Selective Internal Radiation Therapy with Yttrium-90 Resin Microspheres Followed by Gemcitabine plus Cisplatin for Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Single-Arm Multicenter Clinical Trial.

Introduction: This investigator-initiated clinical trial aims to study the efficacy and safety of administering selective internal radiation therapy with resin yttrium-90 microspheres (SIRT) followed by standard chemotherapy in unresectable intrahepatic cholangiocarcinoma (ICC). Methods: A phase 2 single-arm multicenter study was conducted in patients with unresectable ICC (NCT02167711). SIRT was administered at dose of 120 Gy targeted at tumor followed by commencement of gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days one and eight of a 21-day cycle. The primary endpoint was overall survival (OS), and the secondary endpoints include progression-free survival (PFS), response rate according to Response Evaluation Criteria in solid tumors 1.1, toxicity, and time from SIRT to commencement of chemotherapy. Results: Total 31 patients were screened and twenty-four were recruited. All patients completed SIRT and 16 of them underwent subsequent chemotherapy. The median cycle of chemotherapy was 5 (range: 1-8). The median OS was 13.6 months (95% CI: 5.4-21.6) for the intent-to-treat population. Among 16 patients undergoing chemotherapy, the median OS was 21.6 months (95% CI: 7.3-25.2) and the median PFS was 9 months (95% CI: 3.2-13.1). The response rate was 25% (95% CI: 3.8-46.2%), and the disease control rate was 75% (95% CI: 53.8-96.2%). No new safety signal was observed, with fewer than 10% of patients suffering from grade 3 or higher treatment-related adverse events. The median time from SIRT to chemotherapy was 29 (range: 7-42) days. Eight patients could not receive chemotherapy due to rapid progressive disease (n = 4), underlying treatment unrelated comorbidities (n = 2), and withdrawal of consent due to personal reasons (n = 2). Conclusions: Treatment of SIRT followed by standard gemcitabine and cisplatin chemotherapy is feasible and effective for unresectable ICC. Further studies are required to study the optimal sequence of SIRT and chemotherapy.

Percutaneous thermal ablation of subcapsular hepatocellular carcinomas: influence of tumor-surface contact and protrusion on therapeutic efficacy and safety.

PURPOSE: To evaluate therapeutic efficacy and complication of percutaneous thermal ablation of subcapsular hepatocellular carcinomas (HCCs), and how these may be influenced by the degree of tumor to liver surface contact and tumor protrusion from liver surface. MATERIALS AND METHODS: Our retrospective study was approved by the Institutional Review Board. Between January 2006 and December 2013, 290 patients (82 women, 208 men; mean age, 64.5 years; range, 33-89 years) with 474 subcapsular (within 1 cm to the liver surface) HCCs (mean size, 23.7 mm; range, 6-71 mm) underwent percutaneous thermal ablation. The HCCs were divided into surface contact group (n = 243) and non-surface contact group (n = 231). The former was further subdivided into exophytic and non-exophytic HCCs. Technical success, primary technique efficacy, local tumor progression (LTP), and secondary technique efficacy rates were analyzed and compared by the chi-square test or Fisher exact test. Prognostic factors for LTP and secondary technique efficacy were assessed using the Cox regression model. Major complications were also assessed. RESULTS: With median follow-up of 15 months (range, 1-87 months), technical success and primary technique efficacy were 98.7% and 95.7% % in the non-surface contact group; 96.4% and 94.0% in the non-exophytic group; and 100% and 94.7% in the exophytic group (p > 0.05). Tumor size > 3 cm was a significant predictor for LTP, but not for secondary efficacy. Overall major complication rate was 3.8% (24/624) and was not different among the three groups. CONCLUSION: Subcapsular HCCs can be effectively treated with thermal ablation techniques. Degree of tumor-surface contact including moderate protrusion does not appear to limit feasibility or procedure effectiveness. KEY POINTS: • Subcapsular HCCs can be effectively treated with thermal therapy when proper image-guided technique and assistive techniques are applied. • Degree of tumor surface contact including moderate protrusion does not appear to limit feasibility or procedure effectiveness. • Major complications after percutaneous thermal ablation of subcapsular HCCs such as tumor seeding can be minimized by avoiding breach of the tumor capsule exposed to the peritoneal surface and use of tract ablation.

Screening values of carcinoembryonic antigen and cytokeratin 19 fragment for lung cancer in combination with low-dose computed tomography in high-risk populations: Initial and 2-year screening outcomes.

OBJECTIVES: To assess added screening value of Carcinoembryonic Antigen (CEA) and Cytokeratin 19 Fragment (CYFRA 21-1) in combination with LDCT beyond LDCT alone and likelihood ratio of positive (LHR+) of their combination for lung cancer in high-risk populations with indeterminate and positive LDCT after initial screening and 2-year follow up. MATERIALS AND METHODS: LDCT was performed annually at baseline and for 2 years in 634 heavy smokers (>30 pack-years) who were aged 50-70 years, and it was classified as negative, indeterminate, or positive (suspicious for lung cancer). Serum CEA and CYFRA 21-1 were examined and followed with LDCT in the indeterminate and positive LDCT groups and defined as positive with an abnormal level of either CEA or CYFRA 21-1. RESULTS: A total of 17 lung cancer cases were diagnosed (9 from initial screening and 8 from follow-up cycles). Seventy and 22 patients had indeterminate and positive baseline LDCT, respectively. Among indeterminate baseline LDCT, the LHR+ for lung cancer diagnosed after initial screening with a positive marker was 6.61 (p = .039) and 1.51 (p = .502) with a negative marker. After 2 years follow up, the LHR+ was 6.31 (p = .004) and 0.86 (p = .677), respectively. Among positive baseline LDCT, the LHR+ for lung cancer diagnosed after initial round with positive and negative markers was 69.44 (p < 0.001) and 11.57 (p = .015), respectively. The corresponding LHR+ after 2-year round was 13.61 (p = .002) and 18.15 (p = .001), respectively. The combinations of CEA/CYFRA 21-1 and LDCT, and CEA and LDCT had crude and adjusted added value beyond LDCT alone (crude: 8%, p = .033 and 7%, p = .038; adjusted: 4%, p = .019 and 4%, p = .029, respectively). CONCLUSIONS: CEA in combination with LDCT significantly increases the value of lung cancer screening compared with using LDCT alone particularly in participants with indeterminate baseline LDCT in both initial and 2-year screening outcomes.

Radiofrequency ablation of hepatocellular carcinoma as bridge therapy to liver transplantation: A 10-year intention-to-treat analysis.

In a long-term (10-year) study of radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC) as bridging therapy in patients listed for orthotopic liver transplantation (LT), we evaluated the impact of RFA on waiting list dropout rate, post-LT tumor recurrence, and long-term intention-to-treat, disease-specific survival (DSS). From March 2004 to October 2014, RFA was performed as the initial stand-alone bridge therapy to LT for 121 patients (men/women ratio, 83:38; mean age, 60.0 years) with 156 de novo HCCs (mean size, 2.4 cm). Follow-up period from initial RFA ranged from 1.3 to 128.0 months (median, 42.9 months). We assessed the overall and tumor-specific waiting list dropout rates, post-LT tumor recurrence, and 10-year post-LT and intention-to-treat survival rates. Dropout from the waiting list due to tumor progression occurred in 7.4% of patients. HCC recurrence after LT occurred in 5.6% of patients. The post-LT overall survival (OS) rate at 5 and 10 years was 75.8% and 42.2%, respectively, and the recurrence-free survival (RFS) rate was 71.1% and 39.6%, respectively. Intention-to-treat OS, RFS, and DSS rates for the entire study population at 5 and 10 years were 63.5% and 41.2%, 60.8% and 37.7%, and 89.5% and 89.5%, respectively. CONCLUSION: RFA as a first-line stand-alone bridge therapy to LT achieves excellent long-term overall and tumor-specific survivals, with a low dropout rate from tumor progression despite long wait list times and a sustained low tumor recurrence rate upon post-LT follow-up of up to 10 years. (Hepatology 2017;65:1979-1990).

Hepatocellular carcinoma screening and surveillance in 2293 chronic hepatitis B patients in an endemic area.

AIM: To determine the role of screening and surveillance of hepatocellular carcinoma (HCC) in treatment-naïve chronic hepatitis B (CHB) patients. METHODS: We recruited 2293 CHB patients (both males and females; aged 20-65 years). All patients were screened and underwent surveillance using abdominal ultrasonography (AUS) and serum alpha-fetoprotein (AFP) assay every 6 mo. The diagnosis, staging and treatment of HCC followed the American Association for the Study of Liver Diseases practice guidelines and the Barcelona Clinic Liver Cancer guidelines. The exclusion criteria included: decompensated cirrhosis; a history of any cancer in the last 5 years; previous antiviral treatment for CHB; concurrent infection with hepatitis C virus or human immunodeficiency virus; a Karnofsky Performance Status score < 60%; or any medical condition preventing eligibility to complete the protocol. The prevalence and incidence rates of HCC were determined; survival rates were calculated at 3-year post HCC diagnosis. The sensitivity and specificity were calculated on a per-patient basis. RESULTS: Among 2293 treatment-naïve CHB patients, seven cases had HCC at initial screening, giving a prevalence rate of 305 per 100000 persons; 3.3% were diagnosed with liver cirrhosis, all of which were Child-Pugh class A. With a median follow-up time of 42 (range, 3-48) mo, 10 additional cases were diagnosed with HCC, resulting in an incidence rate of 143 per 100000 persons per year. This burden was as high as that reported in other studies from East Asian countries. All HCC patients were aged ≥ 40 years. Most were at an early stage (Stage 0, A or B); 14/17 cases were successfully treated with surgical resection or radiofrequency ablation, with a high 3-year survival rate of 90%. Hemangioma was the most common focal liver lesion in CHB patients detected by AUS; the main causes of AFP elevation at the initial screening were cirrhosis, increased alanine aminotransferase level and HCC. AUS detected 16/17 HCC cases whereas AFP levels ≥ 20 µg/L at diagnosis were observed in only 7/17 patients, most with a tumor size > 5 cm. For HCC screening and surveillance, AUS had a sensitivity and specificity of 94% and 82%, respectively, whereas the sensitivity and specificity of AFP at a cut-off value of ≥ 20 µg/L were 41% and 98%, respectively. Combined use of AUS and AFP assay did not improve effectiveness. CONCLUSION: Implementation of active screening and surveillance using AUS to detect early-stage HCC in naïve CHB patients aged ≥ 40 years in an endemic area is of benefit.

Ultrasound screening for cholangiocarcinoma could detect premalignant lesions and early-stage diseases with survival benefits: a population-based prospective study of 4,225 subjects in an endemic area.

BACKGROUND: Thailand has a high incidence of cholangiocarcinoma (CCA), particularly in the north and northeastern regions. Most CCA patients come at a late, unresectable stage and presently no optimal screening test for CCA has been established. We determined the prevalence of CCA in a remote northern village and explored if screening could lead to early detection and survival benefits. METHODS: A 5-year population-based study was started in October, 2011 for consented Thai individuals, aged 30-60 years. The screening program comprised blood testing, stool examination and serial ultrasonography every 6 months. RESULTS: During the first 3 years, 4,225 eligible individuals were enrolled. CCA was detected in 32 patients, with a mean age of 51.9 years (41-62 years), and 21/32 cases were at a curative resectable stage. The prevalence rate of CCA was 165.7 per 100,000 and one- and two-year incidence rate was 236.7/100,000 and 520.7/100,000, respectively. One- and 2-year overall survival rates of CCA patients were 90.9 and 61.5 %, respectively. Prognosis was better in resectable cases with 100 % 1-year and 77.8 % 2-year survival rates. Interestingly, premalignant pathological lesions (stage 0) were identified in 11 cases with 100 % 3-year survival rate. Serum biomarkers and alkaline phosphatase were not sufficient to detect early-stage disease. In 22 patients, stool samples were positive for Opistorchis viverrini, based on polymerase chain reaction. CONCLUSION: Detection of premalignant lesions and early-stage resectable CCA by ultrasonography resulted in improved clinical outcome. Ultrasonography should be offered as a first screening tool for CCA in an endemic area until other useful biological markers become available.