ABSTRACT
BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.
Subject(s)
Antibodies, Monoclonal, Humanized , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols , Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/mortality , Carcinoma, Hepatocellular/pathology , Liver Neoplasms/drug therapy , Liver Neoplasms/mortality , Liver Neoplasms/pathology , Male , Female , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Middle Aged , Aged , Sorafenib/administration & dosage , Sorafenib/therapeutic use , Sorafenib/adverse effects , Survival Rate , AdultABSTRACT
The National Consensus was prepared with the participation of the National Medical Association for the Study of the Multimorbidity, Russian Scientific Liver Society, Russian Association of Endocrinologists, Russian Association of Gerontologists and Geriatricians, National Society for Preventive Cardiology, Professional Foundation for the Promotion of Medicine Fund PROFMEDFORUM. The aim of the multidisciplinary consensus is a detailed analysis of the course of non-alcoholic fatty liver disease (NAFLD) and the main associated conditions. The definition of NAFLD is given, its prevalence is described, methods for diagnosing its components such as steatosis, inflammation and fibrosis are described. The association of NAFLD with a number of cardio-metabolic diseases (arterial hypertension, atherosclerosis, thrombotic complications, type 2 diabetes mellitus, obesity, dyslipidemia, etc.), chronic kidney disease and the risk of developing hepatocellular cancer were analyzed. The review of non-drug methods of treatment of NAFLD and modern opportunities of pharmacotherapy are presented. The possibilities of new molecules in the treatment of NAFLD are considered: agonists of nuclear receptors, antagonists of pro-inflammatory molecules, etc. The positive properties and disadvantages of currently used drugs (vitamin E, thiazolidinediones, etc.) are described. Special attention is paid to the multi-target ursodeoxycholic acid molecule in the complex treatment of NAFLD as a multifactorial disease. Its anti-inflammatory, anti-oxidant and cytoprotective properties, the ability to reduce steatosis an independent risk factor for the development of cardiovascular pathology, reduce inflammation and hepatic fibrosis through the modulation of autophagy are considered. The ability of ursodeoxycholic acid to influence glucose and lipid homeostasis and to have an anticarcinogenic effect has been demonstrated. The Consensus statement has advanced provisions for practitioners to optimize the diagnosis and treatment of NAFLD and related common pathogenetic links of cardio-metabolic diseases.
Subject(s)
Anticarcinogenic Agents , Diabetes Mellitus, Type 2 , Liver Neoplasms , Non-alcoholic Fatty Liver Disease , Thiazolidinediones , Adult , Humans , Non-alcoholic Fatty Liver Disease/diagnosis , Non-alcoholic Fatty Liver Disease/epidemiology , Non-alcoholic Fatty Liver Disease/therapy , Diabetes Mellitus, Type 2/complications , Ursodeoxycholic Acid/therapeutic use , Antioxidants/therapeutic use , Anticarcinogenic Agents/therapeutic use , Liver/pathology , Thiazolidinediones/therapeutic use , Glucose , Inflammation , Vitamin E , Anti-Inflammatory Agents/therapeutic use , LipidsABSTRACT
Liquid biopsy is a promising approach to molecular tumor testing in the context of targeted therapy. During this pilot study we applied a high-sensitivity protocol for detection of tumor-derived mutations in circulating plasma DNA of EGFR-positive non-small cell lung cancer (NSCLC) patients during EGFR-TKI therapy. We showed that this protocol was well suited for dynamic monitoring during targeted therapy as well as for detection of acquired resistance mutations.
Subject(s)
Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm/genetics , Protein Kinase Inhibitors/administration & dosage , Adult , Aged , Aged, 80 and over , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/blood , Circulating Tumor DNA/genetics , ErbB Receptors/blood , ErbB Receptors/genetics , Female , Humans , Male , Middle Aged , Molecular Targeted Therapy , Mutation , Pilot Projects , Protein Kinase Inhibitors/adverse effectsABSTRACT
The problem of primary multiple tumors is relevant to current clinical oncology because of increasing of number of patients with multiple malignant tumors and unsolved issues of treatment. Primary multiple malignant lung tumors is a common oncological situation requires an individualized, differentiated approach to treatment. The results of treatment are associated with the prevalence of the process, stages of tumor development, spare capacity of patients. There is presented clinical example of a patient with metachronous primary multiple malignant tumors of one lung.
Subject(s)
Lung Neoplasms , Neoplasms, Multiple Primary , Precision Medicine/methods , Female , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Lung Neoplasms/therapy , Male , Middle Aged , Neoplasms, Multiple Primary/metabolism , Neoplasms, Multiple Primary/pathology , Neoplasms, Multiple Primary/therapyABSTRACT
The paper gives information on current approaches to diagnosing and treating intrahepatic cholangiocarcinoma (IHC), its microscopic and macroscopic varieties. It details the specific features of images of IHC by ultrasonography, X-ray computed tomography, magnetic resonance imaging (MRI), including those by diffusion-weighted MRI. Dynamic intravenous contrast enhancement and analysis of tumor hemodynamic features are emphasized to play a crucial role in different examination (arterial, venous, and delayed) phases. Diffuse heterogeneous enhancement of the whole volume of the tumor in the arterial phase with pronounced peripheral and progressing centripetal enhancement in ensuing phases is considered to be the most common type of an IHC image, which can recognize with confidence this comparatively rare neoplasm.
Subject(s)
Bile Duct Neoplasms , Bile Ducts, Intrahepatic , Cholangiocarcinoma , Hepatectomy/methods , Liver Neoplasms , Liver , Bile Duct Neoplasms/diagnosis , Bile Duct Neoplasms/pathology , Bile Duct Neoplasms/surgery , Bile Ducts, Intrahepatic/pathology , Bile Ducts, Intrahepatic/surgery , Cholangiocarcinoma/diagnosis , Cholangiocarcinoma/pathology , Cholangiocarcinoma/surgery , Contrast Media , Humans , Liver/diagnostic imaging , Liver Neoplasms/diagnosis , Liver Neoplasms/pathology , Liver Neoplasms/surgery , Magnetic Resonance Imaging/methods , Neoplasm Invasiveness , Neoplasm Staging , Prognosis , Radiographic Image Enhancement/methods , Tomography, X-Ray Computed/methods , UltrasonographyABSTRACT
KRAS mutations in patients with metastatic colorectal cancer (CRC) are a negative marker of the effectiveness of anti-EGFR therapy and have prognostic significance. KRAS genotyping was performed in the material from patients with metastatic CRC. KRAS mutations were determined in tumor DNA from archival biopsies of 573 patients using PCR and sequencing. Mutations in the exon 2 of the KRAS gene were detected in 36.3% of cases of CRC, while often in women (41.1%) than in men (31.2%). There were identified eight types of KRAS mutations, the most frequent--replacement of G12D (33.7%), G12V (32.7%) and G13D (12.5%). There were revealed differences in the frequency and spectrum of KRAS mutations in CRC of various locations; in tumors of the rectum dominated mutation G12V (39%). The Russian CRC patients find out a higher frequency of mutations G12V and a lower frequency of mutations G13D, than patients from Europe and it should be taken into account when assessing the response of CRC patients with different mutant KRAS status on chemotherapy and targeted therapy.
Subject(s)
Amino Acid Substitution , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Mutation , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adult , Aged , Aspartic Acid , Female , Glycine , Humans , Incidence , Male , Middle Aged , Neoplasm Staging , Proto-Oncogene Proteins p21(ras) , ValineABSTRACT
Phase-I clinical studies of teraphtal and a "teraphtal + ascorbic acid" catalytic system have been completed. The dose-limiting toxicity and maximum tolerable dose were not reached even at the end of maximal dose trials. No side-effects characteristic of antitumor cytostatic drugs were registered. The gravest side-effect ever recorded was a collapse which could not be linked to teraphtal dosage and was probably caused by hypersensitivity to the drug. The drug was recommended for phase II trials.
Subject(s)
Antineoplastic Agents/therapeutic use , Indoles/therapeutic use , Adrenal Gland Neoplasms/drug therapy , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Breast Neoplasms/drug therapy , Colonic Neoplasms/drug therapy , Female , Humans , Indoles/administration & dosage , Indoles/adverse effects , Kidney Neoplasms/drug therapy , Male , Melanoma/drug therapy , Middle Aged , Sarcoma/drug therapy , Skin Neoplasms/drug therapy , Soft Tissue Neoplasms/drug therapyABSTRACT
The purpose of this study was to evaluate the efficacy and toxicity of paclitaxel and cisplatin combination chemotherapy as salvage treatment in patients with non-seminomatous germ cell tumour. Sixteen patients with histologically proven germ cell tumour, measurable disease and/or elevated serum tumour markers were eligible for the protocol. All patients had previously not achieved a complete remission (CR) to platinum-based induction chemotherapy and cytoreductive surgery. The treatment consisted of paclitaxel 175-225 mg/m2 as a 3-hour infusion, followed by cisplatin 100 mg/m2, repeated every 3 weeks for up to four cycles. Seven patients achieved a marker-positive partial remission (PR) by the end of the cisplatin-based induction chemotherapy; the remainder had disease progression at the start of the paclitaxel plus cisplatin treatment. One (6%) CR and 3 (19%) PRs were achieved, with an overall response rate of 25% (90% confidence interval 7-43). The duration of the CR is currently 9+ months; two PRs lasted 2 months. One patient with a PR has been lost to follow-up. During a median follow-up of 8 months (range 1-11), 12 patients died from the disease progression. The median survival for the whole group was 7 months. Toxicity was moderate, with neutropenia grade 3 occurring in 29% of patients, thrombocytopenia grade 1-3 in 29%, creatinine > 130 mmol/l in 36%, peripheral neuropathy grade 1-2 in 50%, and nausea and vomiting in 43%. Paclitaxel plus cisplatin showed modest activity, with an overall response rate of 31% in patients with poor prognosis who had not achieved a CR on induction chemotherapy.