Presence Of Extrahepatic Disease Research Articles

Resection of colorectal carcinoma liver metastases: A population-based study in outcomes and factors associated with recurrent disease

ObjectiveTo assess the hepatic disease-free survival (HDFS) and overall survival (OS) of patients who underwent resection of colorectal cancer liver metastases (CRCLM) in our population, and evaluate what factors are associated with these outcomes. MethodsPatients with resected non-mucinous CRCLM between January 2013-February 2020 were retrospectively identified. Dates of diagnosis, surgery, and, if applicable, death were recorded. HDFS and OS were calculated using a census date of 24 September 2022. Separate Cox multivariate regression analyses were performed to evaluate for association between HDFS and OS and the following factors: pre-operative imaging interval (<4 weeks vs. ≥4 weeks); pre-operative imaging modality (CT only vs. MRI+CT); extrahepatic disease at time of hepatectomy (yes vs. no); tumor burden score (TBS, where TBS2 = (largest axial dimension of CRCLM)2 + (number of CRCLM)2); pT and pN; and neoadjuvant chemotherapy. Results137 subjects (mean age, 61 ± 11 years, 86 males) were included. Associations with recurrent hepatic disease were found with chemotherapy (HR 2.11[95 % CI = 1.13–3.92]), TBS (HR 1.30[95 % CI = 1.17–1.45]), MRI+CT (HR 2.12[95 % CI = 1.29–3.48]), and extrahepatic disease at hepatectomy (HR 2.16[95 % CI = 1.08–4.35]). For mortality, associations were found with TBS (HR 1.22[95 % CI = 1.09–1.37]), pT (HR 1.45[95 % CI = 1.05–2.00]), and extrahepatic disease at hepatectomy (HR 2.10[95 % CI = 1.31–3.36]). ConclusionIn our population, non-imaging related factors TBS, neoadjuvant chemotherapy, pT and presence of extrahepatic disease at time of hepatectomy were associated with HDFS and/or OS. The preoperative imaging interval and use of preoperative MRI were not associated with improved patient outcomes.

Local Treatment of Colorectal Liver Metastases in the Presence of Extrahepatic Disease: Survival Outcomes from the Amsterdam Colorectal Liver Met Registry (AmCORE).

The simultaneous presence of colorectal liver metastases (CRLMs) and extrahepatic metastases in patients with colorectal cancer (CRC) can be considered a relative contraindication for local treatment with curative intent. This study aims to assess the survival outcomes of patients with CRLMs and extrahepatic metastases after comprehensive local treatment of all metastatic sites. Patients with CRLMs who received local treatment of all metastatic sites were extracted from the prospective AmCORE registry database and subdivided into two groups: CRLM only vs. CRLM and extrahepatic metastasis. To address potential confounders, multivariate analysis was performed. The primary endpoint was overall survival (OS). In total, 881 patients with CRLM only and 60 with CRLM and extrahepatic disease were included, and the median OS was 55.7 months vs. 42.7 months, respectively. Though OS was significantly lower in patients with concomitant extrahepatic metastases (HR 1.477; 95% CI 1.029-2.121; p = 0.033), the survival curve plateaued after 6.2 years. Extrahepatic manifestations were pulmonary (43.3%), peritoneal (16.7%) and non-regional lymph node metastases (10.0%). In patients with pulmonary and non-regional lymph node metastases, OS did not significantly differ from patients with CRLM-only disease; concomitant peritoneal metastases showed an inferior OS (HR 1.976; 95% CI 1.017-3.841, p = 0.041). In this comparative series, OS was inferior for patients with multi-organ metastatic CRC versus patients with CRLMs alone. Nonetheless, the long-term survival curve plateau seemed to justify local treatment in a subset of patients with multi-organ metastatic CRC, especially for patients with CRLMs and pulmonary or lymph node metastases.

Cabozantinib plus atezolizumab versus sorafenib for advanced hepatocellular carcinoma (COSMIC-312): final results of a randomised phase 3 study

The aim of the COSMIC-312 trial was to evaluate cabozantinib plus atezolizumab versus sorafenib in patients with previously untreated advanced hepatocellular carcinoma. In the initial analysis, cabozantinib plus atezolizumab significantly prolonged progression-free survival versus sorafenib. Here, we report the pre-planned final overall survival analysis and updated safety and efficacy results following longer follow-up. COSMIC-312 was an open-label, randomised, phase 3 study done across 178 centres in 32 countries. Patients aged 18 years or older with previously untreated advanced hepatocellular carcinoma were eligible. Patients must have had measurable disease per Response Evaluation Criteria in Solid Tumours version 1.1 (RECIST 1.1), and adequate marrow and organ function, including Child-Pugh class A liver function; those with fibrolamellar carcinoma, sarcomatoid hepatocellular carcinoma, or combined hepatocellular cholangiocarcinoma were ineligible. Patients were randomly assigned (2:1:1) using a web-based interactive response system to a combination of oral cabozantinib 40 mg once daily plus intravenous atezolizumab 1200 mg every 3 weeks, oral sorafenib 400 mg twice daily, or oral single-agent cabozantinib 60 mg once daily. Randomisation was stratified by disease aetiology, geographical region, and presence of extrahepatic disease or macrovascular invasion. Dual primary endpoints were for cabozantinib plus atezolizumab versus sorafenib: progression-free survival per RECIST 1.1, as assessed by a blinded independent radiology committee, in the first 372 randomly assigned patients (previously reported) and overall survival in all patients randomly assigned to cabozantinib plus atezolizumab or sorafenib. The secondary endpoint was progression-free survival in all patients randomly assigned to cabozantinib versus sorafenib. Outcomes in all randomly assigned patients, including final overall survival, are presented. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT03755791. Between Dec 7, 2018, and Aug 27, 2020, 432 patients were randomly assigned to combination treatment, 217 to sorafenib, and 188 to single-agent cabozantinib, and included in all efficacy analyses. 704 (84%) patients were male and 133 (16%) were female. 824 of these patients received at least one dose of study treatment and were included in the safety population. Median follow-up was 22·1 months (IQR 19·3-24·8). Median overall survival was 16·5 months (96% CI 14·5-18·7) for the combination treatment group and 15·5 months (12·2-20·0) for the sorafenib group (hazard ratio [HR] 0·98 [0·78-1·24]; stratified log-rank p=0·87). Median progression-free survival was 6·9 months (99% CI 5·7-8·2) for the combination treatment group, 4·3 months (2·9-6·1) for the sorafenib group, and 5·8 months (99% CI 5·4-8·2) for the single-agent cabozantinib group (HR 0·74 [0·56-0·97] for combination treatment vs sorafenib; HR 0·78 [99% CI 0·56-1·09], p=0·05, for single-agent cabozantinib vs sorafenib). Grade 3 or 4 adverse events occurred in 281 (66%) of 429 patients in the combination treatment group, 100 (48%) of 207 patients in the sorafenib group, and 108 (57%) of 188 patients in the single-agent cabozantinib group; the most common were hypertension (37 [9%] vs 17 [8%] vs 23 [12%]), palmar-plantar erythrodysaesthesia (36 [8%] vs 18 [9%] vs 16 [9%]), aspartate aminotransferase increased (42 [10%] vs eight [4%] vs 17 [9%]), and alanine aminotransferase increased (40 [9%] vs six [3%] vs 13 [7%]). Serious adverse events occurred in 223 (52%) patients in the combination treatment group, 84 (41%) patients in the sorafenib group, and 87 (46%) patients in the single agent cabozantinib group. Treatment-related deaths occurred in six (1%) patients in the combination treatment group (encephalopathy, hepatic failure, drug-induced liver injury, oesophageal varices haemorrhage, multiple organ dysfunction syndrome, and tumour lysis syndrome), one (<1%) in the sorafenib group (general physical health deterioration), and four (2%) in the single-agent cabozantinib group (asthenia, gastrointestinal haemorrhage, sepsis, and gastric perforation). First-line cabozantinib plus atezolizumab did not improve overall survival versus sorafenib in patients with advanced hepatocellular carcinoma. The progression-free survival benefit of the combination versus sorafenib was maintained, with no new safety signals. Exelixis and Ipsen.

Liver steatosis and fibrosis as independent prognostic factors affecting survival in colorectal cancer with liver metastases.

165 Background: Colorectal cancer is one of the leading causes of cancer-related death, and the liver represents the most common site of metastases. Greater depth of tissue invasion and lymph node metastases (more advanced T and N stage) are associated with increased risk of liver metastases, but how co-pathologies of the liver associate with disease progression and survival are not known. Further, prognostic factors associated with overall survival in patients with colorectal liver metastases (CRLM) remain poorly understood. Clinical factors affecting liver morphology and biomechanical properties, such as preexisting fibrosis or steatosis, may impact the pathogenesis of CRLM and thus the clinical prognosis. Current literature is mixed about whether prior steatosis and fibrosis contribute significantly to CRLM pathogenesis and prognosis. The purpose of this study is to evaluate whether liver steatosis and fibrosis impact outcomes in patients with CRLM. Methods: All CLRM cases (n = 197) that underwent resection between 2003 and 2007 from The Cancer Imaging Archive were included in our study cohort. For each clinical covariate, we generated a univariate model for overall survival and those meeting a modest predictive threshold (p &lt; 0.15) were included in a multivariable model. These included: presence of major comorbidity, chemotherapy preceding resection of liver metastases, clinical risk score, presence of extrahepatic disease at time of diagnosis, presence of steatosis on CT imaging, percentage of residual tumor after treatment, and presence of fibrosis on CT. All statistics were performed in R (v.2022.12.0). Results: A multivariable Cox proportional hazards model identified four statistically significant clinical factors predictive of overall survival: clinical risk score (HR = 1.60, p = 0.026), presence of extrahepatic disease (HR = 2.33, p = 0.027), presence of steatosis (HR = 0.51, p = 0.0057), and fibrotic proportion of liver tissue less than 40% (HR = 2.63, p = 0.033). There were also four statistically significant clinical factors predictive of disease-free survival in the liver: chemotherapy preceding resection of liver metastases (HR = 2.28, p = 0.0011), presence of extrahepatic disease (HR = 2.18, p = 0.024), presence of steatosis (HR = 0.49, p = 0.0030), and fibrotic proportion of liver tissue less than 40% (HR = 2.74, p = 0.016). Conclusions: Our findings suggest that increased steatosis and fibrosis, as assessed by CT scans, are paradoxically protective in CRLM, showing longer disease-free survival and overall survival rates. We hypothesize that liver fibrosis and steatosis impact the microenvironment of the neoplastic cells in the liver, impairing tumor progression in this milieu. Further research is needed to assess how non-neoplastic co-pathologies resulting in biophysical changes affect tumor growth and overall survival.

Risk of relapse and patient selection for metastatic colorectal cancer liver surgery.

96 Background: Previous data on surgery for colorectal cancer (CRC) liver metastases (CRLM) documented improvement in overall survival (OS) and low perioperative mortality, but patient (pt) selection requires complex multidisciplinary work. Predictive scores such as the Comprehensive Evaluation of Relapse Risk (CERR) estimate relapse risk after surgery and help in the pre-operative decision. Objectives: This study aims to evaluate OS and progression-free survival (PFS) in a population of pts who had surgery for CRLM, and to analyse survival outcomes by risk groups, according to the CERR score. We identified individual, anatomic and biological factors with potential prognostic impact. Methods: We retrospectively analysed the medical records of pts who had CRLM surgery between January 2012 and December 2021 in two Portuguese reference centres. Outcomes for CRLM surgery were analysed by risk groups according to the CERR score of each pt (based on nodal status, preoperative CEA/CA 19.9 values, KRAS/BRAF status, presence of extrahepatic disease and modified tumour burden score). Univariate and multivariate survival analyses were performed with the log-rank test and Cox proportional-hazards regression models. Results: A total of 174 pts were included: 66,1% (n=115) male, mean age at CRLM diagnosis 62,1 (±11,5) years, 80,5% (n=140) with isolated liver metastases. Thirty-three pts (19%) had a second surgery, independently of the CERR score (chi-square p = 0,60). Eighteen (10,3%) pts had a CERR score of 0-1 (low-risk, LR), 96 (55,2%) of 2-3 (medium-risk, MR) and 60 (34,5%) of 4-5 (high-risk, HiR). With a median (MED) follow-up of 85,1 (15,6-186,5) months (mo), 100 (57.5%) pts have died. MED OS was 88,0 mo (95% confidence interval [CI] 40,6-135,4) for LR, 46,4 mo (95% CI 38,7-54,1) for MR and 30,7 mo (95% CI 23,1-38,4) for HiR pts (p=0,02); ECOG performance status was an independent prognostic factor (p=0,002) for OS. Median PFS was 88,0 mo (95% CI 6,9-169,0) for LR, 12,9 mo (95% CI 9,1-16,7) for MR and 7,7 mo (95% CI 5,9-9,4) for HiR pts (p&lt;0,001); positive resection margins and prior induction chemotherapy (CT) were additional independent negative prognostic factors for PFS (p&lt;0,001). Conclusions: These results suggest a significant association between relapse risk after surgery for CRLM and both OS and PFS. The CERR score can be used to select potential candidates for CRLM surgery and improve the impact of this intervention in pts with CRC. The link between induction CT and worse survival may reflect selection bias as these pts possibly had a higher volume of disease and therefore received initial systemic therapy. Prospective studies are required to confirm these results.

The prognostic factors in patients with advanced hepatocellular carcinoma: impact of treatment sequencing

The prognosis of patients with advanced HCC can vary widely depending on factors such as the stage of the cancer, the patient’s overall health, and treatment regimens. This study aimed to investigate survival outcomes and associated factors in patients with hepatocellular carcinoma (HCC). In this retrospective study, data from 23 medical oncology clinics were analyzed. Progression-free survival (PFS) and overall survival (OS) values were estimated using the Kaplan–Meier method. Prognostic factors associated with survival which were identified in univariate analysis were subsequently evaluated in a multivariate Cox-regression survival analysis was conducted using the backward stepwise (Conditional LR) method to determine the independent predictors of PFS and OS. Of 280 patients, 131 received chemotherapy and 142 received sorafenib, 6 received atezolizumab plus bevacizumab and 1 received nivolumab for first-line setting. The median follow-up time was 30.4 (95%CI 27.1–33.6) months. For-first line, median PFS was 3.1 (95%CI2.7–3.5) months, and it was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab (PFS 5.8 (95%CI 4.2–7.5) than in those received chemotherapy (PFS 2.1 (95%CI 1.9–2.3) in the first-line setting (p < 0.001). Multivariate analysis revealed that male gender (HR: 2.75, 95% CI: 1.53–4.94, p = 0.01), poor ECOG performance score (HR: 1.88, 95% CI: 1.10–3.21, p = 0.02), higher baseline AFP level (HR: 2.38, 95% CI: 1.54–3.67, p < 0.001) and upfront sorafenib treatment (HR,0.38; 95% CI: 0.23–0.62, p < 0.001) were significantly associated with shorter PFS. The median OS was 13.2 (95%CI 11.1–15.2) months. It was significantly longer in patients who received sorafenib or atezolizumab-bevacizumab or nivolumab in the first-line setting followed by TKIs (sorafenib or regorafenib, OS 18.6 (95%CI 13.8–23.5)) compared to those who received chemotherapy (OS 10.3 (95%CI 6.6–14.1)) in the first-line setting. The multivariate analysis revealed that upfront chemotherapy treatment approach, male gender (HR: 1.77, 95% CI: 1.07–2.94, p = 0.02), poor ECOG performance score (HR: 1.96, 95% CI: 1.24–3.09, p = 0.004) and Child-Pugh score, presence of extrahepatic disease (HR: 1.54, 95% CI: 1.09–2.18, p = 0.01), and higher baseline AFP value (HR: 1.50, 95% CI: 1.03–2.19, p = 0.03) were significantly associated with poor prognosis. Additionally, regarding of treatment sequence, upfront sorafenib followed by regorafenib showed a significantly lower risk of mortality (HR: 0.40, 95% CI: 0.25–0.66, p < 0.001). Sorafenib followed by regorafenib treatment was associated with a significantly lower risk of mortality rather than upfront sorafenib followed by BSC group or upfront chemotherapy followed by TKIs. These findings underscore the importance of the optimal treatment sequences to improve survival in patients with advanced HCC.

Prognostic significance of socioeconomic deprivation in patients with colorectal liver metastasis undergoing liver resection: a retrospective cohort study.

To evaluate the effect of socioeconomic deprivation on overall survival (OS) in patients undergoing liver resection for colorectal liver metastasis (CRLM). The STROCSS guideline for observational studies was followed to conduct a single-centre retrospective cohort study. All consecutive patients undergoing resection of CRLM between 2013 and 2021 were considered eligible for inclusion. The Welsh Index of Multiple Deprivation (WIMD) rank was used to determine socioeconomic deprivation status of each patient. Prognostic significance of socioeconomic deprivation was determined by Kaplan-Meier survival statistics and stepwise Cox proportional-hazards regression model. A total of 455 patients were eligible for inclusion; 237 patients were classed as least socioeconomically deprived and 218 patients as most socioeconomically deprived. Kaplan-Meier survival statistics showed that socioeconomic deprivation was associated with significantly lower probability of overall survival (HR: 1.55, 95% CI 1.23-1.95; logrank test: P = 0.0001). The stepwise Cox proportional-hazards regression analysis identified socioeconomic deprivation as predictor of OS (HR: 1.56, P = 0.0003) alongside the following variables: ASA status 1 (HR: 0.43, P = 0.0349), presence of extrahepatic disease (HR: 1.51, P = 0.0075), number of tumours (HR: 1.07, P = 0.0221), size of largest tumour (HR: 1.01, P = 0.0003), extended hemihepatectomy (HR: 3.24, P = 0.0018) and absence of recurrence (HR: 0.55, P < 0.0001). Socioeconomic deprivation reduces the probability of long-term overall survival following liver resection in patients with CRLM. This should be taken into account at different levels of health care planning for management of patients with CRLM including preoperative risk assessment, health care need assessment and allocation of resources.

Survival of Patients with Colorectal Liver Metastases after Transarterial Chemoembolization Using Irinotecan-Eluting Microspheres: A Single-Center Retrospective Analysis Comparing RECIST 1.1 and Choi Criteria

PurposeTo evaluate the factors that affected overall survival and hepatic progression–free survival using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and Choi criteria in patients with colorectal liver metastases treated with transarterial chemoembolization (TACE) using irinotecan-eluting microspheres (IEMs) who failed at least 1 line of systemic chemotherapy. Materials and MethodsA single-institution retrospective analysis was performed including patients with unresectable liver metastases from a colorectal primary malignancy and treated with IEM-TACE. Radiologic hepatic progression–free survival was measured using the RECIST 1.1 and Choi criteria. ResultsThe median patient age was 61.5 years, with 80 (67%) men. A total of 328 IEM-TACE procedures were performed during the study period. One hundred eighteen patients who failed at least 1 line of systemic chemotherapy before TACE demonstrated a median overall survival of 12.7 months. Overall survival was higher in patients who had previous primary resection (P < .05), prior ablation (P < .05), or completed the scheduled TACE treatments (P < .05) but was adversely affected by the presence of extrahepatic disease (P < .05) and larger preprocedural tumor burden (P < .01). Prior systemic chemotherapy lines (P = .98) and microsphere size (P = .34) did not affect survival. Partial radiologic response to treatment using the Choi criteria (n = 28, P < .01) correlated significantly with survival, a correlation not seen with the RECIST 1.1 measurements (n = 5, P = .13). ConclusionsA partial response to treatment of unresectable colorectal liver metastases treated by TACE with IEMs measured using the Choi criteria correlated significantly with improved survival, while RECIST 1.1 measurements did not.

Clinical outcomes with atezolizumab plus bevacizumab or lenvatinib in patients with hepatocellular carcinoma: a multicenter real-world study.

The purpose of this study is to compare response rates of lenvatinib and atezolizumab plus bevacizumab, in first-line real-world setting. Overall cohort included Western and Eastern hepatocellular carcinoma (HCC) patient populations from 46 centres in 4 countries (Italy, Germany, Japan, and Republic of Korea). 1312 patients were treated with lenvatinib, and 823 patients were treated with atezolizumab plus bevacizumab. Objective response rate (ORR) was 38.6% for patients receiving lenvatinib, and 27.3% for patients receiving atezolizumab plus bevacizumab (p < 0.01; odds ratio 0.60). For patients who achieved complete response (CR), overall survival (OS) was not reached in both arms, but the result from univariate Cox regression model showed 62% reduction of death risk for patients treated with atezolizumab plus bevacizumab (p = 0.05). In all multivariate analyses, treatment arm was not found to be an independent factor conditioning OS. Comparing ORR achieved in the two arms, there was a statistically significant difference in favor of lenvatinib compared to atezolizumab plus bevacizumab in all subgroups except for Eastern patients, Child-Pugh B patients, presence of portal vein thrombosis, α-feto-protein ≥ 400ng/mL, presence of extrahepatic disease, albumin-bilirubin (ALBI) grade 2, and no previous locoregional procedures. Lenvatinib achieves higher ORR in all patient subgroups. Patients who achieve CR with atezolizumab plus bevacizumab can achieve OS so far never recorded in HCC patients. This study did not highlight any factors that could identify patient subgroups capable of obtaining CR.

Evaluation of Inflammatory Scores in Metastatic Colorectal Cancer Patients Undergoing Transarterial Radioembolization.

To evaluate the correlation of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), aspartate aminotransferase-to-lymphocyte ratio (ALRI), systemic inflammation index (SII), and lymphocyte count to oncologic outcomes in metastatic colorectal cancer (mCRC) patients undergoing transarterial radioembolization (TARE). All patients undergoing TARE for mCRC were retrospectively reviewed at a single academic institution. A receiver operating characteristics (ROC) curve analysis was performed using a landmark survival point of 12months, with an area under the curve (AUC) calculated. A cutoff point was determined by Youden's index and used to separate patients for OS and PFS analysis. Cox proportional-hazards models which included pertinent clinical factors were also created to evaluate PFS and OS. In total, 41 patients who underwent 66 TARE treatments were included. A correlation was seen between post-treatment ALRI < 45 (HR: 0.38 (95%CI: 0.17-0.86), p = 0.02) and PFS. Patients with a pretreatment ALRI score < 20 had a significantly longer OS (HR: 0.49 (95%CI: 0.19-0.88), p = 0.02) as did those with a post-treatment lymphocyte count > 1.1 109/L (HR: 0.27 (95%CI: 0.11-0.68), p = 0.005). In multivariate analysis of PFS, post-treatment lymphocyte count (HR: 8.46 (95%CI: 1.14-62.89), p = 0.044) was the only significantly associated inflammatory marker and presence of extrahepatic disease (HR:8.46 (95%CI: 1.14-62.89, p = 0.044) also correlated. Multivariate analysis of OS showed that pretreatment PLR (HR:1.01 (95%CI:1.-1.03), p = 0.02) and post-treatment NLR (HR:0.33 (95%CI:0.14-0.76), p = 0.009), PLR (HR:0.98 (95%CI:0.97-1), p = 0.046), SII (HR:1.04 (95%CI:1.01-1.08), p = 0.014), and lymphocyte count (HR:0.07 (95%CI:0.01-0.16), p = 0.003) were significantly associated. Inflammatory markers may be associated with OS and PFS in mCRC patients undergoing TARE.

Prognostic Factors in Patients with Breast Cancer Liver Metastases Undergoing Liver Resection: Systematic Review and Meta-Analysis.

Simple SummaryRobust predictive and prognostic tools are needed in the management of breast cancer liver metastases (BCLMs). Until now, surgery has not been the gold standard of treatment of patients with BCLMs. The present manuscript highlights several predictive factors related to the primary tumor and the BCLM that may help to identify candidates for surgery with favorable outcomes in a large cohort of patients.Background: The role of surgical resection of liver metastases in patients with breast cancer liver metastasis (BCLM) remains controversial. A systematic review and meta-analysis of prognostic factors related to survival after BCLM resection was performed. Methods: An electronic search of relevant publications was performed. Pooled outcome measures were expressed as hazard ratios (HRs), including 95% confidence interval values (95% CIs), and calculated through a random-effects model. Heterogeneity was tested through the I2 index. Results: Thirty-five publications reported analyses on prognostic factors and survival. A total of 2782 patients who underwent liver resection for BCLM were included. Positive axillary lymph nodes at breast cancer diagnosis were an unfavorable survival factor (HR 1.74, 95% CI 1.25 to 2.41, I2 = 0%). Cumulative predictive factor HRs (multiple liver metastases, size of the metastases, short interval between primary tumor and onset of liver disease) related to the BCLM pattern were 1.32 (95% CI 1.17 to 1.48, I2 = 71%) and 1.51 (95% CI 1.15 to 1.98, I2 = 76%) for surgical and pathological features (resection margin and presence of extrahepatic disease), respectively. Conclusion: Resection of BCLM may provide a survival benefit for selected patients. For better long-term results, surgical selection should consider both primary tumor and BCLM features such as negative axillary lymph nodes at breast resection, a single hepatic lesion, a time longer than 24 months between breast and hepatic diagnosis, and a realizable R0 liver resection. However, the high heterogeneity among studies suggests the need for an RCT to validate the present findings.

Prognostic factors of overall survival in patients with recurrent disease following liver resection for colorectal cancer metastases: A multicenter external validation study

The clinical course of patients experiencing recurrence following hepatectomy for colorectal cancer metastases (CRM) is poorly defined. Previous studies associated shorter time to recurrence (TTR) in months, node-positive primary tumor, and more than one site of recurrence with worse outcomes. We conducted a retrospective cohort study across four Canadian institutions to externally validate previously established prognostic factors of overall survival (OS). We included consecutive adult patients who had a recurrence following curative-intent liver resection for CRM. Prognostic factors were explored using a multivariable Cox regression model. Risk group cutoffs were identified through recursive partitioning. OS between low- and high-risk groups was compared using the Kaplan-Meier method. This study included 471 patients. Shorter TTR in months (hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.93-0.97), presence of extrahepatic disease at first hepatectomy (HR: 2.54, 95% CI: 1.18-5.50), and larger tumor size in millimetres (HR: 1.01, 95% CI: 1.00-1.02) were associated with worse OS. Median OS in the high- and low-risk groups were 40.5 (95% CI: 34.0-45.7 months) versus 64.7 months (95% CI: 57.9-72.3 months; p < 0.001), respectively. We externally validated the prognostic significance of shorter TTR (<8.5 months) as a predictor of worse OS in patients who recur the following hepatectomy for CRM.

Prognostic Factors in Patients with Breast Cancer Liver Metastases (BCLM) Undergoing Liver Resection: Systematic Review and Meta-Analysis

Introduction: Surgical treatment of Breast Cancer Liver Metastasis (BCLM) is debated. We perform a systematic review and meta-analysis of prognostic factors on survival after hepatic resection for BCLM. Methods: An electronic search was performed using PubMed/MEDLINE and Cochrane library databases. Two independent reviewers screened the titles and abstracts. Qualitative and quantitative evaluation of included studies was performed. The pooled effect was calculated using the random-effects model. Results: Thirty-five publications reported analysis on the role of prognostic factors influencing survival after hepatic resection for BCLM and were included in the meta-analysis. Two thousand seven hundred eighty-two patients underwent liver resection for BCLM. The positivity of the axillary lymph nodes at breast cancer diagnosis and the negative Estrogen Receptor status were survival unfavorable factors (HR 1.74, CI 95% 1.25 to 2.41, I2=0% and HR 2.09, CI 95% 1.40 to 3.12, I2=0%). Cumulative HR for predictive factors (multiple liver metastases, size of the metastasis, short interval between primary tumour and onset of liver disease, resection margin and presence of extrahepatic disease) related to the BCLM pattern was 1.32 (CI 95% 1.17 to 1.48, I2=71%) and 1.51 (CI 95% 1.15 to 1.98, I2=76%) for surgical and pathological features. Conclusion: Surgical treatment of BCLM is an option with survival advantages for selected patients. For better long-term results, surgical selection should consider both primary tumour and BCLM features. N0 stage at breast diagnosis, metachronous disease limited to the liver, single BCLM, and highly achievable R0 liver resection may determine the ideal candidate to resection.

VP10-2021: Cabozantinib (C) plus atezolizumab (A) versus sorafenib (S) as first-line systemic treatment for advanced hepatocellular carcinoma (aHCC): Results from the randomized phase III COSMIC-312 trial

The multikinase inhibitor C has shown promising clinical activity in combination with immune checkpoint inhibitors, including A, in multiple tumor types. COSMIC-312 (NCT03755791) is evaluating C+A vs S as first-line systemic treatment for aHCC. In this open-label, global, phase 3 trial, patients (pts) were randomized 2:1:1 to C 40 mg QD plus A 1200 mg Q3W or S 400 mg BID or C 60 mg QD stratified by etiology, geographic region, and presence of extrahepatic disease and/or macrovascular invasion (EHD/MVI). Eligible pts had HCC not amenable to curative treatment or locoregional therapy, Child-Pugh class A, ECOG PS ≤1, and no prior systemic therapy for HCC. The dual primary endpoints were PFS by blinded independent review committee per RECIST 1.1 for C+A vs S in the first 372 pts randomized to these 2 arms and OS for C+A vs S in all randomized pts. The secondary endpoint was PFS for C vs S. Prespecified interim analyses of OS for C+A vs S and PFS for C vs S were performed at the primary PFS analysis. 837 pts were randomized to C+A (N=432), S (N=217), or C (N=188). 30% of pts had HBV, 31% had HCV without HBV, and 39% had non-viral etiology; 29% enrolled in Asia; and 69% had EHD/MVI. The study met the primary PFS endpoint; C+A significantly improved PFS vs S (HR 0.63, 99% CI 0.44–0.91; p=0.0012; median PFS 6.8 vs 4.2 mo). The interim analysis of OS did not show a statistically significant benefit for C+A vs S (HR 0.90, 96% CI 0.69–1.18; p=0.438). Grade 3/4 treatment-related AEs (TRAEs) occurred for 54% of pts with C+A vs 32% with S; the most common events were PPE (7.9% vs 8.2%), hypertension (7.0% vs 6.3%), AST increased (6.5% vs 2.4%), and ALT increased (6.3% vs 1.9%). Grade 5 TRAEs were 1.9% vs 0.5%. TRAEs led to discontinuations of C and A in 6.1%, C and/or A in 14%, and S in 7.7% of pts. Interim results for PFS with C vs S will also be presented. C+A showed statistically significant and clinically meaningful improvement of PFS vs S in pts with aHCC not previously treated with systemic therapy. The safety profile of C+A was manageable and consistent with the known safety profile of each agent. Follow-up for the final OS analysis is ongoing.

Clinical determinants of long-term survival in metastatic uveal melanoma

This study aimed to identify prognostic factors in patients with metastatic uveal melanoma (UM) that were associated with long-term survival in a real-world setting. A total of 94 patients with metastatic UM were included from German skin cancer centers and the German national skin cancer registry (ADOReg). Data were analyzed for the response to treatment, progression-free survival, and overall survival (OS). Prognostic factors were explored with univariate Cox regression, log-rank, and χ2-tests. Identified factors were subsequently validated after the population was divided into two cohorts of short-term survival (< 2 years OS, cohort A, n = 50) and long-term survival (> 2 years OS, cohort B, n = 44). A poor ECOG performance status (hazard ratio [HR] 2.0, 95% confidence interval [CI] 1.0–3.9) and elevated serum LDH (HR 2.0, 95% CI 1.0–3.8) were associated with a poor OS, whereas a good response to immune checkpoint blockade (ICB, p < 0.001), radiation therapy (p < 0.001), or liver-directed treatments (p = 0.01) were associated with a prolonged OS. Long-term survivors (cohort B) showed a higher median number of organs affected by metastasis (p < 0.001), while patients with liver metastases only were more common in cohort A (40% vs. 9%; p = 0.002). A partial response to ICB was observed in 16% (12/73), being 21% (8/38) for combined ICB, 17% (1/6) for single CTLA4 inhibition, and 10% (3/29) for single PD1 inhibition. One complete response occurred in cohort B with combined ICB. We conclude that the response to ICB and the presence of extrahepatic disease were favorable prognostic factors for long-term survival.

Survival Advantage of Yttrium-90 Radioembolization to Systemic Therapy in Patients with Hepatic Metastases from Colorectal Cancer in the Salvage Setting: Results of a Matched Pair Study

Patients with hepatic metastases from colorectal cancer have a poor prognosis in the salvage setting. This study assessed the survival benefit of adding transarterial 90Y radioembolization in the salvage setting to systemic therapy. In this retrospective, matched-pair study, 21 patients who underwent radioembolization plus systemic therapy were matched with a cohort of 173 patients who received systemic chemotherapy alone in the salvage setting, defined as progression on at least two different regimens of systemic chemotherapy. Patients were matched one-to-one on Eastern Cooperative Oncology Group Performance Status, presence of extrahepatic disease, and presence of tumor KRAS mutation. Radioembolization patients underwent treatment using standard dosimetry to either a hepatic lobe or the whole liver. Survival data was analyzed using Kaplan-Meier analysis. Patients who underwent radioembolization plus systemic therapy vs. those who had systemic therapy alone had similar demographics and exposure to prior systemic chemotherapies. Median survival from the date of primary diagnosis was 38 (95% CI 26 to 50) v 25 (95% CI 15 to 35) months in radioembolization with systemic therapy vs. systemic therapy alone (p=0.17). Median survival from the date of hepatic metastases was 31 (95% CI 23.8 to 38.2) v 20 months (95% CI 10.2 to 29.8) in radioembolization with systemic therapy vs. systemic therapy alone (p=0.03). The addition of radioembolization to systemic therapy in patients with metastatic colorectal cancer to the liver may improve survival in the salvage setting.

Single Institution Retrospective Analysis Of Local Control And Survival Outcomes Using Radiation For The Management Of Colorectal Cancer Liver Metastases

Colorectal liver metastases (CLM) represent a radioresistant histology. The purpose of this study was to investigate outcomes after radiation treatment for patients with CLM and explore the interaction between biologically effective dose (BED) and lesion size. Consecutive patients with CLM treated with radiation at a single institution were analyzed retrospectively for their baseline characteristics and predictors of treatment outcomes. Freedom from local progression (FFLP) as defined by Response Evaluation Criteria on Solid Tumors (RECIST) 1.1, progression free survival (PFS), and overall survival (OS) were analyzed by Kaplan-Meier and Cox proportional hazards regression methods. 97 patients with 129 CLM lesions were treated from 02/2006 to 02/2019 with a variety of fractionation schemes with median BED (α/β = 10) of 97.9 Gy (39.0 – 187.5 Gy), with the fractionation scheme largely influenced by physician and evolving institutional practice over time. Median follow up was 15.8 months for all patients and 19.3 months for surviving patients. The median lesion size was 3.1 cm (0.3 – 14.3 cm). 56, 25, and 16 patients had 1, 2 and ≥3 lesions, respectively. 94 patients (97%) received prior systemic therapy, and 78 patients (80%) received prior liver-directed therapy, including surgical resection (n = 68), hepatic arterial infusion pump chemotherapy (n = 58), radiofrequency ablation (n = 33), yttrium-90 (n = 6) and arterial embolization (n = 9). Median FFLP, PFS and OS were 14.3 months (95% CI 12.0-16.6), 3.0 months (1.5-4.5) and 18.2 months (15.7-20.7), respectively. On univariate analysis, BED and lesion size were predictive of FFLP (p<0.001 and p = 0.003, respectively). For 88 lesions receiving ablative doses (≥95Gy), 2yr FFLP for lesions < 3cm were 58.0% vs. 26.4% for lesions ≥ 3 cm (p = 0.041). On multivariate analysis, both BED ≥ 95 Gy (HR 0.36, 95% CI 0.20 – 0.66, p<0.001) and size ≥ 3 cm (HR 1.86, 95% CI 1.02 – 3.38, p = 0.043) remained significant predictors of FFLP. Multivariate analysis showed BED ≥ 95 Gy (HR 0.55, 95% CI 0.31 – 0.98, p = 0.042), size ≥ 3 cm (HR 2.00, 95% CI 1.06 – 3.75, p = 0.032), presence of extrahepatic disease (HR 4.22, 95% CI 2.03 – 8.76, p<0.001) and number of hepatic lesions (HR 2.65, 95% CI 1.45 – 4.84, p = 0.002) to be significant predictors of OS. In a large single institution series of CLM treated with a variety of radiation doses and fractionation schemes, we show that both BED and lesion size are independently predictive of FFLP and OS. Dose escalation above 95Gy should be considered for lesions ≥3cm as allowed by normal tissue constraints. Studies investigating further dose escalation for larger CLM are warranted.

Aggressive recurrences determine oncologic outcomes after resection of liver metastases from primary right colon cancer: Results of a case-control study

BackgroundDespite recent studies suggest that, among patients operated on for colorectal liver metastases (CLM), the primary tumor location may impact on postoperative survivals, results are still contrasting. Objectiveevaluating survivals (overall (OS) and (DFS)) following liver resection of CLM from Right colon Cancer (RcC-CLM) versus Left colon Cancer (LcC-CLM), among patients undergoing preoperative chemotherapy (pCHT), identifying survival predictors, and investigating impact of recurrent disease pattern and management on survival. MethodsAmong 727 patients operated for CLM(1989–2016), after excluding patients with primary transverse colon/rectum tumor and patients not receving pCHT, 297 patients were identified. Among them, 81 with RcC-CLM were matched 1:1 with LcC-CLM, according to CLM number and diameter, disease-free interval between primary tumor and CLM diagnosis, primary tumor N-status, and the presence of extrahepatic disease. ResultsOverall, 66.7% of patients had multiple CLM, 21% had CLM>5 cm, 82.7% had DFI<12 months, 67.9% had N+ primary tumor, and 11.1% had extrahepatic disease at time of hepatectomy. RcC-CLM patients were similar to LcC-CLM in terms of demographic, clinical, perioperative, and pathologic characteristics. Patients operated for RcC-CLM, compared to LcC-CLM, had significantly shorter 5y-DFS(18% versus 39%) and 5y-OS(38% vs 65%). At multivariate analysis, being operated for RcC-CLM, compared to LcC-CLM, was the strongest predictor of recurrence (Hazard Ratio:2.265,p < .001) and death (HR:2.234,p = .001). Among 107 patients experiencing recurrent disease, curative recurrence resection was associated with higher 5y-OS(64% vs 17%; p < .001). However, recurrence resection was less frequently feasible among RcC-CLM(26%) patients, compared to LcC-CLM(44%,p = .05). Conclusionsresection of RcC-CLM, compared to LcC-CLM, is associated with worse survivals, probably related to a different pattern of recurrence precluding recurrence resection among RcC-CLM patients.

Oncological outcomes and predictors of radiofrequency ablation of colorectal cancer liver metastases.

BACKGROUNDSurgical resection is considered the standard treatment option for long-term survival in colorectal cancer liver metastasis (CRLM) patients, but only a small number of patients are suitable for resection following diagnosis. Radiofrequency ablation (RFA) is an accepted alternative therapy for CRLM patients who are not suitable for resection. However, the relatively high rate of local tumor progression (LTP) is an obstacle to the more widespread use of RFA.AIMTo determine the oncological outcomes and predictors of RFA in CRLM patients.METHODSA retrospective analyze was performed on the clinical data of 85 consecutive CRLM patients with a combined total of 138 liver metastases, who had received percutaneous RFA treatment at our institution from January 2013 to December 2018. Contrast-enhanced computed tomography was performed the first month after RFA to assess the technique effectiveness of the RFA and to serve as a baseline for subsequent evaluations. The Kaplan-Meier method was used to calculate overall survival (OS) and LTP-free survival (LTPFS). The log-rank test and Cox regression model were used for univariate and multivariate analyses to determine the predictors of the oncological outcomes.RESULTSThere were no RFA procedure-related deaths, and the technique effectiveness of the treatment was 89.1% (123/138). The median follow-up time was 30 mo. The LTP rate was 32.6% (45/138), and the median OS was 36 mo. The 1-, 3-, and 5-year OS rates were 90.6%, 45.6%, and 22.9%, respectively. Univariate analysis revealed that tumor size and ablative margin were the factors influencing LTPFS, while extrahepatic disease (EHD), tumor number, and tumor size were the factors influencing OS. Multivariate analysis showed that tumor size larger than 3 cm and ablative margin of 5 mm or smaller were the independent predictors of shorter LTPFS, while tumor number greater than 1, size larger than 3 cm, and presence of EHD were the independent predictors of shorter OS.CONCLUSIONRFA is a safe and effective treatment method for CRLM. Tumor size and ablative margin are the important factors affecting LTPFS. Tumor number, tumor size, and EHD are also critical factors for OS.

Impact of diseased liver parenchyma on perioperative outcome among patients with hepatocellular carcinoma undergoing hepatectomy: Experience from a developing country

IntroductionLimited data can be found about surgical outcome of patients with hepatocellular carcinoma (HCC) arising in non-diseased liver. The study aim was to compare short- and long-term outcomes among HCC patients with normal and diseased liver parenchyma, undergoing potentially curative liver resection in a developing country. Materials and methodsFrom November 2001 until January 2017, 228 patients with HCC underwent curative-intent hepatectomy at the University Clinic for Digestive Surgery. From that number, 190 patients were eligible for analysis. Diseased liver (DL) was present in 112 patients while 78 patients had HCC in non-diseased liver (NDL). ResultsMedian age, sex, ASA score, the presence of extrahepatic disease and lobar distribution of tumors were similar in both groups. The number of tumors was higher in DL group, while tumor diameter was higher in NDL group. Anatomic liver resection and major liver resections were performed more commonly in NDL than in DL group (66.7 vs 47.4%, p = 0.008; 33.3 vs. 15.2%, p = 0.003). Postoperative morbidity was significantly higher in DL group (p = 0.004). Overall survival was statistically longer in NDL group (p = 0.024). By univariate analysis potential prognostic factors for long-term survival were identified: presence of chronic HCV infection, presence of cirrhosis, Child-Pugh score B and operative time longer than 240 min. The last two were confirmed by multivariate analysis as independent negative prognostic factors for overall survival. ConclusionLiver resection in patients with HCC arising in non-diseased livers, despite of need for extended hepatectomies, provides favorable long-term prognosis.