ABSTRACT
OBJECTIVES: To compare 1D and 3D quantitative tumor response criteria applied to DCE-MRI in patients with advanced-stage HCC undergoing sorafenib therapy to predict overall survival (OS) early during treatment. METHODS: This retrospective analysis included 29 patients with advanced-stage HCC who received sorafenib for at least 60 days. All patients underwent baseline and follow-up DCE-MRI at 81.5 ± 29.3 days (range 35-140 days). Response to sorafenib was assessed in 46 target lesions using 1D criteria RECIST1.1 and mRECIST. In addition, a segmentation-based 3D quantification of absolute enhancing lesion volume (vqEASL) was performed on the arterial phase MRI, and the enhancement fraction of total tumor volume (%qEASL) was calculated. Accordingly, patients were stratified into groups of disease control (DC) and disease progression (DP). OS was evaluated using Kaplan-Meier curves with log-rank test and Cox proportional hazards regression model. RESULTS: The Kaplan-Meier analysis revealed that stratification of patients in DC vs. DP according to mRECIST (p = 0.0371) and vqEASL (p = 0.0118) successfully captured response and stratified OS, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). Multivariable Cox regression identified tumor progression according to mRECIST and qEASL as independent risk factors of decreased OS (p = 0.039 and p = 0.006, respectively). CONCLUSIONS: The study identified enhancement-based vqEASL and mRECIST as reliable predictors of patient survival early after initiation of treatment with sorafenib. This data provides evidence for potential advantages 3D quantitative, enhancement-based tumor response analysis over conventional techniques regarding early identification of treatment success or failure. KEY POINTS: ⢠Tumor response criteria on MRI can be used to predict survival benefit of sorafenib therapy in patients with advanced HCC. ⢠Stratification into DC and DP using mRECIST and vqEASL significantly correlates with OS (p = 0.0371 and p = 0.0118, respectively) early after initiation of sorafenib, while stratification according to RECIST and %qEASL did not correlate with OS (p = 0.6273 and p = 0.7474, respectively). ⢠mRECIST (HR = 0.325, p = 0.039. 95%CI 0.112-0.946) and qEASL (HR = 0.183, p = 0.006, 95%CI 0.055-0.613) are independent prognostic factors of survival in HCC patients undergoing sorafenib therapy.
Subject(s)
Antineoplastic Agents , Carcinoma, Hepatocellular , Liver Neoplasms , Antineoplastic Agents/therapeutic use , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/drug therapy , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/drug therapy , Magnetic Resonance Imaging , Phenylurea Compounds/therapeutic use , Retrospective Studies , Sorafenib/therapeutic use , Treatment OutcomeABSTRACT
Aim: To assess concordance between HER2 status measured by traditional methods and ERBB2 amplification measured by next-generation sequencing and its association with first-line trastuzumab clinical benefit in patients with advanced esophagogastric cancer. Methods: Retrospective analysis of HER2/ERBB2 concordance using a deidentified USA-based clinicogenomic database. Clinical outcomes were assessed for patients with HER2+ advanced esophagogastric cancer who received first-line trastuzumab. Results: Overall HER2/ERBB2 concordance was 87.5%. Among patients who received first-line trastuzumab, concordant HER2/ERBB2 was associated with longer time to treatment discontinuation (adjusted hazard ratio [aHR]: 0.63; 95% CI: 0.43-0.90) and overall survival (aHR: 0.51; 95% CI: 0.33-0.79). ERBB2 copy number ≥25 (median) was associated with longer time to treatment discontinuation (aHR: 0.56; 95% CI: 0.35-0.88) and overall survival (aHR: 0.52; 95% CI: 0.30-0.91). Conclusion: HER2/ERBB2 concordance and higher ERBB2 copy number predicted clinical benefit from trastuzumab.
Lay abstract Trastuzumab is a drug that has been shown to prolong survival in some patients with advanced esophagogastric cancer whose tumor expresses a protein biomarker called HER2. There are different methods for assessing whether a patient's tumor expresses HER2, including but not limited to traditional methods such as immunohistochemistry and in situ hybridization and novel methods such as next-generation sequencing, which detects alterations in the gene (ERBB2) that encodes the HER2 protein. In our study, we assessed concordance between HER2 status (HER2-positive or HER2-negative) measured by traditional methods and ERBB2 amplification measured by next-generation sequencing, to determine whether there was an association between concordance and clinical benefit in patients with advanced esophagogastric cancer treated with trastuzumab. Our results suggest that, when HER2 positivity is detected through traditional methods, both ERBB2 concordance (i.e., agreement that a patient's tumor had the biomarker) and a higher ERBB2 copy number (the amount of the ERBB2 gene expressed by the tumor) were associated with longer time to treatment discontinuation and overall survival in patients with advanced esophagogastric cancer treated with first-line trastuzumab.
Subject(s)
Esophageal Neoplasms/drug therapy , Receptor, ErbB-2/genetics , Trastuzumab/therapeutic use , Aged , Esophageal Neoplasms/mortality , Female , Gene Amplification , Gene Dosage , Humans , Male , Middle Aged , Receptor, ErbB-2/analysis , Retrospective StudiesABSTRACT
OBJECTIVE: The aim of this study was to evaluate socioeconomic discrepancies in current treatment approaches and survival trends among patients with intrahepatic cholangiocarcinoma (ICC). METHODS: The 2004-2015 National Cancer Database was retrospectively analyzed for histopathologically proven ICC. Treatment predictors were evaluated using multinomial logistic regression and overall survival via multivariable Cox models. RESULTS: Overall, 12,837 ICC patients were included. Multiple factors influenced treatment allocation, including age, education, comorbidities, cancer stage, grade, treatment center, and US state region (multivariable p < 0.05). The highest surgery rates were observed in the Middle Atlantic (28.7%) and lowest rates were observed in the Mountain States (18.4%). Decreased ICC treatment likelihood was observed for male African Americans with Medicaid insurance and those with low income (multivariable p < 0.05). Socioeconomic treatment discrepancies translated into decreased overall survival for patients of male sex (vs. female; hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.16-1.26, p < 0.001), with low income (< $37,999 vs. ≥ $63,000 annually; HR 1.07, 95% CI 1.01-1.14, p = 0.032), and with Medicaid insurance (vs. private insurance; HR 1.13, 95% CI 1.04-1.23, p = 0.006). Both surgical and non-surgical ICC management showed increased survival compared with no treatment, with the longest survival for surgery (5-year overall survival for surgery, 33.5%; interventional oncology, 11.8%; radiation oncology/chemotherapy, 4.4%; no treatment, 3.3%). Among non-surgically treated patients, interventional oncology yielded the longest survival versus radiation oncology/chemotherapy (HR 0.73, 95% CI 0.65-0.82, p < 0.001). CONCLUSIONS: ICC treatment allocation and outcome demonstrated a marked variation depending on socioeconomic status, demography, cancer factors, and US geography. Healthcare providers should address these discrepancies by providing surgery and interventional oncology as first-line treatment to all eligible patients, with special attention to the vulnerable populations identified in this study.
Subject(s)
Bile Duct Neoplasms/economics , Bile Duct Neoplasms/mortality , Cholangiocarcinoma/economics , Cholangiocarcinoma/mortality , Health Status Disparities , Healthcare Disparities/statistics & numerical data , Social Class , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/therapy , Cholangiocarcinoma/pathology , Cholangiocarcinoma/therapy , Combined Modality Therapy , Databases, Factual , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , United StatesABSTRACT
PURPOSE: To compare utilization and effectiveness of radiofrequency ablation (RFA) and surgical resection for hepatocellular carcinoma (HCC). METHODS: The 2004-2015 United States National Cancer Database was queried for HCC patients treated by RFA and surgical resection. Patients were 1:1 propensity score matched. Duration of hospital stay, unplanned readmission rates, and overall survival (OS) were compared in the matched cohort via multivariable regression models. RESULTS: Eighteen thousand two hundred ninety-six patients were included (RFA, n = 8211; surgical resection, n = 10,085). RFA was more likely in young male whites with high degree of hepatic fibrosis, high bilirubin levels, high INR, and multifocal HCC; resection was more likely in those with private insurance, high income, high cancer grade and stage, and larger HCC. RFA rates varied between 32.3% (East South Central) and 58.5% (New England). Post-treatment outcomes were superior for RFA versus resection regarding duration of hospital stay (median 1 vs. 5d, p < 0.001), 30-day unplanned hospital readmission rates (3.1% vs. 4.5%, p < 0.001), and 30-/90-day mortality (0% vs. 4.6%/8%, p < 0.001). Overall survival was comparable for RFA and resection for severe hepatic fibrosis/cirrhosis (5-year OS 37.3% vs. 39.4%, p = 0.07), for patients > 65 years old (5-year OS 21.9% vs. 26.5%, p = 0.47), and for HCC < 15 mm (5-year OS 49.7% vs. 52.3%, p = 0.78). OS in the full cohort was superior for surgical resection (5-year OS 29.9% vs. 45.7%, p < 0.01). CONCLUSION: RFA for HCC shows substantial variation by geography, socioeconomic factors, liver function, and tumor extent. RFA offers superior post-treatment outcomes versus surgical resection and may be an alternative for older patients with cirrhosis and/or small HCC. KEY POINTS: ⢠Duration of hospital stay, unplanned readmissions, and 30-/90-day mortality are lower for RFA versus surgical resection. ⢠RFA and surgical resection show similar survival in severe hepatic fibrosis. ⢠In HCC < 15 mm, RFA and surgical resection yield similar survival.
Subject(s)
Carcinoma, Hepatocellular/surgery , Catheter Ablation/methods , Hepatectomy/methods , Liver Neoplasms/surgery , Propensity Score , Registries , Adult , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/epidemiology , Female , Humans , Incidence , Liver Neoplasms/diagnosis , Liver Neoplasms/epidemiology , Male , Middle Aged , Neoplasm Staging , Postoperative Complications/epidemiology , Retrospective Studies , Survival Rate/trends , Treatment Outcome , United States/epidemiologySubject(s)
Neoplasms , Precision Medicine , Genome , Humans , Molecular Targeted Therapy , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/therapyABSTRACT
BACKGROUND: During the process of tumor profiling, there is the potential to detect germline variants. To the authors' knowledge, there currently is no accepted standard of care for how to deal with these incidental findings. The goal of the current study was to assess disclosure preferences among patients with cancer regarding incidental genomic variants that may be discovered during tumor profiling. METHODS: A 45-item questionnaire was administered to 413 patients in ambulatory oncology clinics. The survey captured demographic and disease variables and personal and family history, and presented case scenarios for different types of incidental germline variants that could theoretically be detected during genomic analysis of a patient's tumor. RESULTS: The possibility of discovering non-cancer-related, germline variants did not deter patients from tumor profiling: 77% wanted to be informed concerning variants that could increase their risk of a serious but preventable illness, 56% wanted to know about variants that cause a serious but unpreventable illness, and 49% wanted to know about variants of uncertain significance. The majority of patients (75%) indicated they would share hereditary information regarding predisposition to preventable diseases with family and 62% would share information concerning unpreventable diseases. The most frequent concerns about incidental findings were ability to obtain health (48%) or life (41%) insurance. Only 21% of patients were concerned about privacy of information. CONCLUSIONS: Patients with cancer appear to prefer to receive information regarding incidental germline variants, but there is substantial variability with regard to what information patients wish to learn. The authors recommend that personal preferences for the disclosure of different types of incidental findings be clarified before a tumor profiling test is ordered. Cancer 2016;122:1588-97. © 2016 American Cancer Society.
Subject(s)
Disclosure , Neoplasms/genetics , Neoplasms/psychology , Patient Preference/psychology , Adult , Aged , Aged, 80 and over , Cohort Studies , Cross-Sectional Studies , Germ-Line Mutation , Humans , Male , Middle Aged , Neoplasms/pathology , Surveys and QuestionnairesABSTRACT
BACKGROUND: Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC. METHODS: Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined. RESULTS: In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65-14.32) and PFS 6.1 months (95% CI 5.19-8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0-23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [(18)F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS. CONCLUSIONS: In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Pancreatic Neoplasms/drug therapy , Peritoneal Neoplasms/drug therapy , Adenocarcinoma/mortality , Adenocarcinoma/pathology , Adult , Aged , Camptothecin/administration & dosage , Camptothecin/analogs & derivatives , Female , Fluorouracil/administration & dosage , Follow-Up Studies , Humans , Irinotecan , Leucovorin/administration & dosage , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Lymphatic Metastasis , Male , Middle Aged , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Oxaliplatin , Pancreatic Neoplasms/mortality , Pancreatic Neoplasms/pathology , Peritoneal Neoplasms/mortality , Peritoneal Neoplasms/secondary , Prognosis , Prospective Studies , Survival RateSubject(s)
Chemoradiotherapy/methods , Medical Oncology/standards , Palliative Care/methods , Stomach Neoplasms/therapy , Chemoradiotherapy/standards , Humans , Medical Oncology/methods , Neoplasm Staging , Palliative Care/standards , Randomized Controlled Trials as Topic , Societies, Medical/standards , Stomach Neoplasms/mortality , Stomach Neoplasms/pathology , Survival Analysis , Treatment Outcome , United StatesABSTRACT
The medical oncologist's perspective on hepatocellular carcinoma (HCC) is unique compared with their view on other solid tumors. A patient's underlying liver function should be factored into the selection of treatment options; therefore, a staging system that takes into account other clinical parameters other than only tumor characteristics is important. Sorafenib is currently the only FDA-approved chemotherapy drug for patients with HCC based on the data from the SHARP trial. It is important for oncologists to anticipate and treat the side effects of sorafenib treatment in order to help the patients continue the treatment. In addition, it is important to design clinical trials for HCC that have meaningful endpoints to improve our care for patients with HCC.
Subject(s)
Carcinoma, Hepatocellular/therapy , Liver Neoplasms/therapy , Antineoplastic Agents/therapeutic use , Attitude of Health Personnel , Carcinoma, Hepatocellular/drug therapy , Humans , Liver Neoplasms/drug therapy , Medical Oncology , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , SorafenibABSTRACT
BACKGROUND: Phase 2 trials suggest that prolonged intravenous (IV) infusion of the topoisomerase 1 inhibitor topotecan may be less toxic than when given by standard IV bolus 5-day administration. Oxaliplatin exhibits efficacy in platinum-pretreated disease and shows preclinical synergy with topoisomerase 1 inhibitors. We sought to determine the efficacy and safety of oxaliplatin plus infusion topotecan in recurrent platinum-pretreated ovarian cancer. METHODS: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers previously treated with 1 to 2 prior regimens including platinum and taxane received oxaliplatin (85 mg/m(2) day 1 and day 15) and topotecan (0.4 mg/m(2) per day) by continuous IV infusion over 14 days every 4 weeks. The primary objective of the trial was to estimate the objective response rate in platinum-resistant disease (stratum 1) and in platinum-sensitive disease (stratum 2). Toxicities were assessed in all patients. RESULTS: Thirty-eight patients received 144 cycles of therapy (median, 4; range, 1-6). The most common grade 3 and grade 4 toxicities included thrombocytopenia (grade 3, 37%; and grade 4, 19%), neutropenia (grade 3, 37%; grade 4, 11%), and anemia (grade 3, 15%). Response occurred in 4 of 19 patients in stratum I (21%; 95% confidence intervals, 6%-46%) and 9 of 19 patients in stratum 2 (47%; 95% CI, 24%-71%). Three in each stratum had lengthy complete responses. CONCLUSIONS: Biweekly oxaliplatin plus a 14-day continuous IV infusion of topotecan, given monthly, is an active regimen in platinum-pretreated ovarian cancer and merits additional evaluation.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms, Glandular and Epithelial/drug therapy , Organoplatinum Compounds/administration & dosage , Ovarian Neoplasms/drug therapy , Topotecan/administration & dosage , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Ovarian Epithelial , Chemotherapy, Adjuvant , Female , Humans , Infusion Pumps , Middle Aged , Neoplasms, Glandular and Epithelial/mortality , Organoplatinum Compounds/adverse effects , Ovarian Neoplasms/mortality , Oxaliplatin , Survival Analysis , Topotecan/adverse effectsABSTRACT
INTRODUCTION: Healthcare providers (HCPs) may face numerous dilemmas in optimally screening, diagnosing, and treating patients with, and/or at risk for, hepatocellular carcinoma (HCC). This study aimed to achieve a greater understanding of the challenges in HCC care which in turn could delineate HCP educational opportunities within this oncologic sub-specialty. METHODS: A mixed-methods approach was used to identify practice gaps and clinical barriers experienced by US-based medical oncologists, hepatologists, oncology physician assistants, oncology nurse practitioners, and interventional radiologists involved in HCC care. The qualitative (semi-structured interview) and quantitative (survey) data collection approaches were deployed sequentially with findings subsequently triangulated. RESULTS: A total of 214 HCPs participated in this study. Analysis revealed challenges related to screening and diagnosing HCC, specifically in applying appropriate screening guidelines, and the optimal use and decisions related to diagnostic imaging and biopsy. Issues related to treatment selection included the application of existing HCC guidelines in treatment decision-making, weighing risk/benefit ratios of various antineoplastics regimens (i.e., tyrosine kinase inhibitors-TKIs, immunotherapy agents, chemotherapy), sequencing therapies, potential toxicity management, and optimally educating patients about their HCC. CONCLUSION: These findings highlight the educational needs of those involved in HCC care and provide a starting point for clinicians to both reflect on their practice and identify opportunities to enhance communication within the HCC team and between provider and patient. There is an opportunity to optimize continuing professional development interventions that address the identified gaps in clinical practice specifically related to teamwork and interdisciplinary communication.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Medical Oncology , Health Personnel , Surveys and QuestionnairesABSTRACT
Purpose: O6-methylguanine DNA methyltransferase (MGMT)-silenced tumors reveal sensitivity to temozolomide (TMZ), which may be enhanced by PARP inhibitors. Approximately 40% of colorectal cancer has MGMT silencing and we aimed to measure antitumoral and immunomodulatory effects from TMZ and olaparib in colorectal cancer. Experimental Design: Patients with advanced colorectal cancer were screened for MGMT promoter hypermethylation using methylation-specific PCR of archival tumor. Eligible patients received TMZ 75 mg/m2 days 1-7 with olaparib 150 mg twice daily every 21 days. Pretreatment tumor biopsies were collected for whole-exome sequencing (WES), and multiplex quantitative immunofluorescence (QIF) of MGMT protein expression and immune markers. Results: MGMT promoter hypermethylation was detected in 18/51 (35%) patients, 9 received study treatment with no objective responses, 5/9 had stable disease (SD) and 4/9 had progressive disease as best response. Three patients had clinical benefit: carcinoembryonic antigen reduction, radiographic tumor regression, and prolonged SD. MGMT expression by multiplex QIF revealed prominent tumor MGMT protein from 6/9 patients without benefit, while MGMT protein was lower in 3/9 with benefit. Moreover, benefitting patients had higher baseline CD8+ tumor-infiltrating lymphocytes. WES revealed 8/9 patients with MAP kinase variants (7 KRAS and 1 ERBB2). Flow cytometry identified peripheral expansion of effector T cells. Conclusions: Our results indicate discordance between MGMT promoter hypermethylation and MGMT protein expression. Antitumor activity seen in patients with low MGMT protein expression, supports MGMT protein as a predictor of alkylator sensitivity. Increased CD8+ TILs and peripheral activated T cells, suggest a role for immunostimulatory combinations. Significance: TMZ and PARP inhibitors synergize in vitro and in vivo in tumors with MGMT silencing. Up to 40% of colorectal cancer is MGMT promoter hypermethylated, and we investigated whether TMZ and olaparib are effective in this population. We also measured MGMT by QIF and observed efficacy only in patients with low MGMT, suggesting quantitative MGMT biomarkers more accurately predict benefit to alkylator combinations.
Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Humans , Temozolomide/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , DNA Repair , O(6)-Methylguanine-DNA Methyltransferase , Colorectal Neoplasms/drug therapy , Alkylating AgentsABSTRACT
Therapeutic combinations targeting innate and adaptive immunity and predictive biomarkers of response in esophagogastric cancer (EGC) are needed. We assessed safety and clinical utility of DKN-01 (a novel DKK1-neutralizing IgG4 antibody) combined with pembrolizumab and retrospectively determined DKK1 tumoral expression as a biomarker. Patients with advanced EGC received intravenous DKN-01 (150 or 300 mg) on days 1 and 15 with pembrolizumab 200 mg on day 1 in 21-day cycles. Clinical response was assessed by RECIST v1.1. Association of tumoral DKK1 mRNA expression (H-score: high ≥ upper-tertile, low < upper-tertile) with response was assessed with PD-L1 levels as a covariate. Sixty-three patients received DKN-01 150 mg (n = 2) or 300 mg (n = 61) plus pembrolizumab. Common adverse events were fatigue, anemia, blood alkaline phosphatase elevation, aspartate aminotransferase elevation, and hyponatremia. Among evaluable anti-PD-1/PD-L1-naïve patients receiving DKN-01 300 mg and pembrolizumab, objective response rate (ORR) was 11.4% (5/44) and 18.5% (5/27) in patients with gastroesophageal junction or gastric cancer (GEJ/GC). Among response-evaluable anti-PD-1/PD-L1-naïve patients with GEJ/GC and known tumoral DKK1 expression, ORR was 50% in DKK1-high and 0% in DKK1-low patients, median PFS was 22.1 vs. 5.9 weeks (HR, 0.24; 95% CI, 0.08-0.67), respectively, and median OS was 31.6 weeks vs. 17.4 weeks (HR, 0.41; 95% CI, 0.16-1.07), respectively. Association of DKK1 expression with PFS was independent of PD-L1 expression (adjusted HR, 0.21; 95% CI, 0.06-0.69). DKN-01 combined with pembrolizumab was well tolerated with no new safety signals. Antitumor activity was enriched in anti-PD-1/PD-L1-naïve patients with GEJ/GC whose tumors expressed high DKK1.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Biomarkers, Tumor/metabolism , Esophageal Neoplasms/drug therapy , Programmed Cell Death 1 Receptor/therapeutic use , Stomach Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/pharmacology , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Inflammation and the immune system significantly impact the development, progression, and treatment response of hepatocellular carcinoma (HCC). This retrospective study investigated the neutrophil-to-lymphocyte ratio (NLR) as a prognostic biomarker in Western patients with HCC in the setting of chronic viral hepatitis. METHODS: Patients diagnosed with HCC from 2005 to 2016 were selected from a tertiary care institution. NLR was calculated within 30 days prior to treatment and dichotomized at the median. Kaplan-Meier overall survival (OS) curves and Cox hazard proportional models were utilized. Tumor and liver reserve parameters were included in multivariable analyses (MVA). RESULTS: A total of 581 patients met inclusion criteria (median age 61.0 yr; 78.3% male; 66.3% Caucasian) with median OS = 34.9 mo. 371 patients (63.9%) had viral hepatitis, of which 350 had hepatitis C (94.3%). The low-NLR group (Subject(s)
Carcinoma, Hepatocellular/mortality
, Hepatitis C, Chronic/immunology
, Liver Neoplasms/mortality
, Lymphocytes/immunology
, Neutrophils/immunology
, Aged
, Carcinoma, Hepatocellular/blood
, Carcinoma, Hepatocellular/immunology
, Carcinoma, Hepatocellular/virology
, Female
, Hepatitis C, Chronic/blood
, Hepatitis C, Chronic/epidemiology
, Hepatitis C, Chronic/virology
, Humans
, Inflammation/blood
, Inflammation/diagnosis
, Inflammation/immunology
, Inflammation/virology
, Kaplan-Meier Estimate
, Liver Neoplasms/blood
, Liver Neoplasms/immunology
, Liver Neoplasms/virology
, Lymphocyte Count
, Male
, Middle Aged
, Prognosis
, Retrospective Studies
, Risk Factors
ABSTRACT
BACKGROUND: The rationale for the evaluation of trametinib in advanced biliary cancer (BC) is based on the presence of mitogen-activated protein kinase alterations and on earlier promising results with MEK inhibitors in BC. METHODS: Patients with histologically proven BC who progressed on gemcitabine/platinum were randomised to trametinib daily (arm 1) versus fluoropyrimidine therapy (infusional 5-fluorouracil or oral capecitabine, arm 2). The primary end-point was overall survival (OS). Secondary end-points included progression free survival (PFS) and response rate. A planned interim futility analysis of objective response was performed on the first 14 patients registered to the trametinib arm. RESULTS: The study was stopped early based on the lack of measurable response in the trametinib arm. A total of 44 eligible patients were randomised (24 patients in arm 1 and 20 patients in arm 2). Median age was 62 years and the primary sites of tumour were cholangiocarcinoma (68%) and gallbladder (32%). The overall response rate was 8% (95% CI 0%-19%) in arm 1 versus 10% (95% CI 0%-23%) in arm 2 (p > .99) Median OS was 4.3 months for arm 1 and 6.6 months for arm 2. The median PFS was 1.4 months for arm 1 and 3.3 months for arm 2. CONCLUSIONS: This is the first prospective randomised study of a targeted agent versus chemotherapy for the second-line treatment of BC. In this unselected population, the interim analysis result of unlikely benefit with trametinib resulted in early closure.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biliary Tract Neoplasms/drug therapy , Capecitabine/therapeutic use , Fluorouracil/therapeutic use , Pyridones/therapeutic use , Pyrimidinones/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Biliary Tract Neoplasms/pathology , Capecitabine/pharmacology , Female , Fluorouracil/pharmacology , Humans , Male , Middle Aged , Pyridones/pharmacology , Pyrimidinones/pharmacologyABSTRACT
Image-guided locoregional therapies (LRTs) have long been a vital part of treatment regimens for hepatocellular carcinoma (HCC). Ablation, chemoembolization, and radioembolization are examples of commonly used treatment techniques for HCC. This review describes the various methods utilized to treat HCC in the field of interventional oncology and also focuses on new and novel treatment concepts being developed in the field including the use of novel immunotherapy agents and combination therapy of LRTs with immunotherapy.
ABSTRACT
BACKGROUND: To investigate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) as prognostic biomarkers in intrahepatic cholangiocarcinoma (ICC) with a focus on viral hepatitis and liver status. METHODS: In this retrospective cohort study, patients from the institutional cancer registry with ICC from 2005 to 2016 were stratified by treatment group. Baseline inflammatory markers were dichotomized at the median. Overall survival (OS) was assessed via Kaplan-Meier curves and Cox proportional hazard models. Multiple patient, liver, and tumor factors were included in the multivariable analysis (MVA). RESULTS: About 131 patients (median age 65 years, 52% male, 76% Caucasian) had a median OS of 13.0 months. Resection/interventional oncology with/without systemic therapy had improved survival vs systemic therapy alone in Child-Pugh A patients (P < 0.01). In Child-Pugh B/C patients, this survival difference became nonsignificant (P = 0.22). Increased NLR and SII were associated with decreased survival (P < 0.01), while dichotomized PLR was not (P = 0.3). On MVA, increased NLR remained an independent prognostic factor (HR 1.6, P < 0.05). In Child-Pugh class A (n = 94), low-NLR had higher OS vs high-NLR (25.4 vs 12.2 months, P < 0.01). In Child-Pugh class B/C (n = 28), NLR did not have a significant effect on median OS (low- vs high-NLR: 6.7 vs 2.9 months, P = 0.2). Child-Pugh class acted as an effect modifier on MVA for NLR (P = 0.0124). CONCLUSIONS: The NLR has a stronger impact as a prognostic marker in ICC over the PLR and SII. This survival effect is decreased in advanced liver disease.
Subject(s)
Bile Duct Neoplasms/blood , Blood Platelets , Cholangiocarcinoma/blood , Liver Diseases/blood , Lymphocytes , Neutrophils , Aged , Bile Duct Neoplasms/mortality , Bile Duct Neoplasms/therapy , Biomarkers/blood , Blood Cell Count , Cholangiocarcinoma/mortality , Cholangiocarcinoma/therapy , Female , Humans , Inflammation/blood , Inflammation/mortality , Inflammation/therapy , Male , Middle Aged , Prognosis , Survival AnalysisABSTRACT
BACKGROUND: To investigate the impact of insurance status on outcomes in patients with hepatocellular carcinoma (HCC). METHODS: Patients diagnosed with HCC in the cancer registry from 2005 to 2016 were retrospectively stratified by insurance group. Overall survival was assessed via Kaplan-Meier curves and Cox proportional hazard models including potential confounders in multivariable analyses. RESULTS: Seven hundred and sixty-nine patients met inclusion criteria (median age 63 years, 78.8% male, 65.9% Caucasian). 44.5% had private insurance (n = 342), 29.1% had Medicare (n = 224), and 26.4% had Medicaid (n = 203). At diagnosis, Medicaid patients had higher rates of Child-Pugh B (32.0%) and C disease (23.6%) vs Medicare (28.6% and 9.8%) and private insurance (26.9% and 6.7%, P < 0.0001) and higher MELD scores (median 11.0) vs Medicare (9.0) and private insurance (9.0, P = 0.0266). Across insurance groups, patients had similar distribution of American Joint Committee on Cancer stage, tumor size, and multifocal tumor burden. Patients with private insurance had the highest survival (median OS 21.9 months) vs Medicare (17.7 months) and Medicaid (13.0 months, overall P = 0.0061). On univariate analysis, Medicaid patients demonstrated decreased survival vs private insurance (HR 1.40, 95% CI: 1.146-1.715, P = 0.0011). After adjustment for liver disease factors, this survival difference lost statistical significance (Medicaid vs private insurance, HR 1.02, 95% CI: 0.819-1.266, P = 0.8596). CONCLUSION: Medicaid was associated with advanced liver disease at HCC diagnosis; however, insurance status is not an independent predictor of HCC survival.
Subject(s)
Carcinoma, Hepatocellular/mortality , Insurance Coverage , Liver Neoplasms/mortality , Aged , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/therapy , Female , Hepatitis B/complications , Hepatitis B/mortality , Hepatitis B/therapy , Hepatitis C/complications , Hepatitis C/mortality , Hepatitis C/therapy , Humans , Insurance, Health , Kaplan-Meier Estimate , Liver Neoplasms/etiology , Liver Neoplasms/therapy , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/complications , Non-alcoholic Fatty Liver Disease/mortality , Non-alcoholic Fatty Liver Disease/therapy , Prognosis , Proportional Hazards Models , Social ClassABSTRACT
Pancreatic cancer is characterized by a high rate of metastatic spread and overall poor prognosis. Yet 30% of patients have progressive local disease at the time of death, and local progression can cause significant morbidity. Approximately 30-40% of patients present with locally advanced pancreatic cancer (LAPC) that is not surgically resectable, and the optimal treatment for these patients continues to evolve. The role of radiation in the management of LAPC is an area of controversy, and the recent LAP07 randomized trial reported no survival benefit of radiation following gemcitabine plus or minus erlotinib. However, the efficacy of modern systemic regimens has improved since the design of the LAP07 study, and radiation therapy may be of greater benefit in the context of more effective systemic therapy. Advances in radiation delivery including the increasing use of stereotactic body radiation therapy (SBRT) have the potential to improve outcomes through dose escalation and better treatment tolerability. In addition, the combination of radiation therapy and immune therapy is an area of promising research. These advances suggest that radiation therapy will continue to play an integral role in the management of LAPC.
ABSTRACT
BACKGROUND: To investigate mutational load and histologic biomarkers as prognostic factors in patients with chemorefractory colorectal liver metastases (CRLM) treated with Y-90 radioembolization therapy. MATERIALS AND METHODS: Single institution retrospective study of patients with CRLM who received Y-90 radioembolization after undergoing molecular testing was performed. Patient demographics, systemic therapy regimens, tumor characteristics and overall survival were analyzed between patients with differing histopathologic and genomic status. PIK3CA, KRAS, NRAS, AKT1, MEK1, MLH1, MSH2, MSH6 and PMS2 were analyzed. Kaplan-Meier survival estimation and multivariate Cox regression were analyzed. RESULTS: 23 patients underwent genomic analysis prior to Y-90. Eleven (47.8%) had mutations identified (MUT), and 12 were sequenced as wild type (WT) (52.2%). Median OS of 23 patients after Y-90 was 9.6 months (95% CI 6.67-16.23). Median OS from first Y-90 was significantly greater in WT patients (16.2 mo vs 6.5 mo; p =.0054). The survival difference between poorly differentiated tumors compared to all other histologic grades was significant (poor vs. well p=0.025, HR=26.8; poor vs. moderate p=.014, HR=23.07; poor vs. moderate/poor p=0.014, HR=23.68). When separated into 3 different groups (WT vs. MUT/moderate differentiation vs. MUT/poor differentiation) there was a difference in median OS observed (16.2 vs. 8.0 vs. 3.8 mos; p<.0001). Imaging response via RECIST criteria was significantly different between MUT and WT groups (p=0.02). CONCLUSIONS: Mutational status and histopathologic grade may predict survival after Y-90 radioembolization therapy for CRLM.