectively reviewed and compared in terms of surgical outcomes. All markings were performed using a fine needle to percutaneously inject an indigo carmine and lipiodol mixture under the guidance of computed tomography fluoroscopy. RESULTS: Successful localization was achieved in 66 (96%) patients, of whom 62 (94%) underwent dye pigmentation and 4 (6%) underwent intraoperative fluoroscopy. On images, the marking group showed a significantly longer distance between the lung surface and tumour [mm, 9 (1-17) vs 0 (0-10); P < 0.01] and smaller maximum tumour size [mm, 16 (11-21) vs 17 (13-23); P = 0.03] and consolidation tumour ratio [0.4 (0.3-1) vs 0.8 (0.4-1); P < 0.01] than the non-marking group. Both groups had comparable operative outcomes, perioperative complications, pulmonary function changes and surgical margin distances [mm, 20 (15-21) vs 20 (15-20); P = 0.96] without any local recurrence on the surgical margin. Propensity score-matching analysis also showed similar findings for both groups. CONCLUSIONS: Thoracoscopic pulmonary segmentectomy with preoperative marking using an indigo carmine and lipiodol mixture may be an acceptable therapeutic option for small malignancies located in deep lung parenchyma.

REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset.

BACKGROUND: A phase 3, multinational, randomized, non-inferiority trial (REFLECT) compared the efficacy and safety of lenvatinib (LEN) and sorafenib (SOR) in patients with unresectable hepatocellular carcinoma (uHCC). LEN had an effect on overall survival (OS) compared to SOR, statistically confirmed by non-inferiority [OS: median = 13.6 months vs. 12.3 months; hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.79-1.06], and demonstrated statistically significant improvements in progression-free survival (PFS) and the objective response rate (ORR) in the overall population. The results of a subset analysis that evaluated the efficacy and safety of LEN and SOR in the Japanese population are reported. METHODS: The intent-to-treat population enrolled in Japan was analyzed. RESULTS: Of 954 patients in the overall population, 168 Japanese patients were assigned to the LEN arm (N = 81) or the SOR arm (N = 87). Median OS was 17.6 months for LEN vs. 17.8 months for SOR (HR 0.90; 95% CI 0.62-1.29). LEN showed statistically significant improvements over SOR in PFS (7.2 months vs. 4.6 months) and ORR (29.6% vs. 6.9%). The relative dose intensity of LEN and SOR in the Japanese population was lower than in the overall population. Frequently observed, related adverse events included palmar-plantar erythrodysaesthesia syndrome (PPES), hypertension, decreased appetite, and proteinuria in the LEN arm, and PPES, hypertension, diarrhea, and alopecia in the SOR arm. CONCLUSIONS: The efficacy and safety of LEN in the Japanese population were similar to those in the overall population of REFLECT. With manageable adverse events, LEN is a new treatment option for Japanese patients with uHCC. TRIAL REGISTRATION ID: ClinicalTrials.gov. No. NCT01761266.

The Utility of Indigo Carmine and Lipiodol Mixture for Preoperative Pulmonary Nodule Localization before Video-Assisted Thoracic Surgery.

PURPOSE: To evaluate the safety and efficacy of a mixture of indigo carmine and lipiodol (MIL) as a marker of pulmonary nodule before video-assisted thoracic surgery (VATS). MATERIALS AND METHODS: One hundred sixty-eight sessions of pulmonary marking were performed using MIL before VATS for 184 nodules (mean size, 1.2 ± 0.6 cm; range, 0.3-3.6 cm) on 157 patients (83 men and 74 women; median age, 66 years). The mean distance between the lung surface and the nodule was 0.8 ± 0.7 cm (range, 0-3.9 cm). MIL was injected near the nodule using a 23-gauge needle. Mean number of 1.2 ± 0.4 (range, 1-3) punctures were performed in a session for the target nodules, with mean number of 1.1 ± 0.3 (range, 1-3). Successful targeting, localization, and VATS were defined as achievement of lipiodol accumulation at the target site on computed tomography, detection of the nodule in the operative field by fluoroscopy or visualization of dye pigmentation, and complete resection of the target nodule with sufficient margin, respectively. RESULTS: The successful targeting rate was 100%, and the successful localization rate was 99.5%, with dye pigmentation for 160 nodules (87.0%) and intraoperative fluoroscopy for 23 nodules (12.5%). Successful VATS was achieved for 181 nodules (98.4%). Two nodules (1.1%) were not resectable, and surgical margin was positive in 1 nodule (0.5%). Complications requiring interventions occurred in 5 sessions (3.0%) and included pneumothorax with chest tube placement (n = 3) and aspiration (n = 2). No complication related to the injected MIL occurred. CONCLUSIONS: MIL was safe and useful for preoperative pulmonary nodule marking.

Phase II Trial of Transarterial Embolization Using an n-Butyl-2-Cyanoacrylate/Lipiodol Mixture (JIVROSG-0802).

PURPOSE: To evaluate the embolic effect and the safety of transarterial embolization (TAE) using n-butyl-2-cyanoacrylate (NBCA) in a prospective multicenter trial. MATERIALS AND METHODS: This study was an open-label, multicenter, phase II trial. The inclusion criteria were (1) active bleeding or pseudoaneurysm, (2) true aneurysm, (3) arteriovenous malformation (except cerebral lesion), (4) arteriovenous fistula, or (5) need for arterial distribution before transarterial treatment. Selective TAE with NBCA diluted 2-10 times was performed. The primary endpoint was the success rate of embolization with a per-patient analysis based on the angiographic findings. Secondary endpoints were safety, evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) version 4, and the success rate of embolization with a per-vessel calculation. RESULTS: Sixty-five patients were initially enrolled, but due to protocol violation in two patients, efficacy was ultimately analyzed in 63 patients (103 vessels) and safety was analyzed in 64 patients. The success rate per patient was 98.4% (62/63; 95% confidence interval (CI), 91.5-100.00), and the success rate per vessel was 99.0% (102/103; 95% CI, 94.7-100.0). Adverse events of grade 3 or above based on CTCAE version 4 occurred in 22/64 patients (34.4%). Twelve intraoperative or postoperative adverse events grade 3 or above, which may have been related to embolization using NBCA, occurred in 11/64 patients (17.2%). Three patients died after embolization using NBCA, but their deaths were unrelated to TAE. CONCLUSION: In this prospective multicenter clinical trial, the efficacy of TAE using NBCA was 98.4% and adverse events were clinically acceptable. LEVEL OF EVIDENCE: Level 3b.

Equivalent cross-relaxation rate imaging and diffusion weighted imaging for early prediction of response to bevacizumab-containing treatment in colorectal liver metastases-preliminary study.

PURPOSE: To evaluate and compare the usefulness of equivalent cross-relaxation rate (ECR) imaging (ECRI) and diffusion-weighted imaging (DWI) in the early prediction of the response of bevacizumab-containing treatments of colorectal liver metastases. METHODS AND MATERIAL: Seven patients received bevacizumab-containing treatments for colorectal liver metastases. Serial magnetic resonance imaging was performed to evaluate responses before and 2 weeks after starting chemotherapy. In the ECRI, we adopted the off-resonance technique for preferential saturation of immobile protons to evaluate the ECR values. A single saturation transfer pulse frequency was used at a frequency of 3.5 ppm downfield from the water resonance. In the DWI, the apparent diffusion coefficient (ADC) value commonly used with two b-values was acquired by using diffusion weightings of 0 and 800 s/mm2. The region of interest of the metastatic lesions in the liver was separately measured by ECRI and DWI. Tumor response was assessed by response evaluation criteria in solid tumors criteria 8 weeks after starting chemotherapy. RESULTS: In this study, we had four responders and three nonresponders. There was a significant difference in the pretreatment ECR values between the responders and nonresponders (P=.01); there was no significant difference in the ADC values between the two groups. Analysis of the percentage difference between the pretreatment and post-treatment values, termed as percentage change, showed that there were no significant differences in the percentage change of the ADC values between both groups; however, the percentage change in the ECR value was significantly greater for the responders than for the nonresponders (-41.6%±17.1% vs. -12.9%±6.9%, respectively; P=.04). CONCLUSION: The pretreatment ECR value and percentage change of the ECR value 2 weeks after starting chemotherapy were useful parameters in the early prediction of response to bevacizumab-containing treatment in colorectal liver metastases.

Hepatic arterial infusion chemotherapy with fine-powder cisplatin and iodized-oil suspension in patients with intermediate-stage and advanced-stage (Barcelona Clinic Liver Cancer stage-B or stage-C) hepatocellular carcinoma: multicenter phase-II clinical study.

PURPOSE: This single-arm, multicenter, phase-II trial evaluated the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) using fine-powder cisplatin and iodized-oil suspension in patients with intermediate- and advanced-stage [Barcelona Clinic Liver Cancer (BCLC) stage-B and stage-C] hepatocellular carcinomas (HCCs). METHODS: The Institutional Review Board approved this study and patients provided written informed consent. Thirty-five patients (24 men and 11 women, mean 74 ± 6 years [range 60-87 years]) with BCLC stage-B (57 %, 20/35) or stage-C (43 %, 15/35) HCCs who were not candidates for other locoregional treatments were enrolled. HAIC was performed using a suspension of fine-powder cisplatin with a maximum dose of 65 mg/m(2) and iodized oil on demand. The primary endpoint was the response rate evaluated based on Response Evaluation Criteria in Solid Tumor (RECIST) and modified RECIST (mRECIST). Secondary endpoints were overall survival, progression-free survival, and safety. RESULTS: The initial and best overall response rates at 4 weeks and 3 months, respectively, were 14 and 17 % based on RECIST, and 57 and 23 % based on mRECIST. The median overall and progression-free survival times were 18 and 4 months, respectively. The most frequent grade-3 or grade-4 adverse events were elevation of serum alanine (23 %) and aspartate aminotransferase (20 %), and thrombocytopenia (17 %). CONCLUSION: This HAIC provides promising therapeutic effects with acceptable safety to patients with intermediate-stage and advanced-stage HCCs.

Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma.

The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m(2) /cycle; level 2, 50 mg/m(2) /cycle; and level 3, 65 mg/m(2) /cycle) from feeding arteries to the HCC. The treatment was repeated every 4-6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m(2) /cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.

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.

Hepatic arterial embolization for unresectable hepatocellular carcinomas: do technical factors affect prognosis?

PURPOSE: To evaluate retrospectively whether technical factors of hepatic arterial embolization affect the prognosis of patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Inclusion criteria of this study were the following: (1) patients received embolization as the initial treatment during 2003-2004, (2) Child A or B liver profile, (3) five or fewer HCCs with maximum diameter of 7 cm or smaller, and (4) no extrahepatic metastasis. Patient data were gathered from 43 centers. Prognostic factors were evaluated using univariate and multivariate analyses. RESULTS: Eight hundred fifteen patients were enrolled. The 1-, 3-, 5-, and 7-year overall survival rates were 92.0 % (95 % CI 90.1-93.9), 62.9 % (95 % CI 59.3-66.6), 39.0 % (95 % CI 35.1-43.0), and 26.7 % (95 % CI 22.6-30.8) in all patients. Univariate analysis showed a Child-Pugh class-A, alpha-fetoprotein level lower than 100 ng/ml, tumor size of 3 cm or smaller, tumor number of 3 or fewer, one-lobe tumor distribution, nodular tumor type, within the Milan criteria, stage I or II, no portal venous invasion, use of iodized oil, and selective embolization were significantly better prognostic factors. In the multivariate Cox model, the benefit to survival of selective embolization remained significant (hazard ratio 0.68; 95 % CI 0.48-0.97; p = 0.033). CONCLUSION: Selective embolization contributes to survival in patients with HCCs.

A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone as treatment for liver metastasis from colorectal cancer: Japan Clinical Oncology Group Study JCOG0603.

A randomized controlled trial is being conducted in Japan to compare hepatectomy alone with hepatectomy followed by adjuvant chemotherapy as treatment in patients with curatively resected liver metastases from colorectal cancer to improve survival with intensive chemotherapy. Between 42 and 70 days after liver resection, patients are randomly assigned to either hepatectomy alone or hepatectomy followed by 12 cycles of modified FOLFOX6 (mFOLFOX6) regimen. A total of 300 patients (including 78 patients in Phase II) will be accrued from 38 institutions within 3 years. The primary endpoint is treatment compliance at nine courses of mFOLFOX6 regimen in Phase II and disease-free survival in Phase III. The secondary endpoints are overall survival, incidence of adverse events and patterns of recurrence.

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.