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.

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.

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.

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.

Clinical Efficacy of Hypofractionated Proton Beam Therapy for Intrahepatic Cholangiocarcinoma.

Forty-seven patients with intrahepatic cholangiocarcinoma (IHCC) who received proton beam therapy (PBT) were analyzed to evaluate the clinical efficacy and safety of hypofractionated PBT in patients with inoperable or recurrent IHCC. The median prescribed dose of PBT was 63.3 GyE (range: 45-80 GyE) in 10 fractions, and the median duration of follow-up in all the patients was 18.3 months (range: 2.4-89.9 months). Disease progression occurred in 35 of the 47 (74.5%) patients; local, intrahepatic, and extrahepatic progression occurred in 5 (10.6%), 20 (42.6%), and 29 (61.7%) patients, respectively. The 2-year freedom from local progression (FFLP), progression-free survival (PFS), overall survival (OS) rates, and median time of OS were 86.9% (95% confidence interval [CI], 74.4-99.4%), 16.8% (95% CI, 4.3-29.3%), 42.7% (95% CI, 28.0-57.4%), and 21.9 months (95% CI, 16.2-28.3 months), respectively; grade ≥ 3 adverse events were observed in four (8.5%) patients. In selected patients with localized disease (no viable tumors outside of the PBT sites), the median time of OS was 33.8 months (95% CI, 5.4-62.3). These findings suggest that hypofractionated PBT is safe and could offer a high rate of FFLP and promising OS in patients with inoperable or recurrent IHCC.

Capecitabine and temozolomide for metastatic intermediate to high-grade pancreatic neuroendocrine neoplasm: a single center experience.

BACKGROUND/AIMS: The combination of capecitabine and temozolomide (CAPTEM) is one of the treatment options for metastatic pancreatic neuroendocrine neoplasms (pNENs). This study aims to evaluate the efficacy of CAPTEM in patients with metastatic intermediate to high-grade pancreatic neuroendocrine tumor (pNET) or carcinoma (pNEC). METHODS: This study was conducted retrospectively in a single center. Patients were treated for intermediate to high-grade tumor with 750 mg/m² of capecitabine twice daily from day 1 to 14 and 200 mg/m² of temozolomide once daily from day 10 to 14, repeating twice in a cycle of 28 days. The primary outcomes were durations of overall survival (OS) and progression-free survival (PFS). The secondary outcomes consisted of objective response rate and disease control rate. RESULTS: A total of 12 patients (grade 2 NET in six, grade 3 NET in three, NEC in three patients) who received CAPTEM were included in this study. Patients received a median of five cycles (range, 2 to 46) of CAPTEM. The median dose combined 1,150 mg of capecitabine and 300 mg of temozolomide. The median OS and PFS were 41.2 months (range, 3.2 to 167) and 39.7 months (range, 2.1 to 100), respectively. Patients with NET had longer OS and PFS compared to those of patients with NEC (p = 0.002 and p = 0.028). High Ki-67 proliferative index (> 50%) was significantly associated with poor survival outcomes. CONCLUSION: CAPTEM showed favorable survival outcomes in patients with metastatic intermediate to high-grade pNENs. Our study supports that CAPTEM may be an effective treatment option for metastatic pNENs.

Proton Beam Therapy for Treatment-Naïve Hepatocellular Carcinoma and Prognostic Significance of Albumin-Bilirubin (ALBI) Grade.

To evaluate the efficacy of proton beam therapy (PBT) as an initial treatment in treatment-naïve hepatocellular carcinoma (HCC) patients and to assess the prognostic significance of albumin-bilirubin (ALBI) grade, 46 treatment-naïve HCC patients treated with PBT were analyzed. The ALBI grade distribution was grade 1 in 11 (23.9%) patients, grade 2 in 34 (73.9%) patients, and grade 3 in 1 (2.2%) patient. The median duration of follow-up was 56.5 months (95% confidence interval [CI], 48.2−64.7). Among the 46 patients, disease progression was observed in 23 (50%) patients: local progression in 3 (6.5%) patients; intrahepatic progression in 22 (47.8%); and extrahepatic progression in 5 (10.9%). The 5-year freedom from local progression (FFLP), progression-free survival (PFS), and overall survival (OS) rates were 92.7% (95% CI, 84.7−100.7), 43.3% (95% CI, 28.2−58.4), and 69.2% (95% CI, 54.9−83.5), respectively. In multivariate analysis, there were no independent factors for FFLP (p > 0.05 each), but tumor stage and ALBI grade were independent factors for PFS and OS (p < 0.05 each). PBT could result in comparable OS in treatment-naïve HCC patients to other recommended first-line treatments, and ALBI grade, in addition to tumor stage, could be useful for predicting OS.

Better survival of patients with hepatitis B virus-related hepatocellular carcinoma in South Korea: Changes in 16-years cohorts.

AIMS: The incidence and mortality of hepatocellular carcinoma (HCC) have decreased over time in South Korea, where hepatitis B virus (HBV) in endemic. This study investigated the changes in the characteristics and clinical outcomes of HCC patients in Korea. METHODS: Patients initially diagnosed with HCC and treated at the National Cancer Center, Korea between 2000 and 2015 (n = 4,291) were followed up until February 2017. Differences in patient characteristics and outcomes were compared between chronological cohorts: cohort A (2000-2004, n = 1,157) vs. B (2005-2009, n = 1,678) vs. C (2010-2015, n = 1,456). RESULTS: The median age of the patient cohort was 57 years (range, 13-98 years), and male predominance was noted (81.6%). HBV infection was the most common etiology (74.8%). The proportion of patients diagnosed with good liver function and small tumors (<2 cm) increased significantly over time: 74.6%, 79.9%, and 87.4% for Child-Pugh class A (p<0.001) and 8.0%, 8.5%, and 12.0% for modified UICC stage I (p<0.001) in cohorts A, B, and C, respectively. Median overall survival improved significantly over time: 14.4 months (95% confidence interval [CI], 12.0-16.8 months), 22.9 months (95% CI, 20.3-25.5 months), and 53.6 months (95% CI, 45.7-61.5 months) in cohorts A, B, and C, respectively. HBV-related patients showed significantly improved survival (12.7 vs. 20.4 vs. 64.5 months, p<0.001) associated with the use of antiviral treatments (adjusted hazard ratio, 0.72; 95% CI, 0.64-0.80). CONCLUSIONS: The survival of patients with HCC, especially HBV-related HCC, has improved significantly over time in Korea.

Sorafenib combined with radiation therapy for advanced hepatocellular carcinoma with portal and hepatic vein invasion extending to the inferior vena cava: a complete response case according to modified RECIST criteria.

The prognosis of patients with advanced hepatocellular carcinoma (HCC) with tumor thrombus extending to the inferior vena cava (IVC) is extremely poor. Herein, we present a rare case of advanced HCC that was treated with sorafenib and radiotherapy, leading to complete remission. This patient had a 9 cm infiltrative HCC occupying almost the entire left lobe with a tumor thrombus extending through the hepatic vein, IVC, and left portal vein. The patient received 400 mg sorafenib twice daily. One year after the start of sorafenib, intensity-modulated radiation therapy for viable HCC and tumor thrombus was performed with a dose of 5,500 cGy. Twenty-seven months after the starting date of sorafenib, there was no intratumoral arterial enhancement, which suggested a complete response according to the modified RECIST criteria. This case suggests that the combination of sorafenib and radiotherapy might provide clinical benefits in patients with advanced HCC with IVC tumor thrombus.

Outcome of Initial Progression During Nivolumab Treatment for Hepatocellular Carcinoma: Should We Use iRECIST?

Immune response evaluation criteria in solid tumors (iRECIST) is recommended during immune checkpoint inhibitors (ICIs) treatment, due to the possibility of pseudoprogression. We evaluated the frequency of pseudoprogression in hepatocellular carcinoma (HCC) patients. This retrospective multicenter study involved 158 consecutive patients who underwent nivolumab treatment for HCC in Korea. At the initial evaluation, 94 patients presented with immune unconfirmed progressive disease, and 22 continued nivolumab. At the second evaluation, 21 of the 22 patients (95.5%) had confirmed progression and no pseudoprogression was observed. Considering low possibility of pseudoprogression, iRECIST may not be required for HCC.

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.

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.

Phase II Study of Hypofractionated Proton Beam Therapy for Hepatocellular Carcinoma.

Background: Proton beam has an excellent depth dose distribution due to its unique physical properties, and thus proton beam therapy (PBT) has been tried and showed promising outcomes in hepatocellular carcinoma (HCC). The purpose of this phase II study is to evaluate the efficacy of hypofractionated PBT in HCC. Methods: The eligibility criteria for this study were as follows: patients with HCC lesion(s) who were failed after, were difficult to treat with, or refused to other local treatments; tumor size and number of ≤7 and ≤2 cm, respectively, and HCC lesion(s) of ≥2 cm from gastrointestinal organs; Child-Pugh score of ≤7; Eastern Cooperative Oncology Group performance status ≤1; and age ≥18 years. The prescribed dose of PBT was 70 Gy equivalent in 10 fractions. The primary endpoint was 3-year local progression-free survival (LPFS) rate. Results: Forty-five patients were prospectively enrolled, and there were 35 men and 10 women with a median age of 63 years (range, 46-78 years). Thirty-seven patients had recurrent and/or residual disease, and eight patients had treatment-naive disease. All patients received the planned treatments without treatment interruption, and grade ≥3 acute toxicity did not occur. The median follow-up duration was 35.1 months (range, 11.2-56.3 months) and local progression occurred in two patients (8.7%). The 3-year rates of LPFS and overall survival (OS) were 95.2% (95% confidence interval [CI], 89.1%-100%) and 86.4% (95% CI, 72.9-99.9%), respectively. Conclusion: Hypofractionated PBT showed promising LPFS and OS, and further studies are warranted to compare PBT with other local modalities.

Development of Patient-Derived Preclinical Platform for Metastatic Pancreatic Cancer: PDOX and a Subsequent Organoid Model System Using Percutaneous Biopsy Samples.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal malignant tumor and more than 50% patients are diagnosed at metastatic stage. The preclinical model systems that reflect the genetic heterogeneity of metastatic tumors are urgently needed to guide optimal treatment. This study describes the development of patient-derived preclinical platform using very small sized-percutaneous liver gun biopsy (PLB) of metastatic pancreatic cancer, based on patient-derived xenograft (PDX)-mediated tissue amplification and subsequent organoid generation. To increase the success rate and shorten the tumor growth period, patient-derived orthotopic xenograft (PDOX) model was developed to directly implant threadlike PLB samples into the pancreas. The engraftment success rate of PDOX samples from 35 patients with metastatic PDAC was 47%, with these samples showing the potential to metastasize to distant organs, as in patients. The PDOX models retained the genetic alterations and histopathological features of the primary tumors. Tumor organoids were subsequently generated from first passage cancer cells isolated from F1 tumor tissue of PDOX that preserve the epithelial cancer characteristics and KRAS mutations of primary tumors. The response to gemcitabine of PDOX-derived organoids correlated with clinical outcomes in corresponding patients as well as PDOX models in vivo, suggesting that this PDOX-organoid system reflects clinical conditions. Collectively, these findings indicate that the proposed PDOX-organoid platform using PLB samples assessed both in vitro and in vivo could predict drug response under conditions closer to those found in actual patients, as well as enhancing understanding of the complexity of metastatic PDAC.

Does Risk-Adapted Proton Beam Therapy Have a Role as a Complementary or Alternative Therapeutic Option for Hepatocellular Carcinoma?

To evaluate the role of risk-adapted proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients, a total of 243 HCC patients receiving risk-adapted PBT with three dose-fractionation regimens (regimen A [n = 40], B [n = 60], and C [n = 143]) according to the proximity of their gastrointestinal organs (<1 cm, 1⁻1.9 cm, and ≥2 cm, respectively) were reviewed: The prescribed doses to planning target volume 1 (PTV1) were 50 gray equivalents (GyE) (EQD2 [equivalent dose in 2 Gy fractions], 62.5 GyE10), 60 GyE (EQD2, 80 GyE10), and 66 GyE (EQD2, 91.3 GyE10) in 10 fractions, respectively, and those of PTV2 were 30 GyE (EQD2, 32.5 GyE10) in 10 fractions. In all patients, the five-year local recurrence-free survival (LRFS) and overall survival (OS) rates were 87.5% and 48.1%, respectively, with grade ≥3 toxicity of 0.4%. In regimens A, B, and C, the five-year LRFS and OS rates were 54.6%, 94.7%, and 92.4% (p < 0.001), and 16.7%, 39.2%, and 67.9% (p < 0.001), respectively. The five-year OS rates of the patients with the Modified Union for International Cancer Control (mUICC) stages I, II, III, and IVA and Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C were 69.2%, 65.4%, 43.8%, and 26.6% (p < 0.001), respectively, and 65.1%, 40%, and 32.2% (p < 0.001), respectively. PBT could achieve promising long-term tumor control and have a potential role as a complementary or alternative therapeutic option across all stages of HCC.

Optimal time of tumour response evaluation and effectiveness of hypofractionated proton beam therapy for inoperable or recurrent hepatocellular carcinoma.

OBJECTIVE: To evaluate the optimal time of tumour response and effectiveness of hypofractionated proton beam therapy (PBT) for hepatocellular carcinoma (HCC). RESULTS: Overall, treatment was well tolerated with no grade toxicity ≥3. Of 71 patients, 66 patients (93%) eventually reached complete response (CR) after PBT: 93.9% (62 of 66) of patients who reached CR within 12 months, and the remaining 4 patients (6.1%) reached CR at 12.5, 16.2, 19.1 and 21.7 months, respectively. The three-year local progression-free survival (LPFS), relapse-free survival (RFS) and OS rates were 89.9%, 26.8%, and 74.4%, respectively. Multivariate analysis revealed that the tumour response was an independent prognostic factor for LPFS, RFS, and OS. CONCLUSION: Most CR was achieved within 1 year after PBT and further salvage treatments in PBT field might be postponed up to approximately 18-24 months. Hypofractionated PBT could be good alternative for HCC patients who are unsuitable for surgical or invasive treatments with curative intent. MATERIALS AND METHODS: Seventy-one inoperable or recurrent HCC patients underwent hypofractionated PBT using 66 GyE in 10 fractions. The tumour responses were defined as the maximal tumour response observed during the follow-up period using the modified Response Evaluation Criteria in Solid Tumors criteria.

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.

Risk-adapted simultaneous integrated boost-proton beam therapy (SIB-PBT) for advanced hepatocellular carcinoma with tumour vascular thrombosis.

PURPOSE: To evaluate clinical effectiveness and safety of simultaneous integrated boost-proton beam therapy (SIB-PBT) in hepatocellular carcinoma (HCC) patients with tumour vascular thrombosis (TVT). MATERIAL AND METHODS: Forty-one HCC patients with TVT underwent SIB-PBT using three dose-fractionation schemes: if gross tumour volume <1cm (n=27), 1-1.9cm (n=7), and ⩾2cm (n=7) from gastrointestinal structures, 50GyE (EQD2, 62.5GyE10), 60Gy (EQD2, 80GyE10), 66Gy (EQD2, 91.3GyE10), respectively, in 10 fractions was prescribed to planning target volume 1 (PTV1), and 30GyE (EQD2, 32.5GyE10) in 10 fractions was prescribed to PTV2. RESULTS: Overall, treatment was well tolerated, with no grade toxicity ⩾3. Median overall survival (OS) was 34.4months and 2-year local progression-free survival (LPFS), relapse free survival (RFS), and OS rates were 88.1%, 25%, and 51.1%, respectively. Patients treated with EQD2 of ⩾80GyE10 tended to show better TVT response (92.8% vs. 55.5%, p=0.002) 2-year LPFS (92.9% vs. 82.5%, p=0.463), RFS (28.8% vs. 19%, p=0.545), and OS (58.4% vs. 46.8%, p=0.428) rates than those with EQD2 of <80GyE10. Multivariate analysis showed that TVT response and Child Pugh classification were independent prognostic factors for OS. CONCLUSIONS: SIB-PBT is feasible and promising for HCC patients with TVT.