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Journal of Clinical Oncology : Official... Dec 2021To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM). (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To study the impact of transarterial Yttrium-90 radioembolization (TARE) in combination with second-line systemic chemotherapy for colorectal liver metastases (CLM).
METHODS
In this international, multicenter, open-label phase III trial, patients with CLM who progressed on oxaliplatin- or irinotecan-based first-line therapy were randomly assigned 1:1 to receive second-line chemotherapy with or without TARE. The two primary end points were progression-free survival (PFS) and hepatic PFS (hPFS), assessed by blinded independent central review. Random assignment was performed using a web- or voice-based system stratified by unilobar or bilobar disease, oxaliplatin- or irinotecan-based first-line chemotherapy, and mutation status.
RESULTS
Four hundred twenty-eight patients from 95 centers in North America, Europe, and Asia were randomly assigned to chemotherapy with or without TARE; this represents the intention-to-treat population and included 215 patients in the TARE plus chemotherapy group and 213 patients in the chemotherapy alone group. The hazard ratio (HR) for PFS was 0.69 (95% CI, 0.54 to 0.88; 1-sided = .0013), with a median PFS of 8.0 (95% CI, 7.2 to 9.2) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. The HR for hPFS was 0.59 (95% CI, 0.46 to 0.77; 1-sided < .0001), with a median hPFS of 9.1 (95% CI, 7.8 to 9.7) and 7.2 (95% CI, 5.7 to 7.6) months, respectively. Objective response rates were 34.0% (95% CI, 28.0 to 40.5) and 21.1% (95% CI, 16.2 to 27.1; 1-sided = .0019) for the TARE and chemotherapy groups, respectively. Median overall survival was 14.0 (95% CI, 11.8 to 15.5) and 14.4 months (95% CI, 12.8 to 16.4; 1-sided = .7229) with a HR of 1.07 (95% CI, 0.86 to 1.32) for TARE and chemotherapy groups, respectively. Grade 3 adverse events were reported more frequently with TARE (68.4% 49.3%). Both groups received full chemotherapy dose intensity.
CONCLUSION
The addition of TARE to systemic therapy for second-line CLM led to longer PFS and hPFS. Further subset analyses are needed to better define the ideal patient population that would benefit from TARE.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Case-Control Studies; Chemoradiotherapy; Colorectal Neoplasms; Embolization, Therapeutic; Female; Follow-Up Studies; Humans; Irinotecan; Liver Neoplasms; Male; Middle Aged; Oxaliplatin; Prognosis; Survival Rate; Yttrium Radioisotopes
PubMed: 34541864
DOI: 10.1200/JCO.21.01839 -
The Lancet. Oncology Apr 2017Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for...
BACKGROUND
Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy associated with infection by human papillomavirus (HPV). No consensus treatment approach exists for the treatment of metastatic disease. Because intratumoral HPV oncoproteins upregulate immune checkpoint proteins such as PD-1 to evade immune-mediated cytotoxicity, we did a trial of the anti-PD-1 antibody nivolumab for patients with metastatic SCCA.
METHODS
We did this single-arm, multicentre, phase 2 trial at ten academic centres in the USA. We enrolled patients with treatment-refractory metastatic SCCA, who were given nivolumab every 2 weeks (3 mg/kg). The primary endpoint was response according to Response Evaluation Criteria in Solid Tumors, version 1.1, in the intention-to-treat population. At the time of data cutoff, the study was ongoing, with patients continuing to receive treatment. The study is registered with ClinicalTrials.gov, number NCT02314169.
RESULTS
We screened 39 patients, of whom 37 were enrolled and received at least one dose of nivolumab. Among the 37 patients, nine (24% [95% CI 15-33]) had responses. There were two complete responses and seven partial responses. Grade 3 adverse events were anaemia (n=2), fatigue (n=1), rash (n=1), and hypothyroidism (n=1). No serious adverse events were reported.
INTERPRETATION
To our knowledge, this is the first completed phase 2 trial of immunotherapy for SCCA. Nivolumab is well tolerated and effective as a monotherapy for patients with metastatic SCCA. Immune checkpoint blockade appears to be a promising approach for patients with this orphan disease.
FUNDING
National Cancer Institute/Cancer Therapy Evaluation Program, the HPV and Anal Cancer Foundation, the E B Anal Cancer Fund, The University of Texas MD Anderson Moon Shots Program, and an anonymous philanthropic donor.
Topics: Aged; Antibodies, Monoclonal; Antineoplastic Agents; Anus Neoplasms; Carcinoma, Squamous Cell; Case-Control Studies; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Nivolumab; Prognosis; Prospective Studies; Response Evaluation Criteria in Solid Tumors; Salvage Therapy; Survival Rate
PubMed: 28223062
DOI: 10.1016/S1470-2045(17)30104-3 -
Chinese Journal of Cancer Jun 2013Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of... (Review)
Review
Pancreatic neuroendocrine tumors (PNETs), a group of endocrine tumors arising in the pancreas, are among the most common neuroendocrine tumors. The genetic causes of familial and sporadic PNETs are somewhat understood, but their molecular pathogenesis remains unknown. Most PNETs are indolent but have malignant potential. The biological behavior of an individual PNET is unpredictable; higher tumor grade, lymph node and liver metastasis, and larger tumor size generally indicate a less favorable prognosis. Endocrine testing, imaging, and histological evidence are necessary to accurately diagnose PNETs. A 4-pronged aggressive treatment approach consisting of surgery, locoregional therapy, systemic therapy, and complication control has become popular in academic centers around the world. The optimal application of the multiple systemic therapeutic modalities is under development; efficacy, safety, availability, and cost should be considered when treating a specific patient. The clinical presentation, diagnosis, and treatment of specific types of PNETs and familial PNET syndromes, including the novel Mahvash disease, are summarized.
Topics: Combined Modality Therapy; Gastrinoma; Glucagonoma; Humans; Insulinoma; Multiple Endocrine Neoplasia Type 1; Neuroendocrine Tumors; Pancreatic Neoplasms; Vipoma; von Hippel-Lindau Disease
PubMed: 23237225
DOI: 10.5732/cjc.012.10295 -
Drugs Jun 2021Statins are a group of lipid-lowering drugs that inhibit cholesterol biosynthesis and have anti-inflammatory, anti-tumor, and immunomodulatory properties. Several lines... (Review)
Review
Statins are a group of lipid-lowering drugs that inhibit cholesterol biosynthesis and have anti-inflammatory, anti-tumor, and immunomodulatory properties. Several lines of evidence indicate that statins regulate multiple proteins associated with the regulation of differing cellular pathways. The 5'-adenosine monophosphate-activated protein kinase (AMPK) pathway plays an important role in metabolism homeostasis with effects on cellular processes including apoptosis and the inflammatory responses through several pathways. Recently, it has been shown that statins can affect the AMPK pathway in differing physiological and pathological ways, resulting in anti-cancer, cardio-protective, neuro-protective, and anti-tubercular effects; additionally, they have therapeutic effects on non-alcoholic fatty liver disease and diabetes mellitus-associated complications. Statins activate AMPK as an energy sensor that inhibits cell proliferation and induces apoptosis in cancer cells, whilst exerting its cardio-protective effects through inhibition of inflammation and fibrosis, and promotion of angiogenesis. Furthermore, statin-associated AMPK activation leads to decreased lipid accumulation and decreased amyloid beta deposition in the liver and brain, respectively, and may have therapeutic effects on the liver and neurons. In this review, we summarize the results of studies of AMPK-associated therapeutic effects of statins in different pathological conditions.
Topics: AMP-Activated Protein Kinases; Angiogenesis Inducing Agents; Animals; Apoptosis; Cardiovascular Diseases; Cell Line, Tumor; Cell Proliferation; Fibrosis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Inflammation; Neoplasms; Nervous System Diseases
PubMed: 33939118
DOI: 10.1007/s40265-021-01510-4 -
World Journal of Gastroenterology Dec 2021Impressive survival outcome of our previous study in unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass microspheres transarterial...
Disease control and failure patterns of unresectable hepatocellular carcinoma following transarterial radioembolization with yttrium-90 microspheres and with/without sorafenib.
BACKGROUND
Impressive survival outcome of our previous study in unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass microspheres transarterial radioembolization (TARE) with/without sorafenib according to individuals' disease burden, , intrahepatic tumor load (IHT) and adverse disease features (ADFs) might partly be confounded by other treatments and underlying hepatic function. Therefore, a dedicated study focusing on treatment response and assessment of failure patterns might be a way to improve treatment outcome in addition to patient selection based on the disease burden.
AIM
To assess the tumor response, disease control and patterns of disease progression following TARE with/without sorafenib in unresectable HCC patients.
METHODS
This retrospective study was conducted in successful TARE procedures with available pre- and post-treatment imaging studies ( = 169). Three treatment subgroups were (1) TARE only () for IHT ≤ 50% without ADFs, , macrovascular invasion, extrahepatic disease (EHD) and infiltrative/ill-defined HCC ( = 63); (2) TARE with sorafenib () for IHT > 50% and/or presence of ADFs ( = 81); and (3) TARE only for patients who could not receive sorafenib due to contraindication or intolerance () ( = 25). Objective response rate (ORR; consisted of complete response (CR) and partial response (PR)), disease control rate (DCR; consisted of CR, PR and stable disease) and failure patterns of treated, intrahepatic and extrahepatic sites were assessed using the modified response evaluation criteria in solid tumors. Time to progression (TTP) was calculated from TARE to the first radiologic progression at any site using Kaplan-Meier method. Identification of prognostic factors for TTP using the univariate Kaplan-Meier method and multivariate Cox proportional hazard model were performed in major population subgroups, and .
RESULTS
The median radiologic follow-up time was 4.4 mo (range 0.5-48.8). In treated area, ORR was highest in (53.1%), followed by (41.3%) and (16%). In intrahepatic area, DCR remained highest in (84%), followed by (79.4%) and (44%). The overall DCR was highest in (79.4%), followed by (71.6%) and (40%). Dominant failure patterns were intrahepatic for both (44.5%) and (38.4%). Extrahepatic progression was more common in (32%) and (40%) than in (12.7%). TTP was longest in 8.6 mo; 95%CI: 3.4-13.8, followed by (5.1 mo; 95%CI: 4.0-6.2) and 2.7 mo; 95%CI: 2.2-3.1). Pre-existing EHD (HR: 0.37, 95%CI: 0.24-0.56, < 0.001) was a sole prognostic factor for TTP in with no prognostic factor for TTP in .
CONCLUSION
TARE with/without sorafenib according to individuals' disease burden provided DCR approximately 70% with intrahepatic progression as dominant failure pattern. Extrahepatic progression was more common in procedures with initially high disease burden.
Topics: Carcinoma, Hepatocellular; Embolization, Therapeutic; Humans; Liver Neoplasms; Microspheres; Retrospective Studies; Sorafenib; Treatment Outcome; Yttrium Radioisotopes
PubMed: 35068861
DOI: 10.3748/wjg.v27.i47.8166 -
Journal of Hepatocellular Carcinoma 2016Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer globally and predominantly develops in the setting of various grades of underlying chronic... (Review)
Review
Hepatocellular carcinoma (HCC) is the fifth most frequently occurring cancer globally and predominantly develops in the setting of various grades of underlying chronic liver disease, which affects management decisions. Image-guided percutaneous ablative or transarterial therapies have acquired wide acceptance in HCC management as a single treatment modality or combined with other treatment options in patients who are not amenable for surgery. Recently, such treatment modalities have also been used for bridging or downsizing before definitive treatment (ie, surgical resection or liver transplantation). This review focuses on the use of minimally invasive image-guided locoregional therapies for HCC. Additionally, it highlights recent advancements in imaging and catheter technology, embolic materials, chemotherapeutic agents, and delivery techniques; all lead to improved patient outcomes, thereby increasing the interest in these invasive techniques.
PubMed: 27785450
DOI: 10.2147/JHC.S92732 -
Journal of Hepatocellular Carcinoma 2016The safety and efficacy of the combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) to treat advanced hepatocellular carcinoma (HCC) is not well...
PURPOSE
The safety and efficacy of the combined use of sorafenib and yttrium-90 resin microspheres (Y90 RMS) to treat advanced hepatocellular carcinoma (HCC) is not well established. We determined the incidence of adverse events with this combination therapy in patients with advanced HCC at our institution and analyzed the treatment and survival outcomes.
MATERIALS AND METHODS
We reviewed the records of 19 patients with Barcelona Clinic Liver Cancer class B or C HCC who underwent treatment with Y90 RMS (for 21 sessions) while receiving full or reduced doses of sorafenib between January 2008 and May 2010. Therapy response was evaluated using Response Evaluation Criteria in Solid Tumors. We evaluated median overall survival (OS) and progression-free survival (PFS) as well as hepatic and extrahepatic disease PFS and incidence of adverse events.
RESULTS
The median patient age was 67 years, and portal or hepatic venous invasion was present in eight patients (42%). Ten patients received reduced doses of sorafenib. The median Y90 radiation activity delivered was 41.2 mCi. The partial response of Response Evaluation Criteria in Solid Tumors was observed in four patients (19%). The median hepatic disease PFS was 7.82 months, extrahepatic disease PFS was 8.94 months, OS was 19.52 months, and PFS was 6.63 months. Ninety days after treatment with Y90 RMS, five patients (26%) had grade II adverse events and four patients (21%) had grade III adverse events.
CONCLUSION
OS and PFS outcomes were superior to those observed in prior studies evaluating sorafenib alone in patients with a similar disease status, warranting further study of this treatment combination.
PubMed: 27574586
DOI: 10.2147/JHC.S62261 -
Journal of Hepatocellular Carcinoma 2021The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and...
PURPOSE
The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors.
METHODS
We enrolled 38 Child-Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival.
RESULTS
A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III-IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8-14.4) and 13.2 months (95% CI 7.9-18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3-90) weeks, and average dose was 622 (466-800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-Y treatment.
CONCLUSION
This is the first prospective study to evaluate sorafenib followed by Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC.
CLINICAL TRIAL REGISTRATION NUMBER
NCT01900002.
PubMed: 34527608
DOI: 10.2147/JHC.S318865 -
Molecular Genetics and Metabolism... Dec 2018Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in...
Glucagon receptor (GCGR) defect (Mahvash disease) is an autosomal recessive hereditary pancreatic neuroendocrine tumor (PNET) syndrome that has only been reported in adults with pancreatic α cell hyperplasia and PNETs. We describe a 7-year-old girl with persistent hyperaminoacidemia, notable for elevations of glutamine (normal ammonia), alanine (normal lactate), dibasic amino acids (arginine, lysine and ornithine), threonine and serine. She initially was brought to medical attention by an elevated arginine on newborn screening (NBS) and treated for presumed arginase deficiency with a low protein diet, essential amino acids formula and an ammonia scavenger drug. This treatment normalized plasma amino acids. She had intermittent emesis and anorexia, but was intellectually normal. Arginase enzyme assay and sequencing and deletion/duplication analysis were normal. Treatments were stopped, but similar pattern of hyperaminoacidemia recurred. She also had hypercholesterolemia type IIa, with only elevated LDL cholesterol, despite an extremely lean body habitus. Exome sequencing was initially non-diagnostic. Through a literature search, we recognized the pattern of hyperaminoacidemia was strikingly similar to that reported in the knockout mice. Subsequently the patient was found to have an extremely elevated plasma glucagon and a novel, homozygous c.958_960del (p.Phe320del) variant in . Functional studies confirmed the pathogenicity of this variant. This case expands the clinical phenotype of GCGR defect in children and emphasizes the clinical utility of plasma amino acids in screening, diagnosis and monitoring glucagon signaling interruption. Early identification of a GCGR defect may provide an opportunity for potential beneficial treatment for an adult onset tumor predisposition disease.
PubMed: 30294546
DOI: 10.1016/j.ymgmr.2018.09.006 -
Cancer Discovery Nov 2021Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint...
Malignant peritoneal mesothelioma (MPeM) is a rare but aggressive malignancy with limited treatment options. VEGF inhibition enhances efficacy of immune-checkpoint inhibitors by reworking the immunosuppressive tumor milieu. Efficacy and safety of combined PD-L1 (atezolizumab) and VEGF (bevacizumab) blockade (AtezoBev) was assessed in 20 patients with advanced and unresectable MPeM with progression or intolerance to prior platinum-pemetrexed chemotherapy. The primary endpoint of confirmed objective response rate per RECISTv1.1 by independent radiology review was 40% [8/20; 95% confidence interval (CI), 19.1-64.0] with median response duration of 12.8 months. Six (75%) responses lasted for >10 months. Progression-free and overall survival at one year were 61% (95% CI, 35-80) and 85% (95% CI, 60-95), respectively. Responses occurred notwithstanding low tumor mutation burden and PD-L1 expression status. Baseline epithelial-mesenchymal transition gene expression correlated with therapeutic resistance/response ( = 0.80; = 0.0010). AtezoBev showed promising and durable efficacy in patients with advanced MPeM with an acceptable safety profile, and these results address a grave unmet need for this orphan disease. SIGNIFICANCE: Efficacy of atezolizumab and bevacizumab vis-à-vis response rates and survival in advanced peritoneal mesothelioma previously treated with chemotherapy surpassed outcomes expected with conventional therapies. Biomarker analyses uncovered epithelial-mesenchymal transition phenotype as an important resistance mechanism and showcase the value and feasibility of performing translationally driven clinical trials in rare tumors...
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; B7-H1 Antigen; Bevacizumab; Biomarkers, Tumor; Humans; Mesothelioma; Vascular Endothelial Growth Factor A
PubMed: 34261675
DOI: 10.1158/2159-8290.CD-21-0331