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JAMA Oncology Jun 2022Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent... (Clinical Trial)
Clinical Trial
IMPORTANCE
Therapies for patients with advanced well-differentiated neuroendocrine tumors (NETs) have expanded but remain inadequate, with patients dying of disease despite recent advances in NET therapy. While patients with other cancers have seen long-term disease control and tumor regression with the application of immunotherapies, initial prospective studies of single-agent programmed cell death 1 inhibitors in NET have been disappointing.
OBJECTIVE
To evaluate the response rate following treatment with the combination of the vascular endothelial growth factor inhibitor bevacizumab with the programmed cell death 1 ligand 1 inhibitor atezolizumab in patients with advanced NETs.
DESIGN, SETTING, AND PARTICIPANTS
This single-arm, open-label nonrandomized clinical study in patients with rare cancers included 40 patients with advanced, progressive grade 1 to 2 NETs (20 with pancreatic NETs [pNETs] and 20 with extrapancreatic NETs [epNETs]) treated at a tertiary care referral cancer center between March 31, 2017, and February 19, 2019. Data were analyzed from June to September 2021.
INTERVENTIONS
Patients received intravenous bevacizumab and atezolizumab at standard doses every 3 weeks until progression, death, or withdrawal.
MAIN OUTCOMES AND MEASURES
The primary end point was objective radiographic response using Response Evaluation Criteria in Solid Tumors, version 1.1, with progression-free survival (PFS) as a key secondary end point.
RESULTS
Following treatment of the 40 study patients with bevacizumab and atezolizumab, objective response was observed in 4 patients with pNETs (20%; 95% CI, 5.7%-43.7%) and 3 patients with epNETs (15%; 95% CI, 3.2%-37.9%). The PFS was 14.9 (95% CI, 4.4-32.0) months and 14.2 (95% CI, 10.2-19.6) months in these cohorts, respectively.
CONCLUSIONS AND RELEVANCE
In this nonrandomized clinical trial, findings suggest that clinical responses in patients with NET may follow treatment with the combination of bevacizumab and atezolizumab, with a PFS consistent with effective therapies.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03074513.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Humans; Neuroectodermal Tumors, Primitive; Neuroendocrine Tumors; Prospective Studies; Treatment Outcome; Vascular Endothelial Growth Factor A
PubMed: 35389428
DOI: 10.1001/jamaoncol.2022.0212 -
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 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 -
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 -
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 -
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 -
European Journal of Nuclear Medicine... May 2021A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90...
PURPOSE
A multidisciplinary expert panel convened to formulate state-of-the-art recommendations for optimisation of selective internal radiation therapy (SIRT) with yttrium-90 (Y)-resin microspheres.
METHODS
A steering committee of 23 international experts representing all participating specialties formulated recommendations for SIRT with Y-resin microspheres activity prescription and post-treatment dosimetry, based on literature searches and the responses to a 61-question survey that was completed by 43 leading experts (including the steering committee members). The survey was validated by the steering committee and completed anonymously. In a face-to-face meeting, the results of the survey were presented and discussed. Recommendations were derived and level of agreement defined (strong agreement ≥ 80%, moderate agreement 50%-79%, no agreement ≤ 49%).
RESULTS
Forty-seven recommendations were established, including guidance such as a multidisciplinary team should define treatment strategy and therapeutic intent (strong agreement); 3D imaging with CT and an angiography with cone-beam-CT, if available, and Tc-MAA SPECT/CT are recommended for extrahepatic/intrahepatic deposition assessment, treatment field definition and calculation of the Y-resin microspheres activity needed (moderate/strong agreement). A personalised approach, using dosimetry (partition model and/or voxel-based) is recommended for activity prescription, when either whole liver or selective, non-ablative or ablative SIRT is planned (strong agreement). A mean absorbed dose to non-tumoural liver of 40 Gy or less is considered safe (strong agreement). A minimum mean target-absorbed dose to tumour of 100-120 Gy is recommended for hepatocellular carcinoma, liver metastatic colorectal cancer and cholangiocarcinoma (moderate/strong agreement). Post-SIRT imaging for treatment verification with Y-PET/CT is recommended (strong agreement). Post-SIRT dosimetry is also recommended (strong agreement).
CONCLUSION
Practitioners are encouraged to work towards adoption of these recommendations.
Topics: Embolization, Therapeutic; Humans; Liver Neoplasms; Microspheres; Positron Emission Tomography Computed Tomography; Technetium Tc 99m Aggregated Albumin; Yttrium Radioisotopes
PubMed: 33433699
DOI: 10.1007/s00259-020-05163-5 -
Oral Oncology Nov 2020Complex interactions take place during cancer formation and progression. In this regard, there has been increasing focus on the non-malignant cells that make up the... (Review)
Review
Complex interactions take place during cancer formation and progression. In this regard, there has been increasing focus on the non-malignant cells that make up the tumour microenvironment (TME), and how they interact with malignant tumour cells. TME is highly heterogeneous and has a major influence on tumour behaviour and therapy response. Cancer-associated fibroblasts (CAFs), one of the main components of the TME, establish dangerous liaisons with cancer cells and other components of the TME to shape a tumour-supportive environment in many types of cancer. Head and neck squamous cell carcinoma (HNSCC) encompass the malignant neoplasms arising from the mucosal lining of the oral cavity, pharynx and larynx. The TME of HNSCC contributes to tumour progression and this stromal compartment may be an interesting target for treatment. There is an emerging picture of the behaviour of CAFs in HNSCC; how they affect and are affected by the TME. We aim to summarise and discuss the current understanding of CAFs in head and neck cancer, exploring CAF activation and heterogeneity, and interaction with cancer cells and other cells within the TME.
Topics: Actins; Animals; Biomarkers; Cancer-Associated Fibroblasts; Cytokines; Disease Management; Disease Susceptibility; Drug Resistance, Neoplasm; Energy Metabolism; Epithelial-Mesenchymal Transition; Exosomes; Fibroblasts; Head and Neck Neoplasms; Humans; MicroRNAs; Neoplastic Stem Cells; Papillomavirus Infections; Tumor Microenvironment
PubMed: 33011636
DOI: 10.1016/j.oraloncology.2020.104972 -
Journal of Hepatocellular Carcinoma 2020To assess the overall survival (OS) and progression-free survival (PFS) of unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass-microsphere...
PURPOSE
To assess the overall survival (OS) and progression-free survival (PFS) of unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass-microsphere transarterial radioembolization (TARE) with and without concurrent sorafenib.
METHODS
OS and PFS were analyzed in 55 patients with an intrahepatic tumor (IHT) ≤50% without advanced or aggressive disease features (ADFs), which was referred to presence of infiltrative/ill-defined HCC, macrovascular invasion, or extrahepatic disease treated with only TARE (TARE_alone) and in 74 patients with IHT ≤50% with ADFs or IHT >50% treated with TARE and sorafenib (TARE_sorafenib). Prognostic factors for OS and PFS were identified using univariate and multivariate analyses.
RESULTS
Median OS and PFS of TARE_alone patients were 21.6 (95% CI 6.1-37.1) and 9.1(95% CI 5.2-13.0) months, respectively, and for TARE_sorafenib patients 12.4 (95% CI 9.1-15.6) and 5.1 (95% CI 2.6-7.5) months, respectively. Better OS was associated with serum AFP <400 (HR 0.27, =0.02) in TARE_alone, and IHT ≤50% (HR 0.39, =0.004) and AFP <400 (HR 0.5, =0.027) in TARE_sorafenib. Unilobar involvement (HR 0.43, =0.029) and AFP <400 ng/mL (HR 0.52, =0.015) correlated with better PFS in TARE_alone and TARE_sorafenib, respectively. Adverse events (AEs) were more frequent in TARE_sorafenib than TARE_alone (92.4 vs 80.3%), but only 9.3% were grade 3 or higher AEs.
CONCLUSION
TARE_alone provided the most prominent survival benefit in IHT ≤50%-without ADF patients who had unilobar HCC and serum AFP <400 ng/mL. TARE and sorafenib yielded the best outcomes in patients with IHT ≤50% and serum AFP <400 ng/mL, with some additional grade 1-2 AEs compared to TARE only.
PubMed: 32984089
DOI: 10.2147/JHC.S248314 -
The Biochemical Journal Aug 2020The detailed metabolic characterization of the glucagon receptor (Gcgr)V369M+/+ mutant mice described in Lin et al. in the Biochemical Journal is of interest and...
The detailed metabolic characterization of the glucagon receptor (Gcgr)V369M+/+ mutant mice described in Lin et al. in the Biochemical Journal is of interest and resulting in the expected metabolic profile. We would like to point out that these mice might also be extremely useful as a precision medicine model of mild Mahvash disease, a rare hereditary pancreatic neuroendocrine tumor syndrome characterized by inactivating mutations in the glucagon receptor. Further characterization of pancreas morphology and histology in the GcgrV369M+/+ mice at more advanced ages will be critically important to understand mild Mahvash disease in humans.
Topics: Animals; Glucagon; Humans; Metabolic Diseases; Mice; Mutation; Precision Medicine; Receptors, Glucagon
PubMed: 32785645
DOI: 10.1042/BCJ20200522