Purpose: Risk factors predicting distant metastasis (DM) in extrahepatic bile duct cancer (EHBDC) patients treated with curative resection were investigated. Materials and Methods: Medical records of 1,418 EHBDC patients undergoing curative resection between Jan 2000 and Dec 2015 from 14 institutions were reviewed. After resection, 924 patients (67.6%) were surveilled without adjuvant therapy, 297 (21.7%) were treated with concurrent chemoradiotherapy (CCRT) and 148 (10.8%) with CCRT followed by chemotherapy. To exclude the treatment effect from innate confounders, patients not treated with adjuvant therapy were evaluated. Results: After a median follow-up of 36.7 months (range, 2.7 to 213.2 months), the 5-year distant metastasis-free survival (DMFS) rate was 57.7%. On multivariate analysis, perihilar or diffuse tumor (hazard ratio [HR], 1.391; p=0.004), poorly differentiated histology (HR, 2.014; p < 0.001), presence of perineural invasion (HR, 1.768; p < 0.001), positive nodal metastasis (HR, 2.670; p < 0.001) and preoperative carbohydrate antigen (CA) 19-9 ≥ 37 U/mL (HR, 1.353; p < 0.001) were significantly associated with inferior DMFS. The DMFS rates significantly differed according to the number of these risk factors. For validation, patients who underwent adjuvant therapy were evaluated. In patients with ≥ 3 factors, additional chemotherapy after CCRT resulted in a superior DMFS compared with CCRT alone (5-year rate, 47.6% vs. 27.7%; p=0.001), but the benefit of additional chemotherapy was not observed in patients with 0-2 risk factors. Conclusion Tumor location, histologic differentiation, perineural invasion, lymph node metastasis, and preoperative CA 19-9 level predicted DM risk in resected EHBDC. These risk factors might help identifying a subset of patients who could benefit from additional chemotherapy after resection.

Purpose: Clinical prognostic criteria using preoperative factors were not developed for post–neoadjuvant therapy (NAT) surgery of pancreatic ductal adenocarcinoma (PDAC). We aimed to identify preoperative factors associated with overall survival (OS) in PDAC patients who underwent post-NAT curative-intent surgery and develop risk stratification criteria. Materials and Methods: Consecutive PDAC patients who underwent post-NAT curative-intent surgeries between 2007 and 2020 were retrospectively analyzed. Demographic, laboratory, surgical, and histopathologic variables were collected. Baseline, preoperative, and interval changes of computed tomography (CT) findings proposed by the Society of Abdominal Radiology and the American Pancreatic Association were analyzed. Cox proportional hazard analysis was used to select preoperative variables associated with OS. We developed risk stratification criteria composed of the significant preoperative variables, i.e., post-NAT response criteria. We compared the discrimination performance of post-NAT response criteria with that of post-NAT pathological (yp) American Joint Cancer Committee TNM staging system. Results: One hundred forty-five PDAC patients were included. Stable or increased tumor size on CT (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.58 to 4.21; p < 0.001) and elevated preoperative carbohydrate antigen 19-9 (CA19-9) level (HR, 1.98; 95% CI, 1.11 to 3.55; p=0.021) were independent factors of OS. The OS of the patient groups stratified by post-NAT response criteria which combined changes in tumor size and CA19-9 showed significant difference (p < 0.001). Such stratification was comparable to ypTNM staging in discrimination performance (difference of C-index, 0.068; 95% CI, –0.012 to 0.142). Conclusion “Any degree of decrease in tumor size on CT” and CA19-9 normalization or staying normal were independent favorable factors of OS. The combination of the two factors discriminated OS comparably to ypTNM staging.

Purpose: The locally advanced unresectable intrahepatic cholangiocarcinoma (ICC) has detrimental oncological outcomes. In this study, we aimed to investigate the efficacy of radiotherapy in patients with locally advanced unresectable ICC. Materials and Methods: Between 2001 and 2021, 116 patients were identified through medical record who underwent radiotherapy for locally advanced unresectable ICC. The resectability of ICC is determined by the multidisciplinary team at each institution. Overall survival (OS) were analyzed using the Kaplan-Meier method, and prognostic factors were analyzed using the Cox proportional hazards model. Results: The median equivalent radiotherapy dose in 2 Gy fractions (EQD2) was 52 Gy (range, 30 to 110 Gy). Forty-seven patients (40.5%) received sequential gemcitabine-cisplatin based chemotherapy (GEM-CIS CTx). Multivariate analysis identified two risk factors, EQD2 of ≥ 60 Gy and application of sequential GEM-CIS CTx for OS. Patients were grouped by these two risk factors: group 1, EQD2 ≥ 60 Gy with sequential GEM-CIS CTx (n=25); group 2, EQD2 < 60 Gy with sequential GEM-CIS CTx or fluoropyrimidine-based concurrent chemoradiotherapy (n=70); and group 3, radiotherapy alone (n=21). Curative resection was more frequently undergone in group 1 than in groups 2 or 3 (28% vs. 8.6% vs. 0%, respectively). Consequently, OS was significantly better in group 1 than in groups 2 and 3 (p < 0.05). Conclusion Combined high-dose radiotherapy with sequential GEM-CIS CTx improved oncologic outcomes in patients with locally advanced unresectable ICC. Further prospective studies are required to validate these findings.

Hepatocellular carcinoma (HCC) is a highly lethal cancer with limited treatment options and poor prognosis. Carbon ion radiotherapy (CIRT) has emerged as a promising treatment modality for HCC due to its unique physical and biological properties. CIRT uses carbon ions to target and destroy cancer cells with a high precision and efficacy. The Bragg Peak phenomenon allows precise dose delivery to the tumor while minimizing damage to healthy tissues. In addition, the high relative biological effectiveness of carbon ions can be shown against radioresistant and hypoxic tumor areas. CIRT also offers a shorter treatment schedule than conventional radiotherapy, which increases patient convenience and compliance. The clinical outcomes of CIRT for HCC have shown excellent local control rates with minimal side effects. Considering its physical and biological properties, CIRT may be a viable option for complex clinical scenarios such as patients with poor liver function, large tumors, re-irradiation cases, and tumors close to critical organs. Further research and larger studies are needed to establish definitive indications for CIRT and to compare its efficacy with that of other treatment modalities. Nevertheless, CIRT offers a potential breakthrough in HCC management, providing hope for improved therapeutic outcomes and reduced treatment-related toxicities.

Recently, the superiority of atezolizumab plus bevacizumab (AteBeva) over sorafenib was proven in the IMbrave150 trial, and AteBeva became the first-line systemic treatment for untreated, unresectable hepatocellular carcinoma (HCC). While the results are encouraging, more than half of patients with advanced HCC are still being treated in a palliative setting. Radiotherapy (RT) is known to induce immunogenic effects that may enhance the therapeutic efficacy of immune checkpoint inhibitors. Herein, we report the case of a patient with advanced HCC with massive portal vein tumor thrombosis treated with a combination of RT and AteBeva, who showed near complete response in tumor thrombosis and favorable response to HCC. Although this is a rare case, it shows the importance of reducing the tumor burden via RT to combination immunotherapy in patients with advanced HCC.

Hepatocellular carcinoma (HCC) with distant metastasis is an absolute contraindication for liver transplantation (LT). However, it is still unclear whether LT is feasible or acceptable in such patients, albeit after being treated with a multidisciplinary approach and after any metastatic lesion is ruled out. We report one such successful treatment with living donor LT (LDLT) after completely controlling far-advanced HCC with inferior vena cava tumor thrombosis and multiple lung metastases. The patient has been doing well without HCC recurrence for eight years since LDLT. The current patient could be an anecdotal case, but provides a case for expanding LDLT indications in the context of advanced HCC and suchlike.

The clinical efficacy of local ablative treatment for oligometastasis is widely accepted in most cancers. However, due to limited data, this has not been the case for hepatocellular carcinoma (HCC). Here, we report a case of pulmonary oligometastasis of a huge HCC that was treated by multimodality with liver-directed concurrent chemoradiotherapy (CCRT) plus subsequent resection of the primary lesion and local ablative radiotherapy (RT) for subsequent lung oligometastatic lesions. In this patient, liver-directed CCRT induced significant tumor shrinkage with compensatory hypertrophy of the non-tumor liver, followed by curative resection. Surgical resection of the first and second pulmonary metastatic lesions as well as local ablative RT of the third lesion achieved complete tumor regression, which led to long-term survival of 6 years. Therefore, the active use of local ablative RT requires full consideration in cases of oligometastatic HCC.

Purpose: The optimal timing for radiotherapy (RT) after incomplete transarterial chemoembolization (TACE) remains unclear. This study investigated the optimal timing to initiate RT after incomplete TACE in patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. Materials and Methods: This study included 116 lesions in 104 patients who were treated with RT after TACE between 2001 and 2016. The time interval between the last TACE session and RT initiation was retrospectively analyzed. The optimal cut-off time interval that maximized the difference in local failure-free rates (LFFRs) was determined using maximally selected rank statistics. Results: The median time interval was 26 days (range: 2–165 days). At a median follow-up of 18 months (range: 3–160 months), the median overall survival was 18 months. The optimal cut-off time interval appeared to be 5 weeks; using this cut-off, 65 and 39 patients were classified into early and late RT groups, respectively. Early RT group had a significantly poorer Child-Pugh class and higher alpha-fetoprotein levels compared to late RT group. Other characteristics, including tumor size (7 cm vs. 6 cm; p=0.144), were not significantly different between the groups. The 1-year LFFR was significantly higher in the early RT group than in the late RT group (94.6% vs. 70.8%; p=0.005). On multivariate analysis, early RT was identified as an independent predictor of favorable local failure-free survival (hazard ratio: 3.30, 95% confidence interval: 1.50–7.29; p=0.003). Conclusion The optimal timing for administering RT after incomplete TACE is within 5 weeks. Early administration of RT is associated with better local control.

Purpose: Radiation-induced lymphopenia is associated with worse outcomes in solid tumors. We assessed the impact of interleukin-7 (IL-7), a key cytokine in lymphocyte homeostasis, on radiation-induced lymphopenia. Materials and Methods: A post-hoc analysis was performed in a prospective cohort of 98 patients with hepatocellular carcinoma who were treated with radiotherapy in 2016-2018. Blood IL-7 levels were assayed before and at the end of radiotherapy. Acute severe lymphopenia (ASL) was defined as a total lymphocyte count of < 200/μL during radiotherapy. Cox and logistic regression analyses were performed to identify predictors of survival and ASL development, respectively. Results: Patients with ASL (n=41) had significantly poorer overall survival than those without (12.0 months vs. 25.3 months, p=0.001). Patients with lymphocyte recovery showed significantly longer overall survival than those without (21.8 months vs. 10.3 months, p=0.042). ASL was an independent predictor of poor survival (hazard ratio, 2.07; p=0.015). Patients with ASL had significantly lower pre-radiotherapy IL-7 levels (2.07 pg/mL vs. 3.01 pg/mL, p=0.010). A high pre-radiotherapy IL-7 level was an independent predictor of a reduced risk of ASL development (hazard ratio, 0.40; p=0.004). IL-7 levels reflected a feedback response to ASL, with a higher ΔIL-7 in patients with ASL and a lower ΔIL-7 in those without ASL (0.48 pg/mL vs. –0.66 pg/mL, p < 0.001). Post-radiotherapy IL-7 levels were significantly positively correlated with the total lymphocyte counts at 2 months. Conclusion IL-7 is associated with the development of and recovery from ASL, which may impact survival. To overcome radiation-induced lymphopenia, a novel strategy using IL-7 may be considered.

Purpose: The optimal timing for radiotherapy (RT) after incomplete transarterial chemoembolization (TACE) remains unclear. This study investigated the optimal timing to initiate RT after incomplete TACE in patients with Barcelona Clinic Liver Cancer stage B hepatocellular carcinoma. Materials and Methods: This study included 116 lesions in 104 patients who were treated with RT after TACE between 2001 and 2016. The time interval between the last TACE session and RT initiation was retrospectively analyzed. The optimal cut-off time interval that maximized the difference in local failure-free rates (LFFRs) was determined using maximally selected rank statistics. Results: The median time interval was 26 days (range: 2–165 days). At a median follow-up of 18 months (range: 3–160 months), the median overall survival was 18 months. The optimal cut-off time interval appeared to be 5 weeks; using this cut-off, 65 and 39 patients were classified into early and late RT groups, respectively. Early RT group had a significantly poorer Child-Pugh class and higher alpha-fetoprotein levels compared to late RT group. Other characteristics, including tumor size (7 cm vs. 6 cm; p=0.144), were not significantly different between the groups. The 1-year LFFR was significantly higher in the early RT group than in the late RT group (94.6% vs. 70.8%; p=0.005). On multivariate analysis, early RT was identified as an independent predictor of favorable local failure-free survival (hazard ratio: 3.30, 95% confidence interval: 1.50–7.29; p=0.003). Conclusion The optimal timing for administering RT after incomplete TACE is within 5 weeks. Early administration of RT is associated with better local control.