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Macrophage Clever-1 contributes to impaired antigen presentation and suppression of anti-tumor immunity. This first-in-human trial investigates the safety and tolerability of Clever-1 blockade with bexmarilimab in patients with treatment-refractory solid tumors and assesses preliminary anti-tumor efficacy, pharmacodynamics, and immunologic correlates. Bexmarilimab shows no dose-limiting toxicities in part I (n = 30) and no additional safety signals in part II (n = 108). Disease control (DC) rates of 25%-40% are observed in cutaneous melanoma, gastric, hepatocellular, estrogen receptor-positive breast, and biliary tract cancers. DC associates with improved survival in a landmark analysis and correlates with high pre-treatment intratumoral Clever-1 positivity and increasing on-treatment serum interferon γ (IFNγ) levels. Spatial transcriptomics profiling of DC and non-DC tumors demonstrates bexmarilimab-induced macrophage activation and stimulation of IFNγ and T cell receptor signaling selectively in DC patients. These data suggest that bexmarilimab therapy is well tolerated and show that macrophage targeting can promote immune activation and tumor control in late-stage cancer.
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Anticuerpos Monoclonales Humanizados , Neoplasias , Humanos , Anticuerpos Monoclonales Humanizados/farmacología , Activación de Macrófagos , Neoplasias/terapiaRESUMEN
Although hepatocellular carcinoma is increasingly common, debate exists surrounding the management of patients with unresectable disease comparing transarterial embolisation (TAE) or transarterial chemoembolisation (TACE). This study aimed to compare the outcomes of patients receiving TAE and TACE. A systematic review was performed using PubMed, Medline, Embase, and Cochrane databases to identify randomised controlled trials (RCTs) until August 2021. The primary outcome was overall survival (OS) and the secondary outcomes were progression-free survival (PFS) and adverse events. Five studies with 609 patients were included in the analysis. There was no statistically significant difference in the OS (p = 0.36) and PFS (p = 0.81). There was no difference in OS among patients treated with a single TACE/TAE versus repeat treatments. Post-procedural adverse effects were higher in the TACE group but were not statistically significant. TACE has comparable long-term survival and complications profile to TAE for patients with HCC. However, the low-to-moderate quality of current RCTs warrants high-quality RCTs are necessary to provide enough evidence to give a definitive answer and inform treatment plans for the future.
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PURPOSE: Textbook Outcome (TO) is inclusive of quality indicators and it not been provided for trans-arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Data on treatment-naïve HCC patients receiving TACE from 10 centers were reviewed. TO was defined as "no post-TACE grade 3-4 complications, no prolonged hospital stay (defined as a post-procedure stay ≤ 75th percentile of the median values from the total cohort), no 30-day mortality/readmission and the achievement of an objective response (OR) at post-TACE imaging." Grade of adverse event was classified according to the Common Terminology Criteria for Adverse Events and short-term efficacy was assessed by response. Pooled estimates were calculated to account for hospital's effect and risk-adjustment was applied to allow for diversity of patients in each center. RESULTS: A total of 1124 patients (2014-2018) fulfilling specific inclusion criteria were included. Baseline clinical features showed considerable heterogeneity (I2 > 0.75) across centers. TACE-related mortality was absent in 97.6%, readmission was not required after 94.9% of procedures, 91.5% of patients had no complication graded 3-4, 71.8% of patients did not require prolonged hospitalization, OR of the target lesion was achieved in 68.5%. Risk-adjustment showed that all indicators were achieved in 43.1% of patients, and this figure was similar across centers. The median overall survival for patients who achieved all indicators was 33.1 months, 11.9 months longer than for patients who did not. CONCLUSIONS: A useful benchmark for TACE in HCC patients has been developed, which provides an indication of survival and allows for a comparison of treatment quality across different hospitals.
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Carcinoma Hepatocelular , Quimioembolización Terapéutica , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/patología , Resultado del Tratamiento , Quimioembolización Terapéutica/métodos , Estudios RetrospectivosRESUMEN
BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: ESPAC5 (formerly known as ESPAC-5f) was a multicentre, open label, randomised controlled trial done in 16 pancreatic centres in two countries (UK and Germany). Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, biopsy proven pancreatic ductal adenocarcinoma in the pancreatic head, and were staged as having a borderline resectable tumour by contrast-enhanced CT criteria following central review. Participants were randomly assigned by means of minimisation to one of four groups: immediate surgery; neoadjuvant gemcitabine and capecitabine (gemcitabine 1000 mg/m2 on days 1, 8, and 15, and oral capecitabine 830 mg/m2 twice a day on days 1-21 of a 28-day cycle for two cycles); neoadjuvant FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid given according to local practice, and fluorouracil 400 mg/m2 bolus injection on days 1 and 15 followed by 2400 mg/m2 46 h intravenous infusion given on days 1 and 15, repeated every 2 weeks for four cycles); or neoadjuvant capecitabine-based chemoradiation (total dose 50·4 Gy in 28 daily fractions over 5·5 weeks [1·8 Gy per fraction, Monday to Friday] with capecitabine 830 mg/m2 twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Irinotecán/uso terapéutico , Terapia Neoadyuvante/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Capecitabina , Oxaliplatino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Gemcitabina , Leucovorina/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Quimioradioterapia , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/cirugíaRESUMEN
PURPOSE: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102. IMA970A includes 5 HLA-A*24 and 7 HLA-A*02 as well as 4 HLA-DR restricted peptides selected after mass spectrometric identification in human HCC tissues or cell lines. CV8102 is an RNA-based immunostimulator inducing a balanced Th1/Th2 immune response. PATIENTS AND METHODS: A total of 82 patients with very early- to intermediate-stage HCCs were enrolled and screened for suitable HLA haplotypes and 22 put on study treatment. This consisted in a single infusion of low-dose cyclophosphamide followed by nine intradermal coadministrations of IMA970A and CV8102. Only patients with no disease relapse after standard-of-care treatments were vaccinated. The primary endpoints of the HepaVac-101 clinical trial were safety, tolerability, and antigen-specific T-cell responses. Secondary or exploratory endpoints included additional immunologic parameters and survival endpoints. RESULTS: The vaccination showed a good safety profile. Transient mild-to-moderate injection-site reactions were the most frequent IMA970A/CV8102-related side effects. Immune responses against ≥1 vaccinated HLA class I tumor-associated peptide (TAA) and ≥1 vaccinated HLA class II TAA were respectively induced in 37% and 53% of the vaccinees. CONCLUSIONS: Immunotherapy may provide a great improvement in treatment options for HCC. HepaVac-101 is a first-in-human clinical vaccine trial with multiple novel HLA class I- and class II-restricted TAAs against HCC. The results are initial evidence for the safety and immunogenicity of the vaccine. Further clinical evaluations are warranted.
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Vacunas contra el Cáncer , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adyuvantes Inmunológicos , Vacunas contra el Cáncer/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Antígenos HLA-A , Humanos , Inmunoterapia/métodos , Neoplasias Hepáticas/tratamiento farmacológico , PéptidosRESUMEN
PURPOSE: The BILCAP study described a modest benefit for capecitabine as adjuvant therapy for curatively resected biliary tract cancer (BTC), and capecitabine has become the standard of care. We present the long-term data and novel exploratory subgroup analyses. METHODS: This randomized, controlled, multicenter, phase III study recruited patients age 18 years or older with histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer after resection with curative intent and an Eastern Cooperative Oncology Group performance status of < 2. Patients were randomly assigned 1:1 to receive oral capecitabine (1,250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation. The primary outcome was overall survival (OS). This study is registered with EudraCT 2005-003318-13. RESULTS: Between March 15, 2006, and December 4, 2014, 447 patients were enrolled; 223 patients with BTC resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. At the data cutoff of January 21, 2021, the median follow-up for all patients was 106 months (95% CI, 98 to 108). In the intention-to-treat analysis, the median OS was 49.6 months (95% CI, 35.1 to 59.1) in the capecitabine group compared with 36.1 months (95% CI, 29.7 to 44.2) in the observation group (adjusted hazard ratio 0.84; 95% CI, 0.67 to 1.06). In a protocol-specified sensitivity analysis, adjusting for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59 to 0.94). We further describe the prognostic impact of R status, grade, nodal status, and sex. CONCLUSION: This long-term analysis supports the previous analysis, suggesting that capecitabine can improve OS in patients with resected BTC when used as adjuvant chemotherapy after surgery and should be considered as the standard of care.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Sistema Biliar , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Capecitabina , Quimioterapia Adyuvante , Humanos , PronósticoRESUMEN
Prothrombin induced by vitamin K absence II (PIVKA-II) has recently been validated internationally as a diagnostic biomarker for hepatocellular carcinoma (HCC), as part of the GALAD model. However, its role as a treatment response biomarker has been less well explored. We, therefore, undertook a prospective study at a tertiary centre in the UK to evaluate the role of PIVKA-II as a treatment response biomarker in patients with early, intermediate and advanced stage HCC. In a cohort of 141 patients, we found that PIVKA-II levels tracked concordantly with treatment response in the majority of patients, across a range of different treatment modalities. We also found that rises in PIVKA-II levels almost always predated radiological progression. Among AFP non-secretors, PIVKA-II was found to be informative in 60% of cases. In a small cohort of patients undergoing liver transplantation, pre-transplant PIVKA-II levels predicted for microvascular invasion and poorer differentiation. Our results demonstrate the potential utility of PIVKA-II as a treatment response biomarker and in predicting microvascular invasion, in a Western population. PIVKA-II demonstrated improved performance over AFP but, as a single biomarker, its performance was still limited. Further larger prospective studies are recommended to evaluate PIVKA-II as a treatment response biomarker, within the GALAD model.
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BACKGROUND: Advanced hepatocellular carcinoma (HCC) is commonly diagnosed using non-invasive radiological criteria (NIRC) defined by the European Association for the Study of the Liver or the American Association for the Study of Liver Diseases. In 2017, The National Institute for Clinical Excellence mandated histological confirmation of disease to authorise the use of sorafenib in the UK. METHODS: This was a prospective multicentre audit in which patients suitable for sorafenib were identified at multidisciplinary meetings. The primary analysis cohort (PAC) was defined by the presence of Child-Pugh class A liver disease and performance status 0-2. Clinical, radiological and histological data were reported locally and collected on a standardised case report form. RESULTS: Eleven centres reported 418 cases, of which 361 comprised the PAC. Overall, 76% had chronic liver disease and 66% were cirrhotic. The diagnostic imaging was computed tomography in 71%, magnetic resonance imaging in 27% and 2% had both. Pre-existing histology was available in 45 patients and 270 underwent a new biopsy, which confirmed HCC in 93.4%. Alternative histological diagnoses included cholangiocarcinoma (CC) and combined HCC-CC. In cirrhotic patients, NIRC criteria had a sensitivity of 65.4% and a positive predictive value of 91.4% to detect HCC. Two patients (0.7%) experienced mild post-biopsy bleeding. CONCLUSION: The diagnostic biopsy is safe and feasible for most patients eligible for systemic therapy.
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Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Adulto , Anciano , Anciano de 80 o más Años , Biopsia/estadística & datos numéricos , Carcinoma Hepatocelular/tratamiento farmacológico , Colangiocarcinoma , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Imagen por Resonancia Magnética/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Estudios Prospectivos , Tomografía Computarizada por Rayos X/estadística & datos numéricos , Reino Unido , Adulto JovenRESUMEN
PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).
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Antineoplásicos/uso terapéutico , Proteína alfa Potenciadora de Unión a CCAAT/fisiología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Células Mieloides/fisiología , Sorafenib/uso terapéutico , Regulación hacia Arriba , Animales , Humanos , Ratones , Resultado del Tratamiento , Células Tumorales CultivadasRESUMEN
PURPOSE: Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages toward a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of the macrophage scavenger receptor Clever-1 has shown benefit in inducing CD8+ T-cell-mediated antitumor responses in mouse models of cancer, which supports the clinical development of Clever-1-targeting antibodies for cancer treatment. PATIENTS AND METHODS: In this study, we analyzed the mode of action of a humanized IgG4 anti-Clever-1 antibody, FP-1305 (bexmarilimab), both in vitro and in patients with heavily pretreated metastatic cancer (n = 30) participating in part 1 (dose-finding) of a phase I/II open-label trial (NCT03733990). We studied the Clever-1 interactome in primary human macrophages in antibody pull-down assays and utilized mass cytometry, RNA sequencing, and cytokine profiling to evaluate FP-1305-induced systemic immune activation in patients with cancer. RESULTS: Our pull-down assays and functional studies indicated that FP-1305 impaired multiprotein vacuolar ATPase-mediated endosomal acidification and improved the ability of macrophages to activate CD8+ T-cells. In patients with cancer, FP-1305 administration led to suppression of nuclear lipid signaling pathways and a proinflammatory phenotypic switch in blood monocytes. These effects were accompanied by a significant increase and activation of peripheral T-cells with indications of antitumor responses in some patients. CONCLUSIONS: Our results reveal a nonredundant role played by the receptor Clever-1 in suppressing adaptive immune cells in humans. We provide evidence that targeting macrophage scavenging activity can promote an immune switch, potentially leading to intratumoral proinflammatory responses in patients with metastatic cancer.
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Moléculas de Adhesión Celular Neuronal , Activación de Linfocitos , Neoplasias , Receptores Mensajeros de Linfocitos , Humanos , Linfocitos T CD8-positivos/inmunología , Moléculas de Adhesión Celular Neuronal/antagonistas & inhibidores , Regulación hacia Abajo , Activación de Linfocitos/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/inmunología , Receptores Mensajeros de Linfocitos/antagonistas & inhibidoresRESUMEN
BACKGROUND: The neutrophil-lymphocyte ratio (NLR), a presumed measure of the balance between neutrophil-associated pro-tumour inflammation and lymphocyte-dependent antitumour immune function, has been suggested as a prognostic factor for several cancers, including hepatocellular carcinoma (HCC). METHODS: In this study, a prospectively accrued cohort of 781 patients (493 HCC and 288 chronic liver disease (CLD) without HCC) were followed-up for more than 6 years. NLR levels between HCC and CLD patients were compared, and the effect of baseline NLR on overall survival amongst HCC patients was assessed via multivariable Cox regression analysis. RESULTS: On entry into the study ('baseline'), there was no clinically significant difference in the NLR values between CLD and HCC patients. Amongst HCC patients, NLR levels closest to last visit/death were significantly higher compared to baseline. Multivariable Cox regression analysis showed that NLR was an independent prognostic factor, even after adjustment for the HCC stage. CONCLUSION: NLR is a significant independent factor influencing survival in HCC patients, hence offering an additional dimension in prognostic models.
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Carcinoma Hepatocelular/diagnóstico , Enfermedad Hepática en Estado Terminal/diagnóstico , Neoplasias Hepáticas/diagnóstico , Neutrófilos/inmunología , Carcinoma Hepatocelular/inmunología , Estudios de Casos y Controles , Diagnóstico Diferencial , Enfermedad Hepática en Estado Terminal/inmunología , Humanos , Neoplasias Hepáticas/inmunología , Recuento de Linfocitos , Pronóstico , Estudios Prospectivos , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
BACKGROUND: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. METHODS: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. FINDINGS: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). INTERPRETATION: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials. FUNDING: Cancer Research UK, StandUpToCancer, AMMF (The UK Cholangiocarcinoma Charity), and The Christie Charity, with additional funding from The Cholangiocarcinoma Foundation and the Conquer Cancer Foundation Young Investigator Award for translational research.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Biliar/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Sistema Biliar/mortalidad , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Estudios ProspectivosRESUMEN
BACKGROUND: Recent studies have revealed that coadministration of gastric acid suppressants reduces the efficacy of the tyrosine kinase inhibitors erlotinib and sunitinib in patients with non-small cell lung cancer and renal cell carcinoma, respectively. The authors have therefore assessed if the concurrent use of gastric acid suppressants and sorafenib impairs outcomes in patients with advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on all patients treated with sorafenib for advanced HCC at a single tertiary referral unit in the United Kingdom, between January 2008 and January 2014. A multivariate Cox proportional hazard model was used to assess the effect of the concomitant use of gastric acid suppression and sorafenib on progression-free survival (PFS) and overall survival (OS). RESULTS: Data were collected from 197 patients, of which 182 could be assessed for this study; 77 (42%) were on concurrent gastric acid suppression therapy. After adjusting for imbalances between the groups, a Cox regression analysis gave an adjusted hazard ratio for the concurrent acid suppression group compared with the no acid suppression group of 5.4 (95% confidence interval, 3.6-7.9) for PFS and 1.85 (95% confidence interval, 1.3-2.6) for OS. CONCLUSIONS: This single-center experience shows that patients with advanced HCC taking sorafenib and concomitant gastric acid suppression therapy have significantly inferior PFS and OS. This is the first time that this negative interaction has been reported and further prospective validation is warranted.
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Antineoplásicos , Carcinoma Hepatocelular , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Hepáticas , Neoplasias Pulmonares , Antineoplásicos/efectos adversos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Supervivencia sin Enfermedad , Ácido Gástrico , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Niacinamida/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Estudios Retrospectivos , Sorafenib , Resultado del Tratamiento , Reino UnidoRESUMEN
Historically, locally advanced pancreatic adenocarcinoma (LAPDAC) was considered a palliative condition. Advances in treatment have resulted in studies reporting survival after neoadjuvant treatment and surgery similar to earlier disease stages. However, there is no consensus on optimal LAPDAC management. Our aim was a systematic review of published evidence on LAPDAC treatment strategies with curative intent. Twenty-eight studies defining LAPDAC as per established criteria and reporting outcomes after neoadjuvant treatment with a view to resection were included. Primary outcomes were resection rate and proportion of curative resections. Secondary outcomes were postoperative mortality, progression-free survival, and overall survival. Neoadjuvant treatment varied significantly, most common being the combination of folinic acid, fluorouracil, irontecan, and oxaliplatin. Median percentage of patients proceeding to surgery after completion of neoadjuvant pathway was 33.5%. Median resection rate was 25%. Median R0 resection was 80% of resected patients. These outcomes ranged 0% to 100% across studies. Ninety-day postoperative mortality ranged from 0% to 5%. Median progression-free and overall survival for resected patients were 12.9 and 30 months, respectively, versus 13.2 months overall survival for unresected patients. In conclusion, although there is wide variability in reported LAPDAC resection rates post-neoadjuvant chemotherapy, retrospective data suggest that neoadjuvant treatment followed by surgery results in improved survival.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Neoadyuvante , Pancreatectomía , Neoplasias Pancreáticas/terapia , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioterapia Adyuvante , Progresión de la Enfermedad , Humanos , Terapia Neoadyuvante/efectos adversos , Terapia Neoadyuvante/mortalidad , Estadificación de Neoplasias , Pancreatectomía/efectos adversos , Pancreatectomía/mortalidad , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Supervivencia sin Progresión , Radioterapia Adyuvante , Factores de TiempoRESUMEN
PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
Asunto(s)
Antineoplásicos/administración & dosificación , Proteínas Potenciadoras de Unión a CCAAT/agonistas , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Oligorribonucleótidos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Proteínas Potenciadoras de Unión a CCAAT/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Infusiones Intravenosas , Liposomas , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Nanopartículas/administración & dosificación , Estadificación de Neoplasias , Oligorribonucleótidos/efectos adversos , Oligorribonucleótidos/farmacocinética , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BACKGROUND: TG01 is the first cancer immunotherapy targeting KRAS oncogenic mutations. This study assessed the safety and efficacy of TG01/GM-CSF in patients with resected pancreatic adenocarcinoma. METHODS: Patients with stage I or II pancreatic adenocarcinoma who had undergone surgical resection (R0 or R1) received adjuvant gemcitabine with TG01/GM-CSF using two schedules of vaccination. Immune response was defined as a positive delayed-type hypersensitivity (DTH) response and/or positive T-cell proliferation assay. RESULTS: Thirty-two patients were enrolled between February 2013 and May 2016. Nineteen were treated with the high antigen burden, with four serious adverse reactions considered possibly related to TG01 treatment, including three allergic reactions. On this basis, a further 13 patients received a modified vaccination schedule with reduced antigen burden, with no serious adverse events related to TG01. Ninety-five percent patients in the main cohort and 92% in the modified cohort had a positive immune response. Median overall survival (OS) was 33.1 months, and median disease-free survival (DFS) was 13.9 months for the main cohort. For the modified cohort, the median OS was 34.3 months and median DFS was 19.5 months. CONCLUSIONS: TG01/GM-CSF with gemcitabine was well tolerated, with high levels of immune activation. OS and DFS compare favourably with published data for adjuvant gemcitabine. CLINICAL TRIAL REGISTRATION: This clinical trial was registered at ClinicalTrials.gov (NCT02261714).
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/patología , Anciano , Desoxicitidina/farmacología , Desoxicitidina/uso terapéutico , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/cirugía , Gemcitabina , Neoplasias PancreáticasRESUMEN
BACKGROUND: Despite improvements in multidisciplinary management, patients with biliary tract cancer have a poor outcome. Only 20% of patients are eligible for surgical resection with curative intent, with 5-year overall survival of less than 10% for all patients. To our knowledge, no studies have described a benefit of adjuvant therapy. We aimed to determine whether adjuvant capecitabine improved overall survival compared with observation following surgery for biliary tract cancer. METHODS: This randomised, controlled, multicentre, phase 3 study was done across 44 specialist hepatopancreatobiliary centres in the UK. Eligible patients were aged 18 years or older and had histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer who had undergone a macroscopically complete resection (which includes liver resection, pancreatic resection, or, less commonly, both) with curative intent, and an Eastern Cooperative Oncology Group performance status of less than 2. Patients who had not completely recovered from previous surgery or who had previous chemotherapy or radiotherapy for biliary tract cancer were also excluded. Patients were randomly assigned 1:1 to receive oral capecitabine (1250 mg/m2 twice daily on days 1-14 of a 21-day cycle, for eight cycles) or observation commencing within 16 weeks of surgery. Treatment was not masked, and allocation concealment was achieved with a computerised minimisation algorithm that stratified patients by surgical centre, site of disease, resection status, and performance status. The primary outcome was overall survival. As prespecified, analyses were done by intention to treat and per protocol. This study is registered with EudraCT, number 2005-003318-13. FINDINGS: Between March 15, 2006, and Dec 4, 2014, 447 patients were enrolled; 223 patients with biliary tract cancer resected with curative intent were randomly assigned to the capecitabine group and 224 to the observation group. The data cutoff for this analysis was March 6, 2017. The median follow-up for all patients was 60 months (IQR 37-60). In the intention-to-treat analysis, median overall survival was 51·1 months (95% CI 34·6-59·1) in the capecitabine group compared with 36·4 months (29·7-44·5) in the observation group (adjusted hazard ratio [HR] 0·81, 95% CI 0·63-1·04; p=0·097). In a protocol-specified sensitivity analysis, adjusting for minimisation factors and nodal status, grade, and gender, the overall survival HR was 0·71 (95% CI 0·55-0·92; p=0·010). In the prespecified per-protocol analysis (210 patients in the capecitabine group and 220 in the observation group), median overall survival was 53 months (95% CI 40 to not reached) in the capecitabine group and 36 months (30-44) in the observation group (adjusted HR 0·75, 95% CI 0·58-0·97; p=0·028). In the intention-to-treat analysis, median recurrence-free survival was 24·4 months (95% CI 18·6-35·9) in the capecitabine group and 17·5 months (12·0-23·8) in the observation group. In the per-protocol analysis, median recurrence-free survival was 25·9 months (95% CI 19·8-46·3) in the capecitabine group and 17·4 months (12·0-23·7) in the observation group. Adverse events were measured in the capecitabine group only, and of the 213 patients who received at least one cycle, 94 (44%) had at least one grade 3 toxicity, the most frequent of which were hand-foot syndrome in 43 (20%) patients, diarrhoea in 16 (8%) patients, and fatigue in 16 (8%) patients. One (<1%) patient had grade 4 cardiac ischaemia or infarction. Serious adverse events were observed in 47 (21%) of 223 patients in the capecitabine group and 22 (10%) of 224 patients in the observation group. No deaths were deemed to be treatment related. INTERPRETATION: Although this study did not meet its primary endpoint of improving overall survival in the intention-to-treat population, the prespecified sensitivity and per-protocol analyses suggest that capecitabine can improve overall survival in patients with resected biliary tract cancer when used as adjuvant chemotherapy following surgery and could be considered as standard of care. Furthermore, the safety profile is manageable, supporting the use of capecitabine in this setting. FUNDING: Cancer Research UK and Roche.
Asunto(s)
Antimetabolitos Antineoplásicos/administración & dosificación , Neoplasias del Sistema Biliar/terapia , Procedimientos Quirúrgicos del Sistema Biliar , Capecitabina/administración & dosificación , Espera Vigilante , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias del Sistema Biliar/mortalidad , Neoplasias del Sistema Biliar/patología , Procedimientos Quirúrgicos del Sistema Biliar/efectos adversos , Procedimientos Quirúrgicos del Sistema Biliar/mortalidad , Capecitabina/efectos adversos , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Supervivencia sin Progresión , Factores de Tiempo , Reino UnidoRESUMEN
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe. METHODS: A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors. RESULTS: Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis. CONCLUSION: Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.
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Antineoplásicos/uso terapéutico , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Anciano , Carcinoma Ductal Pancreático/epidemiología , Europa (Continente)/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Pancreáticas/epidemiología , Análisis de SupervivenciaRESUMEN
Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC.Patients and Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS).Results: Of 1,318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and ß-catenin (CTNNB1; 37.0%).Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib-this preliminary finding should be further explored. Clin Cancer Res; 24(19); 4650-61. ©2018 AACR.