Presence Of Extrahepatic Metastases Research Articles

Safety and immunological effects of ablative radiotherapy followed by pembrolizumab in patients with advanced adrenocortical carcinoma.

TPS4630 Background: Adrenocortical carcinoma (ACC) is a rare and aggressive cancer with poor prognosis. While pembrolizumab is a NCCN recommended treatment, our prior study showed no benefit in patients with liver metastases (NCT02673333).1 Preclinical evidence suggests combining liver-directed radiation therapy (RT) with pembrolizumab might enhance anti-tumor immunity.2 Our current study will assess the safety and describe preliminary efficacy data for ablative RT to symptomatic liver metastases followed by treatment with pembrolizumab in patients with advanced ACC. Methods: This is a single-center pilot study. Main inclusion criteria include: adult patients with metastatic ACC with symptomatic liver metastases, presence of extrahepatic metastases, ECOG 0-1. Ablative RT in 5 or 10 once daily fractions will be delivered over 1 to 2 weeks; pembrolizumab treatment (200mg Q3W) will begin one week after RT completion. The primary objective is to evaluate the safety of treatment with ablative RT followed by pembrolizumab. The study will include a 6 patient safety lead-in, with 10 to 12 patients enrolled in total. The secondary endpoint, efficacy, is defined as the objective response (partial and complete response) according to RECIST v1.1, in the hepatic and extrahepatic disease. Correlative objectives include evaluation of the innate and adaptive immune response during treatment through analysis of pre- and on-treatment blood and tumor tissue samples, circulating tumor (ct) DNA analyses, and PD-L1 and next-generation sequencing testing in pre-treatment tumor tissue samples to evaluate for biomarkers of response and resistance. This trial began enrollment in 9/27/2023, with 3 patients enrolled to date.

Establishment and evaluation of a prognostic model for patients with unresectable gastric cancer liver metastases.

Liver metastases (LM) is the primary factor contributing to unfavorable outcomes in patients diagnosed with gastric cancer (GC). The objective of this study is to analyze significant prognostic risk factors for patients with GCLM and develop a reliable nomogram model that can accurately predict individualized prognosis, thereby enhancing the ability to evaluate patient outcomes. To analyze prognostic risk factors for GCLM and develop a reliable nomogram model to accurately predict individualized prognosis, thereby enhancing patient outcome assessment. Retrospective analysis was conducted on clinical data pertaining to GCLM (type III), admitted to the Department of General Surgery across multiple centers of the Chinese PLA General Hospital from January 2010 to January 2018. The dataset was divided into a development cohort and validation cohort in a ratio of 2:1. In the development cohort, we utilized univariate and multivariate Cox regression analyses to identify independent risk factors associated with overall survival in GCLM patients. Subsequently, we established a prediction model based on these findings and evaluated its performance using receiver operator characteristic curve analysis, calibration curves, and clinical decision curves. A nomogram was created to visually represent the prediction model, which was then externally validated using the validation cohort. A total of 372 patients were included in this study, comprising 248 individuals in the development cohort and 124 individuals in the validation cohort. Based on Cox analysis results, our final prediction model incorporated five independent risk factors including albumin levels, primary tumor size, presence of extrahepatic metastases, surgical treatment status, and chemotherapy administration. The 1-, 3-, and 5-years Area Under the Curve values in the development cohort are 0.753, 0.859, and 0.909, respectively; whereas in the validation cohort, they are observed to be 0.772, 0.848, and 0.923. Furthermore, the calibration curves demonstrated excellent consistency between observed values and actual values. Finally, the decision curve analysis curve indicated substantial net clinical benefit. Our study identified significant prognostic risk factors for GCLM and developed a reliable nomogram model, demonstrating promising predictive accuracy and potential clinical benefit in evaluating patient outcomes.

Debulking hepatectomy for colorectal liver metastasis: Analysis of risk factors for progression free survival

BackgroundThe study explores the role of liver debulking surgery in cases of unresectable colorectal liver metastases (CRLM), challenging the traditional notion that surgery is not a valid option in such scenarios. Materials and methodsPatients with advanced but resectable disease who underwent surgery with a curative intent (Group I) and those with advanced incompletely resectable disease who underwent a “debulking” hepatectomy (Group II) were compared. ResultsThere was no difference in the intra-operative and post-operative results between the two groups. The 3-year and 5-year OS rates were 69% and 47% for group 1 vs 64% and 35% for group 2 respectively (p = 0.14). The 3-year and 5-year PFS rates were 32% and 21% for group 1 vs 12% and 8% for group 2 respectively (p = 0.009). Independent predictors of PFS in the debulking group were bilobar metastases (HR = 2.70; p = 0.02); the presence of extrahepatic metastasis (HR = 2.65, p = 0.03) and the presence of more than 9 metastases (HR = 2.37; p = 0.04). Iterative liver surgery for CRLM was a significant protective factor (HR = 0.34, p = 0.04). ConclusionAn aggressive palliative surgical approach may offer a survival benefit for selected patients with unresectable CRLM, without increasing the morbidity. The decision for surgery should be made on a case-by-case basis.

Pituitary metastasis arising from hepatocellular carcinoma: a case report and update of the literature.

Hepatocellular carcinoma (HCC) is the sixth most common neoplasia and the third leading cause of cancer-associated deaths worldwide. Most cases arise in patients with cirrhosis, and early detection through periodic screening can make it potentially curable. The presence of extrahepatic metastases (EHM) affects treatment decisions and curability. The lungs are the most common site for EHM, followed by lymph nodes, bones, and the adrenal glands. Interestingly, approximately only 15 cases of HCC metastasizing to the pituitary gland have been reported so far.The most common symptoms of pituitary metastasis (PM) arising from HCC are nerve palsies affecting the third, fourth, and sixth cranial nerves. Other symptoms, such as diabetes insipidus or pituitary insufficiencies, are present in a minority of cases. Detecting PM is difficult given its rarity. Gold-standard treatments for these patients have not yet been established, but the prognosis is dismal, with a median overall survival of only 4.5 months. In this paper, we present an interesting case of PM as the first symptom of an HCC in a 75-year-old female. We also present an overview of all cases reported to date with emphasis on symptom presentation and survival after diagnosis.Given the improvement of systemic therapy, more cases are diagnosed in both oligometastatic and palliative conditions. Therefore, better approaches and treatment modalities for extrahepatic metastases due to HCC should be defined.

Confounding mitigation for the exposure-response relationship of bevacizumab in colorectal cancer patients.

The exposure-response relationship of bevacizumab may be confounded by various factors, including baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response, requiring effective mitigation. This study aimed to investigate the exposure-response relationships of bevacizumab in metastatic colorectal cancer (mCRC) patients while mitigating potential biases. Bevacizumab pharmacokinetics was described using target-mediated drug disposition modelling. Relationships between target kinetics, progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both prognostic-driven and response-driven potential biases were mitigated. These models evaluated the impact of increased antigen target levels, clearance and intensified dosing regimen on survival. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were baseline target levels (R0 = 8.4nM), steady-state dissociation constant (KSS = 10 nM) and antibody-target complexes elimination constant (kint = 0.52 day-1). The distribution of R0 was significantly associated with increased baseline concentrations of carcinoembryonic antigen, circulating vascular endothelial growth factor and the presence of extrahepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increasing baseline target levels and/or clearance values led to decreased bevacizumab unbound concentrations, increased R levels and shortened PFS and OS, while increasing bevacizumab dose led to decreased R and longer survival. This study is the first to demonstrate the relationship between bevacizumab concentrations, target involvement and clinical efficacy by effectively mitigating potential sources of bias. Most of the target amount may be tumoural in mCRC. Future studies should provide a more in-depth description of this relationship.

Development and Assessment of Nomogram Based on AFP Response for Patients with Unresectable Hepatocellular Carcinoma Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have been increasingly used to treat hepatocellular carcinoma (HCC). Prognostic biomarkers are an unmet need. We aimed to develop a prognostic nomogram for patients with unresectable HCC receiving ICIs therapy. A total of 120 patients with unresectable HCC receiving ICIs treatment were enrolled in this study. Patients were randomly divided into a training set (n = 84) and a validation set (n = 36) in a 7:3 ratio. Clinical characteristics were retrospectively analyzed. Serum α-fetoprotein protein (AFP) response was defined as a decline of ≥20% in AFP levels within the initial eight weeks of treatment. Univariable and multivariable Cox analyses were used to select relevant variables and construct the nomogram. The areas under the receiver operating characteristic curves (AUCs) were used to determine the performance of the model. Kaplan-Meier analysis with the log-rank test was used to compare different risk groups. The median progression-free survival (PFS) was 7.7 months. In the multivariate Cox analysis, the presence of extrahepatic metastasis (hazard ratio [HR] = 2.08, 95% confidence interval [CI]: 1.02-4.27, p < 0.05), white blood cell count (HR = 3.48, 95% CI: 1.02-11.88, p < 0.05) and AFP response (HR = 0.41, 95% CI: 0.18-0.95, p < 0.05) independently predicted PFS. A nomogram for PFS was established with AUCs of 0.79 and 0.70 in the training and validation sets, respectively. The median PFS of the high- and low-risk subgroups was 3.5 and 11.7 months, respectively (p < 0.05). The nomogram could predict PFS in patients with unresectable HCC receiving ICIs treatment and further help decision making in daily clinical practice.

Real-World Data on the Diagnosis, Treatment, and Management of Hepatocellular Carcinoma in the Asia-Pacific: The INSIGHT Study

Introduction: Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and the third leading cause of cancer death worldwide. While there has been rapid evolution in the treatment paradigm of HCC across the past decade, the extent to which these newly approved therapies are utilized in clinical practice in the real world is, however, unknown. The INSIGHT study was an investigator-initiated, multi-site longitudinal cohort study conducted to reflect real-world epidemiology and clinical practice in Asia-Pacific in the immediate 7-year period after the conclusion of the BRIDGE study. Methods: Data were collected both retrospectively (planned 30% of the total cohort size) and prospectively (planned 70%) from January 2013 to December 2019 from eligible patients newly diagnosed with HCC from 33 participating sites across 9 Asia-Pacific countries. Results: A total of 2,533 newly diagnosed HCC patients (1,052 in retrospective cohort and 1,481 in prospective cohort) were enrolled. The most common risk factor was hepatitis B in all countries except Japan, Australia, and New Zealand, where the prevalence of hepatitis C and diabetes were more common. The top three comorbidities reported in the INSIGHT study include cirrhosis, hypertension, and diabetes. We observe high heterogeneity in the first-line treatment recorded across countries and across disease stages, which significantly affects survival outcomes. Stratification by factors such as etiologies, tumor characteristics, the presence of extrahepatic metastases or macrovascular invasion, and the use of subsequent lines of treatment were performed. Conclusion: The INSIGHT study describes a wide spectrum of clinical management practices in HCC, where patient demographics, differential costs, and patient access to therapies may lead to wide geographical variations through the patient’s treatment cycle, from diagnosis to clinical outcome. The high heterogeneity in patient outcomes demonstrates the need for more robust and clinical management strategies to be designed and adopted to bring about better patient outcomes.

Neuroendocrine liver metastases treated using transarterial radioembolization: Identification of prognostic parameters at 68Ga-DOTATATE PET/CT

PurposeTo identify prognostic clinical and imaging parameters for patients with neuroendocrine liver metastases (NELMs) undergoing transarterial radioembolization (TARE). Materials and methodsForty-seven patients (27 men; mean age, 64 years) with NELMs who received TARE, along with pre-procedure liver MRI and 68Ga-DOTATATE positron emission tomography/computed tomography were included. Apparent diffusion coefficient and standardized uptake value (SUV) of three liver metastases, normal spleen and liver were measured. SUVmax or SUVmean were used for the calculation of tumor-to-organ ratios (tumor-to-spleen and tumor-to-liver ratios) using all possible combinations (including SUVmax/SUVmax, SUVmax/SUVmean, and SUVmean/SUVmean). Clinical parameters (hepatic tumor-burden, presence of extra-hepatic metastases, chromograninA, Ki-67 and bilirubin levels) were assessed. Overall survival, progression-free survival (PFS) and hepatic progression-free survival (HPFS) were calculated using Kaplan-Meier curves. ResultsMedian overall survival, PFS and HPFS were 49.6, 13.1 and 28.3 months, respectively. In multivariable Cox regression analysis, low Ki-67 (≤ 5%), low hepatic tumor-burden (< 10%), absence of extrahepatic metastases, and increased Tmean/Lmax ratio were significant prognostic factors of longer overall survival and HPFS. High baseline chromograninA (> 1330 ng/mL) was associated with shorter HPFS. Tmean/Lmax > 1.9 yielded a median overall survival of 69 vs. 33 months (P < 0.04), and a median HPFS of 30 vs. 19 months (P = 0.09). For PFS, high baseline SUVmax of NELMs was the single significant parameter in the multivariable model. SUVmax > 28 resulted in a median PFS of 16.9 vs. 6.5 months, respectively (P = 0.001). ConclusionHigh preinterventional Tmean/Lmax ratios, and high SUVmax on 68Ga-DOTATATE positron emission tomography/computed tomography seem to have prognostic value in patients with NELMs undergoing TARE, potentially aiding patient selection and management alongside conventional variables.

Prediction of Local Tumor Progression After Microwave Ablation in Colorectal Carcinoma Liver Metastases Patients by MRI Radiomics and Clinical Characteristics-Based Combined Model: Preliminary Results

To investigate the predictability of local tumor progression (LTP) after microwave ablation (MWA) in colorectal carcinoma liver metastases (CRLM) patients by magnetic resonance imaging (MRI) radiomics and clinical characteristics-based combined model. Forty-two consecutive CRLM patients (67 tumors) with post-MWA complete response at 1st month MRI were included in this retrospective study. One hundred and eleven radiomics features were extracted for each tumor and for each phase by manual segmentation from pre-treatment MRI T2 fat-suppressed (Phase 2) and early arterial phase T1 fat-suppressed sequences (Phase 1). A clinical model was constructed using clinical data, two combined models were created with feature reduction and machine learning by combining clinical data and Phase 2 and Phase 1 radiomics features. The predicting performance for LTP development was investigated. LTP developed in 7 patients (16.6%) and 11 tumors (16.4%). In the clinical model, the presence of extrahepatic metastases before MWA was associated with a high probability of LTP (p < 0.001). The pre-treatment levels of carbohydrate antigen 19-9 and carcinoembryonic antigen were higher in the LTP group (p = 0.010, p = 0.020, respectively). Patients with LTP had statistically significantly higher radiomics scores in both phases (p < 0.001 for Phase 2 and p = 0.001 for Phase 1). The classification performance of the combined model 2, created by using clinical data and Phase 2-based radiomics features, achieved the highest discriminative performance in predicting LTP (p = 0,014; the area under curve (AUC) value 0.981 (95% CI 0.948-0.990). The combined model 1, created using clinical data and Phase 1-based radiomics features (AUC value 0,927 (95% CI 0.860-0.993, p < 0.001)) and the clinical model alone [AUC value of 0.887 (95% CI 0.807-0.967, p < 0.001)] had similar performance. Combined models based on clinical data and radiomics features obtained from T2 fat-suppressed and early arterial-phase T1 fat-suppressed MRI are valuable markers in predicting LTP after MWA in CRLM patients. Large-scale studies with internal and external validations are needed to come to a firm conclusion on the predictability of radiomics models in CRLM patients.

Efficacy and tolerance of LV5FU2-carboplatin chemotherapy in patients with advanced pancreatic ductal adenocarcinoma after failure of standard regimens.

Chemotherapy options in patients with advanced pancreatic ductal adenocarcinoma (PDAC) after failure of standard chemotherapies are limited. We aimed to report the efficacy and safety of the leucovorin and 5-fluorouracil (LV5FU2) and carboplatin combination in this setting. We performed a retrospective study including consecutive patients with advanced PDAC who received LV5FU2-carboplatin between 2009 and 2021 in an expert center. We measured overall survival (OS) and progression-free survival (PFS), and explored associated factors using Cox proportional hazard models. In all, 91 patients were included (55% male, median age 62), with a performance status of 0/1 in 74% of cases. LV5FU2-carboplatin was mainly used in third (59.3%) or fourth line (23.1%), with three (interquartile range: 2.0-6.0) cycles administered on average. The clinical benefit rate was 25.2%. Median PFS was 2.7 months (95% CI: 2.4-3.0). At multivariable analysis, no extrahepatic metastases (p = 0.083), no ascites or opioid-requiring pain (p = 0.023), <2 prior treatment lines (p < 0.001), full dose of carboplatin (p = 0.004), and treatment initiation >18 months after initial diagnosis (p < 0.001) were associated with longer PFS. Median OS was 4.2 months (95% CI: 3.48-4.92) and was influenced by the presence of extrahepatic metastases (p = 0.058), opioid-requiring pain or ascites (p = 0.039), and number of prior treatment lines (0.065). Prior tumor response under oxaliplatin did not impact either PFS or OS. Worsening of preexisting residual neurotoxicity was infrequent (13.2%). The most common grade 3-4 adverse events were neutropenia (24.7%) and thrombocytopenia (11.8%). Although the efficacy of LV5FU2-carboplatin appears limited in patients with pretreated advanced PDAC, it may be beneficial in selected patients.

Sporadic and MEN1-related gastrinoma and Zollinger–Ellison syndrome: differences in clinical characteristics and survival outcomes

PurposeGastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features.MethodsConsecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort.ResultsOf 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger (p = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES (p = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p = 0.034). At univariate-logistic regression, age at diagnosis (p = 0.01, OR = 1.1), G3 grading (p = 0.003, OR = 21.3), Sp-ZES (p = 0.02, OR = 0.3) and presence of extrahepatic metastases (p = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age (p = 0.04, OR = 1.0), size (p = 0.039, OR = 1.0), G3 grade (p = 0.008, OR = 14.6) and extrahepatic metastases (p = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases (p = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS (p = 0.0227). After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively.ConclusionMEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.

Significant muscle loss after stereotactic body radiotherapy predicts worse survival in patients with hepatocellular carcinoma

The relationship between sarcopenia and treatment outcomes, especially in patients with hepatocellular carcinoma (HCC) undergoing stereotactic body radiotherapy (SBRT) has not been well-explored. This study aimed to investigate the effects of sarcopenia on the survival and toxicity after SBRT in patients with HCC. We included 137 patients with HCC treated with SBRT between 2008 and 2018. Sarcopenia was defined as a skeletal muscle index (SMI) of < 49 cm2/m2 for men and < 31 cm2/m2 for women using computed tomography images at the mid-level of the third lumbar vertebra. The SMI change was presented as the change per 90 days. The Kaplan–Meier method was used for survival estimation, and the Cox regression was used to determine prognosticators. Sarcopenia was present in 67 of 137 eligible patients. With the median follow-up of 14.1 months and 32.7 months in the entire cohort and in those alive, respectively, patients with pre-SBRT sarcopenia or SMI loss ≥ 7% after SBRT had worse overall survival than their counterparts. Significant survival predictors on multivariate analysis were SMI loss ≥ 7% after SBRT [hazard ratio (HR): 1.96, p = 0.013], presence of extrahepatic metastasis (HR: 3.47, p < 0.001), neutrophil-to-lymphocyte ratio (HR: 1.79, p = 0.027), and multiple tumors (HR: 2.19, p = 0.003). Separate Cox models according to the absence and presence of pre-SBRT sarcopenia showed that SMI loss ≥ 7% remained a significant survival predictor in patients with sarcopenia (HR: 3.06, p = 0.017) compared with those without sarcopenia. SMI loss ≥ 7% is also a predictor of the Child–Pugh score increase by ≥ 2 points after SBRT. SMI loss ≥ 7% after SBRT is a significant prognostic factor for worse survival and is associated with liver toxicity compared with pre-SBRT sarcopenia.

Hepatic epithelioid hemangioendothelioma: Clinical characteristics, diagnosis, treatment, and prognosis.

BACKGROUNDHepatic epithelioid hemangioendothelioma (HEHE) is a rare hepatic vascular tumor with unpredictable malignant potential. The etiology, characteristics, diagnosis, treatment, and prognosis of HEHE are not well-understood, and large-scale retrospective studies are required to understand better this disease.AIMTo determine the characteristics of HEHE and identify its optimal treatments and prognostic factors.METHODSThe clinical data of two patients diagnosed with HEHE at the Fourth Hospital of Hebei Medical University and 258 previously reported cases retrieved from the China National Knowledge Infrastructure and PubMed databases between 1996 and 2021 were combined and summarized. All cases were pathologically identified as HEHE. Information such as clinical features, laboratory examination findings, imaging findings, pathological characteristics, treatment, and survival periods was reviewed. Kaplan-Meir curves were used for survival analysis. Prognostic factors were identified by Cox regression analysis.RESULTSHEHE primarily affected middle-aged women. The typical manifestations included epigastric pain, hepatosplenomegaly, inappetence, distension, weight loss, and fatigue. Tumor markers were expressed normally. The incidence of extrahepatic metastasis was 34.5% at the time of diagnosis. The most common sites of extrahepatic involvement were the lungs (22.3%), lymph nodes (5.6%), peritoneum (3.6%), bones (6.6%), and spleen (5.1%). Furthermore, “capsular retraction”, “target sign”, and “lollipop sign” were the characteristic features of HEHE on imaging. The immunohistochemical profile for HEHE (expression of vascular markers, such as factor VIII-related antigen, CD31, and CD34; expression levels of D2-40) can facilitate and ensure an accurate diagnosis. The management options for patients with HEHE include liver resection (29.7%), liver transplantation (16.1%), palliative treatments (12.7%), transhepatic arterial chemotherapy and embolization (TACE, 10.2%), chemotherapy (11.0%), antiangiogenic therapy (15.3%), and other treatments (5.1%); the mean survival time was 158.6, 147.3, 4.2, 90.8, 71.4, 83.1, and 55.0 mo, respectively. The survival time of patients who underwent surgical treatment was longer than that of patients who did not. TACE and antiangiogenic therapy tended to prolong survival compared with other nonsurgical treatments. The 1-, 5-, and 10-year survival rates were 82%, 71%, and 64%, respectively. Multivariate analysis showed that liver function (P = 0.045), intrahepatic metastasis (P = 0.029), and treatment (P = 0.045) were independent prognostic factors. The presence of extrahepatic metastases was not an independent risk factor for poor prognosis (P = 0.558).CONCLUSIONThe clinical course of HEHE is rare and variable, and patients with intrahepatic metastases and liver dysfunction may have a poorer prognosis than those without. Surgical intervention, whether liver resection or transplantation, might be warranted regardless of extrahepatic metastasis. For patients without the option for surgery, clinicians should consider the use of TACE with antiangiogenic drugs in the treatment of HEHE.

Efficacy and safety of sequential therapy with sorafenib and regorafenib for advanced hepatocellular carcinoma: a two-center study in China.

Regorafenib is a standard 2nd-line treatment for patients with advanced hepatocellular carcinoma (HCC), but the efficacy and safety of sequential therapy with sorafenib and regorafenib among advanced HCC patients in China is not clear. This was a retrospective, two-center, cohort study of advanced HCC patients who received sequential therapy of sorafenib and regorafenib from October 2018 to April 2020 at 2 Chinese institutions. The patients were converted directly to regorafenib after failing to respond to sorafenib monotherapy. The patients underwent evaluations every 4-6 weeks to determine the efficacy and safety of the treatment according to physiological, laboratory, and radiological results. A radiological evaluation using computed tomography or magnetic resonance imaging scans was conducted. The outcomes included overall survival (OS) and progression-free survival (PFS). A total of 43 patients received regorafenib as a 2nd-line treatment after sorafenib progression. Of these patients, 26 (60.5%) and 17 (39.5%) were diagnosed with Barcelona Clinic Liver Cancer (BCLC) stages B and C, respectively. The median PFS was 11.0 [95% confidence interval (CI): 5.8-16.2] months, and the median OS was 17.0 (95% CI: 12.8-21.2) months. Conversely, the most common toxicities were hand-foot skin reaction (48.8%), diarrhea (32.6%), and hypertension (14%). The most common grade 3-4 toxicities were hypoalbuminemia (4.7%), anemia (4.7%), and thrombocytopenia (4.7%). Alpha-fetoprotein (AFP) ≥400, alanine transaminase (ALT) ≥60 IU/L, and aspartate aminotransferase (AST) ≥60 IU/L before 2nd-line treatment were associated with PFS in the univariable analyses. The Cox proportional-hazards regression analysis showed that AFP [hazard ratio (HR) =0.225; 95% CI: 0.073-0.688; P=0.009], ALT (HR =0.195; 95% CI: 0.051-0.741; P=0.016), AST (HR =0.209; 95% CI: 0.063-0.697; P=0.011), and presence of extrahepatic metastasis (HR =0.074; 95% CI: 0.009-0.608; P=0.015) before 2nd-line treatment were independently associated with PFS. The sequential therapy of sorafenib and regorafenib is well-tolerated and effective in advanced HCC patients after sorafenib progression based on our two-center real-world data. Patients with good liver function reserve and a high level of AFP before 2nd-line treatment may benefit from sequential treatment. These results still need further validation.

Hepatic resection for breast cancer related liver metastases: A single institution experience

Liver resection for breast cancer liver metastases is becoming a more widely accepted therapeutic option for selected groups of patients. The aim of this study was to describe the outcomes of patients undergoing liver resection for breast cancer-related liver metastases and identify any variables associated with recurrence or survival. A retrospective review of a prospectively maintained database was undertaken for the 12 year period between 2009 and 2021. Clinicopathological, treatment, intraoperative, recurrence, survival and follow-up data were collected on all patients. Kaplan-Meier methods, the log-rank test and Cox proportional hazards regression analysis were used to identify variables that were associated with recurrence and survival. A total of 20 patients underwent 21 liver resections over the 12-year period. There were no deaths within 30 days of surgery and an operative morbidity occurred in 23.8% of cases. The median local recurrence free survival and disease free survival times were both 50 months, while the 5 year overall survival rate was 65%. The presence of extrahepatic metastases were associated with a decreased time to local recurrence (p < 0.01) and worse overall survival (p = 0.02). This study has demonstrated that liver resection for breast cancer-related liver metastases is feasible, safe and associated with prolonged disease free and overall survival in selected patients. It is likely that this option will be offered to more patients going forward, however, the difficulty lies in selecting out those who will benefit from liver resection particularly given the increasing number of systemic treatments and local ablative methods available that offer good long-term results.

Appropriate Surgical Selection in Patients with Breast Cancer Liver Metastases to Optimize Surgical Outcome: A Nomogram Based on a Multi-Institutional Experience

Background: The key for success in BCLM is the selection of patients and the possibility to integrate the surgical option in a multidisciplinary treatment, hence the need to focus on the factors determining a patient's prognosis following hepatectomy and to develop a nomogram to predict oncological outcome. Methods: Using a multicentric database including patients who underwent hepatectomy for BCLM at three Italian HPB referral centers between 2000 and 2018, we sought to identify the predictors of survival and develop a clinical tool to predict patient's prognosis after liver resection for BCLM. Results: 154 undergoing surgery with curative intent were included in the analysis. Number of liver lesions (HR 1.66;95% CI, 1.01–2.67; p=0.035), tumor size (HR 1.71;95% CI, 1.22–2.97; p=0.019), triple negative status (HR = 1.07; 95% CI, 1.21 – 2.76; p=0.027), presence of extrahepatic metastases (HR=1.36; 95% CI, 1.19 – 2.91, p=0.032), response to preoperative chemotherapy (HR 1.97; 95% CI, 1.56 – 3.12; p=0.028) were the predictors of recurrence free survival. The beta-coefficients from the final multivariable model were utilized to develop a nomogram. The nomogram demonstrated a good ability to predict risk of recurrence (c-index of 0.741). Patients were stratified by Predicted Recurrence Risk (PRR) groupings: PRR <20%, PRR 20–40%, PRR 40–80%, PRR >80%, which correlated with disease free-survival at 3-year of 85%, 61%, 34%, and 0%, respectively. Conclusion: The developed nomogram accurately (c-index >75 %) staged and predicted the prognosis of patients undergoing liver resection for BCLM, providing an accurate tool to select candidates to liver resection.

Efficacy and Safety of Lenvatinib for Patients With Advanced Hepatocellular Carcinoma: A Retrospective, Real-world Study Conducted in Japan.

We evaluated real-world efficacy and toxicity of lenvatinib in 142 patients with advanced hepatocellular carcinoma (HCC) at six tertiary referral centres. The patients with advanced HCC treated with lenvatinib were grouped into two categories based on REFLECT criteria for analysis of efficacy and safety. The primary endpoint was progression-free survival (PFS). The objective response rate (ORR) at week 12 of therapy was 41.5%, with a median PFS of 176 days. Child-Pugh score of 5 points, the presence of extrahepatic metastasis and adverse effects grade 2 or higher were considered independent factors associated with both better PFS and ORR. The ORR for patients who fulfilled the REFLECT inclusion criteria was significantly higher than that for those who did not. However, no significant differences in PFS were observed between the two groups. The incidence rate of adverse effects grade 3 or higher was 40.1%, which was similar for the two groups. Lenvatinib is safe and effective for patients, whether or not they satisfy REFLECT criteria. The result warrants replication in a larger study.

90Y radioembolization in the treatment of neuroendocrine neoplasms: Results of an international multicenter retrospective study.

In neuroendocrine neoplasms (NENs), the presence of distant metastases has a severe impact on survival leading to a relevant decrease in the 5-y survival rate. Here, 90Y radioembolization (90Y RE) might be an important treatment option; however, data to support clinical benefits for 90Y RE are scarce. Therefore, the purpose of this study was to analyze the use of 90Y RE in NEN patients with hepatic metastases in an international, multicenter retrospective analysis and assess the potential role of 90Y RE in a multimodal treatment concept. Methods: In total, 297 angiographic evaluations in NEN patients before 90Y RE were analyzed. Baseline characteristics and parameters derived from imaging evaluation and 90Y RE were analyzed. Tumor response was assessed using RECIST 1.1, and survival data were collected. Mean overall survival (OS) between different groups was compared using Kaplan-Meier curves and the log rank test. A P value of less than 0.05 indicated statistical significance. Results: After 90Y RE, the disease control rate according to RECIST 1.1 was 83.5% after 3 mo and 50.9% after 12 mo. OS in the entire population was 38.9 ± 33.0 mo. High tumor grade (P < 0.006) and high tumor burden (P= 0.001) were both associated with a significant decrease in OS. The presence of extrahepatic metastases (P = 0.335) and the type of metastatic vascularization pattern (P = 0.460) had no influence on OS. Patients who received 90Y RE as second-line therapy had a slightly longer but not statistically significant OS than patients who had 90Y RE in a salvage setting (44.8 vs. 30.6 mo, P= 0.078). Hepatic and global progression-free survival after 90Y RE was significantly decreased in heavily pretreated patients, compared with patients with second-line therapy (P = 0.011 and P= 0.010, respectively). Conclusion: 90Y RE could be an important alternative to peptide receptor radionuclide therapy as second-line treatment in patients with progressive liver-dominant disease pretreated with somatostatin analogs.

Treatment strategies for hepatocellular carcinoma with extrahepatic metastasis.

Extrahepatic metastasis (EHM) of hepatocellular carcinoma (HCC) has increasingly been seen due to improved survival with effective management of intrahepatic lesions. The presence of EHM indicates an advanced stage of HCC, for which systemic therapy serves as the standard treatment modality. Since the approval of Sorafenib as the first systemic agent in 2007, it took almost a decade to show its efficacy in both first and further lines of setting until the landscape of systemic drugs was finally expanded. Moreover, with inspiring results from immunotherapy trials in HCC, it appears that the introduction of immunotherapy may lead to an evolution in the portfolio of HCC treatment. Although the locoregional approach in the management of EHM is not recommended for advanced-stage HCC, efforts have been made to demonstrate its efficacy in symptom relief and potential benefit for overall survival. This review provides a summary of recent updates of the systemic agents in the treatment of advanced HCC, with an emphasis on aggressive locoregional management of EHM by various treatment modalities.

Clinical Characteristics of Long-Term Survivors After Sorafenib Treatment for Unresectable Hepatocellular Carcinoma: A Korean National Multicenter Retrospective Cohort Study.

Background/AimSorafenib is the first systemic therapy for the treatment of advanced-stage hepatocellular carcinoma (HCC) and progressive HCC after locoregional therapy. The aim of this study was to evaluate the prognostic factors of long-term survivors after sorafenib treatment.MethodsThis multicenter, retrospective, cohort study included 1,566 unresectable HCC patients who received sorafenib treatment between 2007 and 2014 in nine tertiary centers in Korea. The patients were classified into a long-term survivor group (survival more than two years, n = 257) or a control group (n = 1309). The primary outcomes were the prognostic factors affecting long-term survival. Secondary endpoints included time-to-progression and other safety profiles.ResultsThe patients were predominantly men (83.8%) with chronic hepatitis B (77.3%) and Barcelona clinic of liver cancer-stage C (BCLC-C) (78.3%). The median overall survival was 9.0 months. After treatment, eight patients (0.4%) achieved complete response and 139 patients (8.8%) achieved partial response according to the mRECIST criteria. The prognostic factors predicting long-term survival were metformin use (adjusted hazard ratio [aHR] = 3.464; P < 0.001), hand-foot skin reaction (aHR = 1.688; P = 0.003), and concomitant treatment with chemoembolization or radiotherapy (aHR = 2.766; P < 0.001). Poor prognostic factors of long-term survival were a Child-Pugh score of B (HR = 0.422; P < 0.001), the presence of extrahepatic metastasis (HR = 0.639; P = 0.005), main portal vein invasion (HR = 0.502; P = 0.001), and elevated alpha-fetoprotein (>1,000 ng/mL; HR = 0.361; P < 0.001).ConclusionThis large, multicenter, retrospective study showed an objective response rate of 9.1% and a proportion of long-term survivors of 16.4% in Korean patients. The prognostic factors derived in our study can be used in clinical practice during sorafenib treatment.