Proton beam radiotherapy vs. radiofrequency ablation for recurrent hepatocellular carcinoma: A randomized phase III trial.

BACKGROUND & AIMS: Proton beam radiotherapy (PBT) has recently been applied to treat hepatocellular carcinoma (HCC); however, there is no randomized controlled trial-based evidence on its safety and efficacy. We compared the outcomes of PBT and radiofrequency ablation (RFA) in patients with recurrent/residual HCC (rHCC) in a phase III non-inferiority trial. METHODS: Patients with rHCC (size <3 cm, number ≤2) were randomly assigned to receive PBT or RFA according to Child-Pugh score and tumor stage. After randomization, if the assigned treatment was technically infeasible, crossover was allowed. The primary endpoint was 2-year local progression-free survival (LPFS), with a non-inferiority margin of 15% in the per-protocol (PP) population; a complementary analysis was performed in the intention-to-treat (ITT) population (NCT01963429). RESULTS: The ITT population comprised 144 patients receiving either PBT (n = 72) or RFA (n = 72). Six patients switched from the PBT arm to the RFA arm and 19 patients switched from the RFA arm to the PBT arm. In the PP population, the 2-year LPFS rate with PBT (n = 80) vs. RFA (n = 56) was 94.8% vs. 83.9%, a difference of 10.9 percentage points (90% CI 1.8-20.0; p <0.001); in the ITT population, the 2-year LPFS rate with PBT vs. RFA was 92.8% vs. 83.2%, a difference of 9.6 percentage points (90% CI 0.7-18.4; p <0.001), meeting the criteria for non-inferiority. The 3- and 4-year LPFS rates for PBT were also non-inferior to those for RFA. The most common adverse events were radiation pneumonitis (32.5%) and decreased leukocyte counts (23.8%) for PBT and increased alanine aminotransferase levels (96.4%) and abdominal pain (30.4%) for RFA. No Grade 4 adverse events or mortality were noted. CONCLUSIONS: PBT showed LPFS values that were non-inferior to those for RFA; in addition, PBT was tolerable and safe. CLINICAL TRIAL NUMBER: #NCT01963429 (ClinicalTrials.gov). LAY SUMMARY: Radiofrequency ablation is the standard of care for patients with small hepatocellular carcinoma in whom surgery is not feasible. This study is the first phase III randomized controlled trial to evaluate the clinical outcomes of proton beam radiotherapy vs. radiofrequency ablation in patients with recurrent small HCC. Our findings show that this new technique is not inferior and can be applied safely in patients with small recurrent hepatocellular carcinoma.

Varices on computed tomography as predictor of survival after hepatic resection in patients with single hepatocellular carcinoma.

BACKGROUND AND AIM: The aim of this study was to evaluate whether presence of varices on computed tomography (CT) could predict treatment outcome for hepatocellular carcinoma patients. METHODS: We enrolled 241 patients with single hepatocellular carcinoma ≤ 5 cm treated by surgery. With the use of preoperative CT/endoscopy, patients were classified into the following: presence of standard clinically significant portal hypertension (CSPH) surrogate, defined as varices on esophagogastroduodenoscopy and/or thrombocytopenia with splenomegaly (group 1, n = 47); varices on CT without standard CSPH surrogate (group 2, n = 45); and none of both (group 3, n = 149). Development of posthepatectomy liver failure and overall survival (OS) were evaluated for each patient group, and patients were re-classified into two groups according to presence of CT-enhanced CSPH surrogate, defined as standard surrogate and/or varices on CT. Predictive power of each survival model was compared using Harrell's C-index. RESULTS: Posthepatectomy liver failure rate in group 2 was similar to that in group 1 (53.3% [24/45] vs. 55.3% [26/47]; P = 1.000) but significantly higher than that in group 3 (53.3% [24/45] vs. 28.2% [42/149], P = 0.002). Seven-year OS rates in group 2 were similar to those in group 1 (55.6% vs. 60.8%, P = 0.988) but significantly lower than those in group 3 (55.6% vs. 83.3%, P = 0.001). Presence of standard CSPH surrogate (hazard ratio = 1.89 [1.08-3.30], P = 0.025) and CT-enhanced CSPH surrogate (hazard ratio = 2.60 [1.56-4.39], P < 0.001) were significant predicting factor for OS. However, CT-enhanced CSPH surrogate had significantly higher Harrell's C-index than standard surrogate (0.619 vs. 0.553, P = 0.034). CONCLUSION: The presence of CT-enhanced CSPH surrogate including varices on CT was the significant predictive of poor OS, providing better predictive power than standard surrogate.

Oncological Benefits of Neoadjuvant Chemoradiation With Gemcitabine Versus Upfront Surgery in Patients With Borderline Resectable Pancreatic Cancer: A Prospective, Randomized, Open-label, Multicenter Phase 2/3 Trial.

OBJECTIVE: This study was performed to determine whether neoadjuvant treatment increases survival in patients with BRPC. SUMMARY BACKGROUND DATA: Despite many promising retrospective data on the effect of neoadjuvant treatment for borderline resectable pancreatic cancer (BRPC), no high-level evidence exists to support the role of such treatment. METHODS: This phase 2/3 multicenter randomized controlled trial was designed to enroll 110 patients with BRPC who were randomly assigned to gemcitabine-based neoadjuvant chemoradiation treatment (54 Gray external beam radiation) followed by surgery or upfront surgery followed by chemoradiation treatment from four large-volume centers in Korea. The primary endpoint was the 2-year survival rate (2-YSR). Interim analysis was planned at the time of 50% case enrollment. RESULTS: After excluding the patients who withdrew consent (n = 8) from the 58 enrolled patients, 27 patients were allocated to neoadjuvant treatment and 23 to upfront surgery groups. The overall 2-YSR was 34.0% with a median survival of 16 months. In the intention-to-treat analysis, the 2-YSR and median survival were significantly better in the neoadjuvant chemoradiation than the upfront surgery group [40.7%, 21 months vs 26.1%, 12 months, hazard ratio 1.495 (95% confidence interval 0.66-3.36), P = 0.028]. R0 resection rate was also significantly higher in the neoadjuvant chemoradiation group than upfront surgery (n = 14, 51.8% vs n = 6, 26.1%, P = 0.004). The safety monitoring committee decided on early termination of the study on the basis of the statistical significance of neoadjuvant treatment efficacy. CONCLUSION: This is the first prospective randomized controlled trial on the oncological benefits of neoadjuvant treatment in BRPC. Compared to upfront surgery, neoadjuvant chemoradiation provides oncological benefits in patients with BRPC.

Efficacy of pancreatic exocrine replacement therapy for patients with unresectable pancreatic cancer in a randomized trial.

BACKGROUND: Weight loss in pancreatic cancer is associated with maldigestion due to pancreatic duct obstruction. Pancreatic exocrine replacement therapy (PERT) may significantly improve fat and protein absorption. OBJECTIVES: This prospective, double-blind, randomized, placebo-controlled phase II trial assessed whether PERT could reduce or prevent weight loss in patients with unresectable pancreatic cancer. METHODS: Sixty seven patients with unresectable pancreatic cancer were randomized to receive enteric coated PERT, consisting of 6-9 capsules of pancreatin (457.7 mg/capsule), or placebo. Patients took two capsules each three times daily during main meals and one capsule each up to three times daily when having between-meal snacks. The primary endpoint was the percentage change in body weight at eight weeks. RESULTS: The mean percentage change in body weight (1.49% [1.12 kg] vs. 2.99% [1.63 kg], P = 0.381) and the mean percent change in Patient-Generated Subjective Global Assessment (PG-SGA) score (8.85% vs. 15.69%, p = 0.18) did not differ significantly between the PERT and placebo groups. There was no improvement in quality of life and overall survival did not differ significantly between the PERT and placebo groups (5.84 months vs 8.13 months, p = 0.744). CONCLUSIONS: PERT did not reduce weight loss in patients with unresectable pancreatic cancer. Larger randomized trials are needed to identify those patients who may benefit from PERT. TRIAL REGISTRATION: ClinicalTrials.gov Number NCT01587534.

Cytidine Deaminase as a Molecular Predictor of Gemcitabine Response in Patients with Biliary Tract Cancer.

OBJECTIVE: Gemcitabine-based chemotherapy is regarded as the standard treatment for biliary tract cancer (BTC). Potential biomarkers for gemcitabine response include the activities of cytidine deaminase (CDA), human equilibrative nucleoside transporter 1 (hENT1), deoxycytidine kinase (DCK), and ribonucleotide reductase M1 (RRM1). Here, we investigated whether single nucleotide polymorphisms (SNPs) in their encoding genes were associated with the efficacy of gemcitabine chemotherapy in treating BTC. METHODS: We retrospectively evaluated 11 SNPs in the CDA, hENT1, DCK, human concentrative nucleoside transporter 3 (hCNT3), and RRM1 genes in 80 patients with unresectable, metastatic, or recurrent BTC who were treated with gemcitabine plus cisplatin. RESULTS: After the results were adjusted for clinical predictors, the variant allele of rs1048977 in the CDA gene was associated with tumor response in a dominant model (OR, 0.23; 95% CI, 0.06-0.93; p = 0.039). No significant association was detected between the 11 SNPs and grade 3/4 toxicity. CONCLUSIONS: Our findings suggest that the polymorphism of CDA may be a potential predictive marker for the efficacy of gemcitabine-based chemotherapy in patients with BTC.

Effectiveness and safety of proton beam therapy for advanced hepatocellular carcinoma with portal vein tumor thrombosis.

PURPOSE: To evaluate the clinical effectiveness and safety of proton beam therapy (PBT) in advanced hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). PATIENTS AND METHODS: Twenty-seven HCC patients with PVTT underwent PBT, including 22 patients with modified International Union Against Cancer (mUICC) stage IVA,five patients with stage IVB primary tumors, and 16 with main PVTT. A median dose of 55 GyE (range, 50-66 GyE) in 20-22 fractions was delivered to a target volume encompassing both the PVTT and primary tumor. RESULTS: Overall, treatment was well tolerated, with no toxicity of grade ≥ 3. Median overall survival (OS) times in all patients and in stage IVA patients were 13.2 months and 16 months, respectively. Assessments of PVTT response showed complete response in 0 of 27 (0%) patients, partial response in 15 (55.6%), stable disease in 10 (37%), and progressive disease in 2 (7.4%) patients, with an objective response rate of 55.6%. PVTT responders showed significantly higher actuarial 1-year local progression-free survival (LPFS; 85.6% vs. 51.3%), relapse-free survival (RFS; 20% vs. 0%) and OS (80% vs. 25%) rates than nonresponders (p<0.05 each). Multivariate analysis showed that PVTT response and mUICC stage were independent prognostic factors for OS. CONCLUSION: Our data suggest that PBT could improve LPFS, RFS, and OS in advanced HCC patients with PVTT and it is feasible and safe for these patients.

Long-term outcomes of second treatment after initial transarterial chemoembolization in patients with hepatocellular carcinoma.

BACKGROUND & AIMS: All outcome studies concerning the management of hepatocellular carcinoma (HCC) are based on the initial treatment. However, remaining, progressing or recurring tumours (RPRTs) after transarterial chemoembolization (TACE) are common; therefore, various second treatments are administered to HCC patients. Here, we investigated the long-term outcomes of second treatments for RPRT after initial TACE. METHODS: We enrolled 855 consecutive HCC patients who underwent TACE as the initial treatment at the National Cancer Center, Korea, from January 2004 to December 2010. RESULTS: The median follow-up was 43.4 months, and the median progression-free survival following initial TACE was 4.0 months, being 18.1 and 1.0 months for complete remission and progressive disease respectively. Second treatments were administered to 790 RPRT patients (92.4%); the most common was TACE (56.4%), followed by best supportive care (22.8%), systemic chemotherapy (9.4%), external radiotherapy (4.4%), radiation ablation (RFA; 2.9%), resection (2.0%) and liver transplantation (1.4%). Median overall survival (mOS) for initial TACE was 18.8 months [95% confidence interval (CI), 16.6-21.0 months]; after second treatments, it was 12.4 (95% CI, 10.6-14.2) months, differing significantly by mRECIST assessment, BCLC stage and RPRT type (28.0, 5.0 and 3.9 months for intrahepatic, vascular and extrahepatic RPRT, respectively; P < 0.001). Intrahepatic RPRT with a curative treatment as a second treatment showed the best OS. CONCLUSION: These novel insights into the patterns and long-term outcomes of second treatments for RPRT in HCC patients who underwent initial TACE are expected to aid in formulating treatment strategies for HCC patients.

Clinical outcomes of a cohort series of patients with hepatocellular carcinoma in a hepatitis B virus-endemic area.

BACKGROUND AND AIMS: To evaluate the clinical outcomes of patients with hepatocellular carcinoma (HCC) and compare the findings with that of a previous cohort. METHODS: Overall, 1972 HCC patients diagnosed and treated at the National Cancer Center, Korea between 2004 and 2009 were enrolled. The data of this cohort were compared with those of a previous cohort (2000-2003) from the same institution. RESULTS: In all (mean age, 56.4 years; 1642 men), 74.6% was hepatitis B virus (HBV) positive, 81.6% were Child-Pugh (CP) class A, and 64.4% was Barcelona Clinic Liver Cancer (BCLC) stage C. The modified Union for International Cancer Control (mUICC) stage I, II, III, IVa, and IVb was found in 8.9%, 29.6%, 24.8%, 23.1%, and 13.6% patients, respectively. The most common initial treatment was transarterial chemotherapy (58.3%), followed by resection (18.6%). The 5-year survival rate of BCLC stage 0, A, B, and C were 79.6%, 67.2%, 33.9%, and 17.1%, respectively. The performance status, BCLC stage, mUICC stage, CP class, model for end-stage liver disease score, tumor characteristics, portal vein tumor invasion, and serum alpha-fetoprotein level proved to be independent prognostic variables. Overall survival in the present cohort was better than that in the previous cohort (hazard ratio, 0.829; 95% confidence interval, 0.754-0.912), especially for advanced HCC patients with HBV-positive status. CONCLUSIONS: This cohort study provides valuable insights into the characteristics of HCC in Korean patients. Our findings may help develop clinical trials, treatment strategies, and prognosis systems for HCC patients in HBV-endemic areas.

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study.

Background and Aims: Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. Methods: In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3 mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Results: Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n = 21; Vp3, n = 23; Vp4, n = 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Conclusion: Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Impact and implications: Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. ClinicalTrialsgov identifier: NCT04611165.

Appropriate indications of initial endoscopic ultrasound evaluation for detecting mural nodules in branch duct intraductal papillary mucinous neoplasms of the pancreas.

OBJECTIVE: The presence of mural nodules is a strong predictor of malignancy in patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs). Endoscopic ultrasound (EUS) is the most sensitive imaging for the detection of mural nodules. The aim was to evaluate whether initial EUS evaluation is necessary to detect mural nodules in all patients with BD-IPMNs. MATERIAL AND METHODS: We reviewed retrospectively the medical records of all 104 patients with BD-IPMNs diagnosed by EUS from January 2008 to December 2011. Of the 104 patients, 13 (12.5%) had mural nodules (MN-positive group) and 91 (87.5%) did not (MN-negative group). RESULTS: Patients in the MN-positive group were significantly older (69 years vs. 61 years, p = 0.013), had larger-sized cysts on EUS (24.1 ± 8.3 mm vs. 16.2 ± 8.0 mm, p = 0.001), a higher rate of main pancreatic duct dilatation (30.8% vs. 3.3%, p = 0.004), and higher serum CA 19-9 concentrations (67.8 ± 109.4 U/mL vs. 17.5 ± 27.0 U/mL, p = 0.012), than patients in the MN-negative group. Cyst sizes measured by EUS, CT, and MRCP did not differ significantly. Multivariate logistic regression analysis showed that cysts ≥16 mm in size on CT (odds ratio [OR], 9.84; 95% confidential interval [CI], 1.08-89.93; p = 0.043) and main pancreatic duct dilatation (OR, 12.65; 95% CI, 1.62-98.99; p = 0.016) were independent predictors of mural nodules. CONCLUSIONS: Patients with BD-IPMNs, cyst size ≥16 mm, and main pancreatic duct dilatation should be further evaluated by EUS for the presence of mural nodules.

Comparison of uncovered and covered stents for the treatment of malignant duodenal obstruction caused by pancreaticobiliary cancer.

BACKGROUND: Few clinical studies to date have compared different types of self-expandable metallic stents (SEMS) and their outcomes in patients with pure duodenal obstruction caused by pancreaticobiliary cancer. The aim of this study was to compare the clinical effectiveness and side effects of uncovered and covered SEMS for the palliation of duodenal obstruction caused by pancreaticobiliary cancer. METHODS: We retrospectively analyzed all patients with pancreaticobiliary cancer who underwent upper endoscopy with SEMS placement for malignant duodenal obstruction at the National Cancer Center of Korea between April 2003 and December 2010. The technical and clinical success rates of the procedure, complications, and durations of stent patency and overall survival were evaluated. RESULTS: We identified 70 patients with a mean age of 51.2 years (range = 39-81 years); of these, 46 (65.7 %) had pancreatic cancer, 9 (12.9 %) had bile duct cancer, 11 (15.7 %) had gallbladder cancer, and 4 (5.7 %) had cancer of the ampulla of Vater. Twenty-four patients (34.3 %) received covered SEMSs and 46 (65.7 %) received uncovered SEMSs. Technical and clinical success rates were similar for the covered and uncovered stent groups. The complication rate was higher in the covered than in the uncovered group (62.5 vs. 34.8 %, P = 0.025), due primarily to a significantly higher stent migration rate (20.8 vs. 0 %, P = 0.004). Perforation as a late complication occurred in four patients, two in each group (8.3 vs. 4.3 %, P = 0.425). Stent patency tended to be shorter for covered than for uncovered duodenal stents (13.7 ± 8.6 weeks vs. not reached, P = 0.069). CONCLUSIONS: The use of uncovered stents may be a preferred option for duodenal obstruction secondary to pancreaticobiliary malignancies, since they were effective in preventing stent migration and tended to have longer patency than covered stents. Careful attention should be paid to signs and symptoms of perforation during follow-up.

Gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective cohort study.

BACKGROUND AND AIM: Gemcitabine plus cisplatin (GP) is a standard chemotherapy option for patients with advanced biliary tract cancer (BTC). We compared the efficacy and safety of capecitabine plus cisplatin (XP) versus GP in advanced BTC. METHODS: The records of all patients treated with GP or XP chemotherapy for unresectable, metastatic, or recurrent BTC at the National Cancer Center between December 2001 and August 2012 were reviewed retrospectively. Patients with histologically confirmed intrahepatic cholangiocarcinoma, gallbladder cancer, or extrahepatic cholangiocarcinoma were enrolled. RESULTS: Of the 344 patients enrolled, 127 received GP and 217 received XP. At a median follow-up time of 8.9 months, the median time to progression was longer in the GP group than in the XP group (5.6 vs. 4.7 months), but the difference was not statistically significant (p = 0.081). The median overall survival (OS) was 8.4 months (95% CI 6.2-10.7) in the GP group and 7.6 months (95% CI 6.8-8.7) in the XP group (p = 0.024), with statistical significance retained following multivariate analysis (HR 0.72; 95% CI 0.527-0.987; p = 0.004). Grade 3/4 toxicities were significantly more frequent in the GP group than in the XP group (40.9 vs. 24.9%, p = 0.002). CONCLUSIONS: GP was superior to XP in prolonging OS, despite increasing the rate of grade 3/4 adverse events.

Risk of pancreatic cancer in relation to ABO blood group and hepatitis C virus infection in Korea: a case-control study.

Several studies have reported that ABO blood group, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection contribute to the development of pancreatic cancer. The aim of this study was to evaluate the association between these factors and pancreatic cancer in the Korean population. We retrospectively recruited 753 patients with pancreatic cancer and 3,012 healthy controls, matched 4 to 1 with cancer patients for age and sex, between 2001 and 2011, at the National Cancer Center, Korea. A multivariate logistic regression analysis was employed to estimate adjusted odds ratios (AORs). The AOR for pancreatic cancer in subjects with non-O blood types (A, AB, and B), compared to blood type O, was 1.29 (95% CI, 1.05-1.58; P = 0.01). Seropositivity for hepatitis B virus surface antigen was not significantly related to pancreatic cancer, either in univariate (odds ratio 1.03; 95% CI, 0.69-1.53; P = 0.91) or multivariate analysis (AOR, 1.02; 95% CI, 0.67-1.56; P = 0.93). The AOR for pancreatic cancer in subjects displaying seropositivity for anti-HCV was 2.30 (95% CI, 1.30-4.08; P < 0.01). Our results suggest that the non-O blood types and anti-HCV seropositivity, but not HBV infection, may increase the risk of developing pancreatic cancer in Korea, where HBV is endemic.

A case of successful surgical treatment for peritoneal seeding of hepatocellular carcinoma after radiotherapy and atezolizumab plus bevacizumab combination treatment.

Peritoneal seeding of hepatocellular carcinoma (HCC) is incurable and has poor prognosis. A 68-year-old man underwent surgical resection for a 3.5 cm single nodular HCC at the tip of segment 3 and transarterial chemoembolization for a 1.5 cm-sized recurrent HCC at the tip of segment 6. 3 months later, an increasing 1 cm pelvic nodule on the rectovesical pouch warranted radiotherapy. Although it stabilized, a new 2.7 cm-sized peritoneal nodule in the right upper quadrant (RUQ) omentum appeared 3.5 years after radiotherapy. Hence, omental mass and small bowel mesentery mass excision were performed. 3 years later, recurrent peritoneal metastases in the RUQ omentum and rectovesical pouch progressed. 33 cycles of atezolizumab and bevacizumab treatment elicited stable disease response. Finally, laparoscopic left pelvic peritonectomy was performed without tumor recurrence. Herein, we present a case of HCC with peritoneal seeding that was successfully treated with surgery after radiotherapy and systemic therapy, leading to complete remission.

Feasibility of additional radiotherapy in patients with advanced hepatocellular carcinoma treated with atezolizumab plus bevacizumab.

BACKGROUND/AIM: Radiotherapy (RT) is an effective local treatment for hepatocellular carcinoma (HCC). However, whether additional RT is safe and effective in patients with advanced HCC receiving atezolizumab plus bevacizumab remains unclear. This retrospective cohort study aimed to evaluate the feasibility of additional RT in these patients. METHODS: Between March and October 2021, we retrospectively analyzed seven patients with advanced HCC who received RT during treatment with atezolizumab plus bevacizumab. The median prescribed RT dose was 35 Gy (range, 33-66). Freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) after RT were analyzed. RESULTS: The median follow-up duration after RT was 14.2 months (range, 10.0-18.6). Of the seven patients, disease progression was noted in six (85.7%), the sites of disease progression were local in two (28.6%), intrahepatic in four (57.1%), and extrahepatic in four (57.1%). The median time of FFLP was not reached, and PFS and OS times were 4.0 (95% confidence interval [CI], 3.6-4.5) and 14.8% (95% CI, 12.5-17.2) months, respectively. The 1-year FFLP, PFS, and OS rates were 60% (95% CI, 43.8-76.2), 0%, and 85.7% (95% CI, 75.9-95.5), respectively. Grade 3 or higher hematologic adverse events (AEs) were not observed, but grade 3 nonhematologic AEs unrelated to RT were observed in one patient. CONCLUSIONS: The addition of RT may be feasible in patients with advanced HCC treated with atezolizumab plus bevacizumab. However, further studies are required to validate these findings.

Annotation-Efficient Deep Learning Model for Pancreatic Cancer Diagnosis and Classification Using CT Images: A Retrospective Diagnostic Study.

The aim of this study was to develop a novel deep learning (DL) model without requiring large-annotated training datasets for detecting pancreatic cancer (PC) using computed tomography (CT) images. This retrospective diagnostic study was conducted using CT images collected from 2004 and 2019 from 4287 patients diagnosed with PC. We proposed a self-supervised learning algorithm (pseudo-lesion segmentation (PS)) for PC classification, which was trained with and without PS and validated on randomly divided training and validation sets. We further performed cross-racial external validation using open-access CT images from 361 patients. For internal validation, the accuracy and sensitivity for PC classification were 94.3% (92.8-95.4%) and 92.5% (90.0-94.4%), and 95.7% (94.5-96.7%) and 99.3 (98.4-99.7%) for the convolutional neural network (CNN) and transformer-based DL models (both with PS), respectively. Implementing PS on a small-sized training dataset (randomly sampled 10%) increased accuracy by 20.5% and sensitivity by 37.0%. For external validation, the accuracy and sensitivity were 82.5% (78.3-86.1%) and 81.7% (77.3-85.4%) and 87.8% (84.0-90.8%) and 86.5% (82.3-89.8%) for the CNN and transformer-based DL models (both with PS), respectively. PS self-supervised learning can increase DL-based PC classification performance, reliability, and robustness of the model for unseen, and even small, datasets. The proposed DL model is potentially useful for PC diagnosis.

Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma.

BACKGROUND & AIMS: Transarterial chemoembolization (TACE) is an important palliative treatment for unresectable hepatocellular carcinoma (HCC), but TACE-induced ischemic injury can upregulate angiogenic factors and is associated with poor prognosis. The aim of this study was to evaluate the safety and efficacy of concurrent conventional TACE and sorafenib in patients with unresectable HCC. METHODS: The primary objectives of this prospective, single-arm, phase II study were to evaluate safety and time to progression (TTP). Sorafenib was given 3 days after TACE and was administered for up to 24 weeks. Repeated TACE was performed on demand. Tumor response was assessed every 8 weeks. RESULTS: Fifty patients were treated and followed from July 2009 to May 2011. All patients were in Barcelona Clinic Liver Cancer (BCLC) stage B (82%) or C (18%). The median time of follow-up was 14.9 months and a median of 1 TACE session was given (range, 1-4). The median dose intensity of sorafenib was 68.7% (range, 37.3-100) of 800 mg daily. The most common reasons for dose reduction were hand-foot syndrome and thrombocytopenia. Thirty patients completed the study and 17 patients discontinued sorafenib due to disease progression. The overall median TTP was 7.1 months (95% confidence interval (CI), 4.8-7.5 months): 7.3 months in BCLC stage B; 5.0 months in BCLC stage C. The 6-month progression-free survival rate was 52% (95% CI, 37.3-66.1). CONCLUSIONS: Concurrent treatment of unresectable HCC with conventional TACE and sorafenib demonstrates a manageable safety profile and a possibility of promising efficacy.

Patterns of initial disease recurrence after resection of biliary tract cancer.

OBJECTIVES: This study aimed to provide further insights into the indications for adjuvant therapeutic strategies via analysis of the sites of initial recurrence after resection of gallbladder cancer (GBC) and intrahepatic (IHC) and extrahepatic cholangiocarcinoma (EHC). METHODS: Patients with biliary tract cancer who underwent potentially curative resection were identified from the database. Sites of initial disease recurrence were categorized as locoregional or distant. RESULTS: Between March 2001 and April 2009, 231 patients underwent curative resection. Initial GBC and IHC recurrence involving a distant site occurred in 70.8 and 86.8% patients, respectively, compared to 56.9% patients with EHC (p = 0.002). The median time to disease recurrence (TTR) was shorter among the GBC and IHC groups compared with that in EHC patients (6.3 and 6.7 vs. 13.1 months, respectively; p = 0.003). Moreover, median times to distant recurrence in GBC and IHC groups were shorter than that in EHC (5.8 and 6.5 vs. 14.1 months, respectively; p = 0.002). CONCLUSIONS: After resection, recurrent GBC and IHC are more likely to involve a distant site and are associated with significantly shorter TTR than recurrent EHC. These findings suggest that an adjuvant therapeutic strategy targeting distant disease is likely to have a significant impact on the overall management of GBC and IHC.

Severity and timing of progression predict refractoriness to transarterial chemoembolization in hepatocellular carcinoma.

BACKGROUND AND AIM: Patients with hepatocellular carcinoma (HCC) that is refractory to repeated transarterial chemoembolization (TACE) are considered for systemic therapy, but TACE refractoriness is not well defined. The aim of this study was to determine the characteristics of patients whose HCC is refractory to repetitive TACE. METHODS: We evaluated 264 patients with intermediate-stage HCC who underwent TACE between January 2006 and September 2009. We designated the development of vascular invasion or extrahepatic spread during follow up as "stage progression" (SP), and hypothesized that SP might be the surrogate end-point for TACE refractoriness. RESULTS: The median follow up was 18.2 months, and median number of TACE was 3.0 (range, 1-13). Median time-to-progression was 5.5 months (95% confidence interval, 4.8-6.2), and median overall survival was 25.3 months (95% confidence interval, 21.6-29.0). We classified the patients according to disease course as: no progressive disease (PD(-); n = 33); PD without SP (PD(+)SP(-); n = 113); PD followed by SP (PD→SP; n = 47); and simultaneous PD and SP (PD&SP; n = 64). PD(-) and PD(+)SP(-) groups showed no difference in overall survival, PD→SP group had worse overall survival than PD(-) and PD(+)SP(-) groups, and PD&SP group had the worst overall survival. The significant prognostic factors for SP-free survival were development of PD and need for three sessions of TACE during the first 6 months. CONCLUSIONS: SP-free survival can be regarded as an end-point for TACE refractoriness. Development of progression or need for three sessions of TACE within the first 6 months could be predictive of TACE refractoriness.

Capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer: a retrospective single-center study.

BACKGROUND: Palliative chemotherapy is currently the primary therapeutic approach in the treatment of advanced biliary tract cancer (BTC). Our aim was to assess the efficacy and safety of capecitabine plus cisplatin as first-line chemotherapy for patients with advanced BTC and to analyze the relationship between the level of CA19-9 and clinical outcome. METHODS: We retrospectively reviewed the records of patients who had unresectable, metastatic or recurrent BTC who were treated with capecitabine plus cisplatin. Capecitabine was administered orally at a dose of 1,000 mg/m(2) twice a day for 14 days, followed by a 1-week rest period. Cisplatin was administered intravenously on days 1 and 8 at a dose of 30 mg/m(2) for 60 min every 3 weeks. RESULTS: A total of 176 patients were enrolled. Among the 143 assessable patients, 24 (17%) had a partial response. A complete response was radiologically confirmed in 1 patient who had gallbladder cancer. Sixty-two patients (43%) had stable disease and 56 patients (39%) had progressive disease. With a median follow-up of 5.7 months, the median time-to-progression (TTP) was 3.7 months (95% CI 3.1-4.3) and the median overall survival (OS) was 7.4 months (95% CI 6.1-8.7). There was a significant positive correlation between CA19-9 response and TTP (r = 0.66, p = 0.01). CA19-9 response was also significantly correlated with OS (r = 0.57, p < 0.01). The most common grade 3/4 toxicities were nausea/vomiting [12 patients (6.8%)]. CONCLUSIONS: Our results indicate that the capecitabine/cisplatin regimen is well tolerated and has moderate activity against advanced BTC. The CA19-9 response may be a suitable surrogate marker for patients with BTC who are treated with capecitabine/cisplatin.