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BACKGROUND: Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. METHODS: KEYNOTE-966 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 175 medical centres globally. Eligible participants were aged 18 years or older; had previously untreated, unresectable, locally advanced or metastatic biliary tract cancer; had disease measurable per Response Evaluation Criteria in Solid Tumours version 1.1; and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to pembrolizumab 200 mg or placebo, both administered intravenously every 3 weeks (maximum 35 cycles), in combination with gemcitabine (1000 mg/m2 intravenously on days 1 and 8 every 3 weeks; no maximum duration) and cisplatin (25 mg/m2 intravenously on days 1 and 8 every 3 weeks; maximum 8 cycles). Randomisation was done using a central interactive voice-response system and stratified by geographical region, disease stage, and site of origin in block sizes of four. The primary endpoint of overall survival was evaluated in the intention-to-treat population. The secondary endpoint of safety was evaluated in the as-treated population. This study is registered at ClinicalTrials.gov, NCT04003636. FINDINGS: Between Oct 4, 2019, and June 8, 2021, 1564 patients were screened for eligibility, 1069 of whom were randomly assigned to pembrolizumab plus gemcitabine and cisplatin (pembrolizumab group; n=533) or placebo plus gemcitabine and cisplatin (placebo group; n=536). Median study follow-up at final analysis was 25·6 months (IQR 21·7-30·4). Median overall survival was 12·7 months (95% CI 11·5-13·6) in the pembrolizumab group versus 10·9 months (9·9-11·6) in the placebo group (hazard ratio 0·83 [95% CI 0·72-0·95]; one-sided p=0·0034 [significance threshold, p=0·0200]). In the as-treated population, the maximum adverse event grade was 3 to 4 in 420 (79%) of 529 participants in the pembrolizumab group and 400 (75%) of 534 in the placebo group; 369 (70%) participants in the pembrolizumab group and 367 (69%) in the placebo group had treatment-related adverse events with a maximum grade of 3 to 4. 31 (6%) participants in the pembrolizumab group and 49 (9%) in the placebo group died due to adverse events, including eight (2%) in the pembrolizumab group and three (1%) in the placebo group who died due to treatment-related adverse events. INTERPRETATION: Based on a statistically significant, clinically meaningful improvement in overall survival compared with gemcitabine and cisplatin without any new safety signals, pembrolizumab plus gemcitabine and cisplatin could be a new treatment option for patients with previously untreated metastatic or unresectable biliary tract cancer. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
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Neoplasias do Sistema Biliar , Gencitabina , Humanos , Cisplatino , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-Cego , Microambiente TumoralRESUMO
Aim: To evaluate real-world treatment patterns, survival and healthcare-resource utilization in US patients with advanced biliary tract cancers (BTC) receiving systemic therapy.Patients & methods: This study used claims data from the Healthcare Integrated Research Database (HIRD®) linked to clinical data from the Cancer Care Quality Program (January 1, 2015-September 30, 2020).Results: Of 413 patients, 84.5% received gemcitabine-based first-line (1L) treatment, 46% received second-line treatment, and 16.5% received third-line (3L) treatment. All-cause mortality was 53% and approximately 70% of patients had ≥1 inpatient visit. The total mean per-patient-per-month all-cause costs were $19,589 for 1L and $33,534 for 3L treatment.Conclusion: Results showed poor survival, significant resource use and high costs as treatment line progresses for patients with advanced BTC.
Our research explored which treatments US patients with advanced biliary tract cancers (BTC) received and how long they lived for. We analyzed information from a US database, called the Healthcare Integrated Research Database (HIRD®), which holds information related to healthcare insurance claims. Out of 413 patients in the database, 84.5% were initially given a combination treatment involving a chemotherapy called gemcitabine. We also found that 46% of patients received a type of second treatment (also known as second-line therapy), and 16.5% received a third treatment (third-line therapy). During treatment, around 70% of patients needed to stay in hospital at least once. The cost of healthcare was more expensive for patients receiving later lines of therapy, with the average monthly cost per patient for first-line treatment being $19,589 and third-line treatment being $33,534. Furthermore, just over half of the 413 patients died from any causes, showing the poor outlook these patients face. This information is important for understanding the real-world management of patients with BTC, so that their care can be improved in the future.
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Aim: A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Materials & methods: Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were calculated using random effects meta-analysis. Results: Across 31 studies evaluating chemotherapy or targeted treatment regimens in an unselected advanced BTC patient population, pooled ORR was 6.9%, median OS was 6.6 months and median PFS was 3.2 months. Conclusion: The efficacy of conventional treatments for previously treated advanced BTC patients is poor and could be improved by novel therapies.
What is this article about? Most patients with biliary tract cancer are identified with advanced disease, and almost all go through a worsening of the disease after their first treatment. For patients who go on to receive their next treatment, current guidelines are unclear regarding the best treatment choice. Therefore, we examined the available medical literature and performed an analysis of multiple studies to calculate overall estimates of the clinical value of standard treatments for these patients. Our goal was to develop a benchmark against which to compare the clinical value of new treatments that are currently being assessed in clinical trials. What were the results? We identified 31 studies assessing standard treatments (involving chemotherapy or molecularly targeted treatments) in previously treated advanced biliary tract cancer patients. Across these studies, the objective tumor response rate was 6.9%, median overall survival was 6.6 months and median progression-free survival was 3.2 months. What do the results of the study mean? These results indicate that there is limited clinical value of standard treatments for patients with advanced biliary tract cancer whose disease worsened after first treatment. This medical need could potentially be met by new treatments, such as immunotherapies that restore the immune system's ability to attack cancer cells and thereby prolong patient survival.
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Neoplasias do Sistema Biliar , Humanos , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Neoplasias do Sistema Biliar/terapia , Resultado do Tratamento , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estadiamento de Neoplasias , Terapia de Alvo MolecularRESUMO
BACKGROUND: Esophageal adenocarcinoma (EAC) is associated with a dismal prognosis. The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy. The authors present results from the development of a serum-based, 4-protein (biglycan, myeloperoxidase, annexin-A6, and protein S100-A9) biomarker panel for EAC. METHODS: A vertically integrated, proteomics-based biomarker discovery approach was used to identify candidate serum biomarkers for the detection of EAC. Liquid chromatography-tandem mass spectrometry analysis was performed on formalin-fixed, paraffin-embedded tissue samples that were collected from across the Barrett esophagus (BE)-EAC disease spectrum. The mass spectrometry-based spectral count data were used to guide the selection of candidate serum biomarkers. Then, the serum enzyme-linked immunosorbent assay data were validated in an independent cohort and were used to develop a multiparametric risk-assessment model to predict the presence of disease. RESULTS: With a minimum threshold of 10 spectral counts, 351 proteins were identified as differentially abundant along the spectrum of Barrett esophagus, high-grade dysplasia, and EAC (P<.05). Eleven proteins from this data set were then tested using enzyme-linked immunosorbent assays in serum samples, of which 5 proteins were significantly elevated in abundance among patients who had EAC compared with normal controls, which mirrored trends across the disease spectrum present in the tissue data. By using serum data, a Bayesian rule-learning predictive model with 4 biomarkers was developed to accurately classify disease class; the cross-validation results for the merged data set yielded accuracy of 87% and an area under the receiver operating characteristic curve of 93%. CONCLUSIONS: Serum biomarkers hold significant promise for the early, noninvasive detection of EAC.
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Adenocarcinoma/diagnóstico , Anexina A6/sangue , Biglicano/sangue , Biomarcadores Tumorais/sangue , Calgranulina B/sangue , Detecção Precoce de Câncer/métodos , Neoplasias Esofágicas/diagnóstico , Peroxidase/sangue , Adenocarcinoma/sangue , Esôfago de Barrett/sangue , Cromatografia Líquida , Neoplasias Esofágicas/sangue , Humanos , Modelos Biológicos , Espectrometria de Massas em TandemRESUMO
BACKGROUND: Surgery alone is often inadequate for advanced-stage gastric cancer. Surgical complications may delay adjuvant therapy. Understanding these complications is needed for multidisciplinary planning. MATERIAL AND METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried for patients who underwent gastrectomy for malignancy (ICD-9 code 151.x) from 2005 to 2010. Thirty-day mortality and morbidity were evaluated. RESULTS: Overall, 2,580 patients underwent gastrectomy for malignancy, divided as total gastrectomy 999 (38.7 %) and partial gastrectomy 1,581 (61.3 %). Overall, serious morbidity occurred in 23.6 %, and the 30-day mortality was 4.1 %. Patients receiving a total gastrectomy were younger and healthier than those receiving a partial gastrectomy for the following measured criteria: age, diabetes, chronic obstructive pulmonary disease and hypertension. Serious morbidity and mortality were significantly higher in the total gastrectomy group than the partial gastrectomy group (29.3 vs. 19.9 %, p < 0.001; and 5.4 vs. 3.4 %, p < 0.015, respectively). The inclusion of additional procedures increased the risk of mortality for the following: splenectomy (odds ratio [OR] 2.8; p < 0.001), pancreatectomy (OR 3.5; p = 0.001), colectomy (OR 3.6; p < 0.001), enterectomy (OR 2.7; p = 0.030), esophagectomy (OR 3.5; p = 0.035). Abdominal lymphadenectomy was not associated with increased morbidity (OR 1.1; p = 0.41); rather, it was associated with decreased mortality (OR 0.468; p = 0.028). CONCLUSIONS: Gastrectomy for cancer as currently practiced carries significant morbidity and mortality. Inclusion of additional major procedures increases these risks. The addition of lymphadenectomy was not associated with increased morbidity or mortality. Strategies are needed to optimize surgical outcomes to ensure delivery of multimodality therapy for advanced-stage disease.
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Gastrectomia/mortalidade , Excisão de Linfonodo/mortalidade , Complicações Pós-Operatórias , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Morbidade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Neoplasias Gástricas/patologia , Taxa de SobrevidaRESUMO
BACKGROUND: Signet ring cell esophageal adenocarcinoma histology has been difficult to study in single institution series because of its relative rarity, yet has an anecdotal reputation for poor prognosis. The Surveillance, Epidemiology, and End Results (SEER) database was examined to assess the prognostic implications of this esophageal adenocarcinoma subtype. METHODS: All patients with esophageal adenocarcinoma in the SEER database from 2004 to 2009 were included. Univariate and multivariate analyses examining the relationship of signet ring cell histology with overall survival were performed in all patients, as well as those undergoing surgical resection. RESULTS: A total of 596 of 11,825 (5%) study patients had signet ring cell histology. Patients with signet ring cell histology were similar in age, race, and sex distribution, but had a higher grade (P < .001) and higher stage (P < .001) at diagnosis. In both the all-patient group as well as those undergoing surgical resection, univariate analyses showed a worse survival in patients with signet ring cell esophageal cancer (hazard ratio [HR] = 1.24; 95% confidence interval [CI] = 1.13-1.36 and HR = 1.57; 95% CI = 1.29-1.93, respectively). In multivariate analyses adjusting for covariates, patients with signet ring cell cancer had a worse prognosis than those without (HR = 1.18; 95% CI = 1.07-1.30). In surgically resected patients, this remained a trend, but did not reach statistical significance (HR = 1.16; 95% CI = 0.94-1.42). CONCLUSIONS: This large study of esophageal adenocarcinoma confirms the clinical impression that signet ring cell variant of adenocarcinoma is associated with an advanced stage at presentation and a worse prognosis independent of stage of presentation.
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Carcinoma de Células em Anel de Sinete/epidemiologia , Carcinoma de Células em Anel de Sinete/patologia , Neoplasias Esofágicas/epidemiologia , Neoplasias Esofágicas/patologia , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Análise de Variância , Carcinoma de Células em Anel de Sinete/cirurgia , Neoplasias Esofágicas/cirurgia , Esofagectomia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Programa de SEER , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. METHODS: GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. RESULTS: Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). CONCLUSIONS: Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.
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Adenocarcinoma/etiologia , Adenocarcinoma/prevenção & controle , Esôfago de Barrett/etiologia , Esôfago de Barrett/prevenção & controle , Neoplasias Esofágicas/etiologia , Neoplasias Esofágicas/prevenção & controle , Refluxo Gastroesofágico/complicações , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Animais , Benzamidas/farmacologia , Caspase 3/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Proteínas Hedgehog/metabolismo , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Masculino , Quinazolinas/farmacologia , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Receptor SmoothenedRESUMO
BACKGROUND: Small cell cancer (SCC) of the esophagus is an uncommon malignancy with perceived poor prognosis, but there are few data to guide therapeutic decisions. We examined the Surveillance, Epidemiology, and End Results (SEER) database to identify prognostic factors for survival. METHODS: All patients with esophageal cancer in the SEER database between 1973 and 2009 were included. Univariate and multivariate analyses were performed in patients with and without SCC, examining the relationship of small cell histology, surgery, and other potential prognostic factors with overall survival (censored at 72 months). RESULTS: Of 64,799 esophageal cancer patients identified in the SEER database, 387 (0.6 %) had small cell histology. As compared with non-small cell histology, patients with small cell histology were similar in age and race but had a higher proportion of women (p < 0.001), had a higher stage at diagnosis (p < 0.001), and were less likely to undergo surgical resection (p < 0.01). Multivariate predictors associated with poor survival in the overall cohort included age, female gender, black race, and stage. In patients treated with surgery, multivariate predictors associated with poor survival included age, male gender, race, and stage but not small cell histology. In patients with small cell histology, both age and stage were associated with poor survival, but surgery and preoperative radiotherapy were associated with improved survival. CONCLUSIONS: SCC of the esophagus presents at an advanced stage and confers a poor prognosis. The survival benefit of surgery and radiotherapy suggests that all esophageal SCC patients should be considered for preoperative radiotherapy and surgery in a stage-appropriate fashion.
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Carcinoma de Células Pequenas/patologia , Carcinoma de Células Escamosas/patologia , Bases de Dados Factuais , Neoplasias Esofágicas/patologia , Idoso , Carcinoma de Células Pequenas/mortalidade , Carcinoma de Células Pequenas/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/cirurgia , Estudos de Coortes , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Estadiamento de Neoplasias , Prognóstico , Programa de SEER , Taxa de SobrevidaRESUMO
The Hedgehog (Hh) pathway is known to be active in Barrett's carcinogenesis. Therefore, we evaluated the efficacy and underlying mechanisms of inhibition of cancer cell growth by the smoothened (Smo) antagonist BMS-833923 in esophageal adenocarcinoma (EAC) cell lines. Cell proliferation and apoptosis were evaluated by flow cytometry, Western blotting, immunofluorescence, and quantitative reverse transcription polymerase chain reactions. Results showed that the Smo antagonist led to reduced Hh pathway activity, resulting in decreased cell proliferation and induction of apoptosis via the intrinsic pathway in the esophageal cancer cells. In conclusion, the Smo antagonist may have application as an EAC chemotherapeutic agent.
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Adenocarcinoma/metabolismo , Apoptose/fisiologia , Neoplasias Esofágicas/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Adenocarcinoma/patologia , Western Blotting , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Esofágicas/patologia , Citometria de Fluxo , Imunofluorescência , Proteínas Hedgehog/metabolismo , Humanos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Receptor SmoothenedRESUMO
PURPOSE: Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. MATERIALS AND METHODS: Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. RESULTS: The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). CONCLUSIONS: Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population.
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Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/radioterapia , Quinazolinas/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/radioterapia , Quimiorradioterapia/métodos , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/efeitos dos fármacos , Junção Esofagogástrica/patologia , Junção Esofagogástrica/efeitos da radiação , Feminino , Humanos , Masculino , Estudos Prospectivos , Ducto Torácico/efeitos dos fármacos , Ducto Torácico/patologia , Ducto Torácico/efeitos da radiaçãoRESUMO
AIMS: This post hoc analysis evaluated albumin/bilirubin (ALBI) score, an objective measure of liver function, in patients receiving pembrolizumab plus best supportive care (BSC) compared with placebo plus BSC in the KEYNOTE-240 study. METHODS: Patients with confirmed hepatocellular carcinoma (HCC) and progression after/intolerance to sorafenib, Child-Pugh class A liver function, and Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned 2:1 to pembrolizumab 200 mg or placebo intravenously every 3 weeks plus BSC for ⩽35 cycles or until confirmed progression/unacceptable toxicity. Outcomes were assessed by ALBI grade. RESULTS: Of 413 patients, at baseline 116 had an ALBI grade 1 score (pembrolizumab, n = 74; placebo, n = 42) and 279 had an ALBI grade 2 score (n = 193; n = 86). Change from baseline in ALBI score to the end of treatment was similar in both arms [difference in least squares mean, -0.039; 95% confidence interval (CI): -0.169 to 0.091]. Time to ALBI grade increase was similar in both arms [median for pembrolizumab versus placebo: 7.8 versus 6.9 months; hazard ratio (HR) = 0.863 (95% CI: 0.625-1.192)]. Regardless of baseline ALBI grade, a trend toward improved overall survival was observed with pembrolizumab [grade 1: HR = 0.725 (95% CI: 0.454-1.158); grade 2: HR = 0.827 (95% CI: 0.612-1.119)]. CONCLUSION: Pembrolizumab did not adversely impact liver function compared with placebo in patients with HCC, as measured by changes in ALBI scores. A trend toward improved overall survival was observed with pembrolizumab in both ALBI grade groups. ClinicalTrials.gov identifier: NCT02702401.
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The purpose of our study was to evaluate the efficacy of a combination of pralatrexate plus oxaliplatin in advanced esophagogastric cancer (EGC), analyze the impact of polymorphisms in folate metabolism pathway genes on toxicity and efficacy of pralatrexate, and to evaluate microRNA profile of tumor epithelium as a predictive biomarker. This was a two-stage trial with a safety lead in cohort and a primary endpoint of overall response rate (ORR). Patients received biweekly intravenous oxaliplatin (85 mg/m2) and pralatrexate (Dose level 1 [D1], 120 mg/m2; dose level-1 [D-1] 100 mg/m2). Single-nucleotide polymorphisms (SNP) in genes encoding proteins involved in pralatrexate metabolism were evaluated in germline DNA. microRNA profiling of the tumor epithelium was performed. ORR was 26%. Dose-limiting toxicities were observed in 2 of 4 patients at D1 and none at D-1. The T>C polymorphism in DHFR rs11951910 was significantly associated with lower progression-free survival (PFS; P ≤ 0.01), whereas the presence of the SLC19A1 rs2838957 G>A polymorphism was associated with improved PFS (P = 0.02). Presence of the GGH rs3780130 A>T and SLC19A1 rs1051266 G>A polymorphisms were significantly associated with better overall survival (OS; P = 0.01), whereas GGH rs7010484 T>C polymorphism was associated significantly with reduced OS (P = 0.04). There was no correlation between epithelial microRNA expression profile with disease progression or response. We conclude that the combination of oxaliplatin and pralatrexate is safe, is well tolerated, and has modest efficacy in advanced EGC. Pharmacogenomic analysis may be relevant to the use of pralatrexate in combination with platinum agents.
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Aminopterina/análogos & derivados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Aminopterina/farmacologia , Aminopterina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Humanos , Masculino , Oxaliplatina/farmacologiaRESUMO
BACKGROUND: Hematologic toxicity (HT) commonly occurs during chemoradiation therapy (CRT) for esophageal cancer. We sought to determine radiation doses that correlate with declines in blood counts due to vertebral body (VB) irradiation during CRT. METHODS: We analyzed 53 esophageal cancer patients who were treated with weekly neoadjuvant carboplatin, paclitaxel and RT with weekly complete blood counts (CBC) available during treatment. HTs were graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). Dose volume histogram (DVH) parameters of Vx, defined as percentage of entire bony vertebra (body, pedicles, laminae, processes) receiving at least x Gy of radiation, were collected for VB V5 (VBV5), VBV10-VBV60 in increments of 10, and mean vertebral dose (MVD). Linear and logistic regressions were performed to identify associations between leukopenia nadirs and DVH parameters. Receiver operator curves identified thresholds to avoid grade ≥3 leukopenia. RESULTS: A proportion of 32.1% of patients (n=17) developed grade 3 leukopenia and 5.7% (n=3) developed grade 4 leukopenia. VBV5, VBV10, VBV20, VBV30, and MVD were significantly associated with worsening leukopenia on univariate and multivariate analysis. Associations with leukopenia were not seen with VBV40 and VBV50 DVH values. Thresholds to avoid grade ≥3 leukopenia were VBV10 <49.1%, VBV20 <45.6%, and MVD <17.2 Gy. CONCLUSIONS: VBV5, VBV10, VBV20, VBV30 associate with leukopenia during CRT for esophageal cancer patients. Improved radiation sparing of the VB may decrease HT and may improve tolerability of concurrent chemotherapy and allow for intensification of systemic therapy during RT.
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Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide, with a majority of HCC patients not suitable for curative therapies. Approximately 70% of initially diagnosed patients cannot undergo surgical resection or transplantation due to locally advanced disease, poor liver function/underlying cirrhosis, or additional comorbidities. Local therapeutic options for patients with unresectable HCC, who are not suitable for thermal ablation, include transarterial embolization (bland, chemoembolization, radioembolization) and/or external beam radiation therapy (EBRT). Regarding EBRT specifically, technological advancements provide a means for safe and effective radiotherapy delivery in a wide spectrum of HCC patients. In multiple prospective studies, EBRT delivery in a variety of different fractionation schemes or in combination with transcatheter arterial chemoembolization (TACE) demonstrate improved outcomes, particularly with combination therapy. The Barcelona Clinic Liver Cancer classification provides a framework for treatment selection; however, given the growing complexity of treatment strategies, this classification system tends to simplify decision-making. In this review, we discuss the current literature regarding unresectable HCC and propose a modified treatment algorithm that emphasizes the role of radiation therapy for Child-Pugh score A or B patients with ≤3 nodules measuring >3 cm, multinodular disease or portal venous thrombosis.
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BACKGROUND: ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. METHODS: Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. RESULTS: Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. CONCLUSIONS: Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. TRIAL REGISTRATION: NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors).
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Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Receptores de Dopamina D2/imunologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Humanos , Pessoa de Meia-IdadeRESUMO
Colorectal cancer incidence and death rates have been declining over the past 10 years. However, it remains the second leading cause of death in men ages 60-79 and the third leading cause of death in men over 80 and in women over 60 years old. However, there is little data specific to the treatment of the elder patient, since few of these patients are included in trials. With the advent of improved therapies, there are many alternative options available. Still, no definitive consensus or guidelines have been defined for this particular patient population. The goal of this study is to review the literature on the management of rectal cancer in the elderly and to propose treatment algorithms to help the oncology team in treatment decision-making.
RESUMO
Rectal cancer predominantly affects patients older than 70 years, with peak incidence at age 80 to 85 years. However, the standard treatment paradigm for rectal cancer oftentimes cannot be feasibly applied to these patients owing to frailty or comorbid conditions. There are currently little information and no treatment guidelines to help direct therapy for patients who are elderly and/or have significant comorbidities, because most are not included or specifically studied in clinical trials. More recently various alternative treatment options have been brought to light that may potentially be utilized in this group of patients. This critical review examines the available literature on alternative therapies for rectal cancer and proposes a treatment algorithm to help guide clinicians in treatment decision making for elderly and comorbid patients.
Assuntos
Algoritmos , Tomada de Decisão Clínica/métodos , Tomada de Decisões , Neoplasias Retais/radioterapia , Fatores Etários , Idoso , Braquiterapia/métodos , Quimioterapia Adjuvante , Comorbidade , Humanos , Participação do Paciente , Neoplasias Retais/cirurgiaRESUMO
OBJECTIVES: Vascular endothelial growth factor overexpression, seen in 42% to 76% of biliary tract cancers (BTCs), correlates with poor survival. We explored the safety/efficacy and potential biomarkers for bevacizumab in combination with gemcitabine-capecitabine in advanced BTCs. PATIENTS AND METHODS: Inoperable stage III/IV BTC patients in our prospective study were given 1000 mg/m of gemcitabine (on days 1, 8), 650 mg/m of capecitabine (on days 1 to 14), and 15 mg/kg of bevacizumab (on day 1) in 21-day cycles. Circulating tumor cells and quality of life were assessed at baseline and before cycle 2 and 3. RESULTS: In total, 50 patients with gallbladder cancer (22%), intrahepatic (58%), and extrahepatic (20%) cholangiocarcinoma, received a median of 8 treatment cycles for median treatment duration of 5.8 months. Common grade 3/4 toxicities were neutropenia (36%), thrombocytopenia (16%), fatigue (20%), infections (14%), and hand-foot syndrome (10%). There were 12 partial response (24%), 24 stable disease (48%) with clinical benefit rate of 72%. Median progression-free survival was 8.1 months (95% confidence interval, 5.3-9.9). Median overall survival was 10.2 months (95% confidence interval, 7.5-13.7). Circulating tumor cells were identified at baseline in 21/46 patients (46%), who had lower median overall survival compared with those without (9.4 vs. 13.7 mo; P=0.29). Patients with quality of life scores greater than the group median by the end of first cycle of treatment had improved survival compared with those who did not (13.3 vs. 9.4 mo; P=0.39). CONCLUSIONS: Addition of bevacizumab to gemcitabine/capecitabine did not improve outcome in an unselected group of patients with advanced BTC compared with historical controls. The selective benefit of vascular endothelial growth factor inhibition in BTC remains to be explored.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias do Sistema Biliar/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Idoso de 80 Anos ou mais , Bevacizumab/administração & dosagem , Neoplasias dos Ductos Biliares/secundário , Neoplasias do Sistema Biliar/patologia , Capecitabina/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , GencitabinaRESUMO
Of all patients diagnosed with pancreatic adenocarcinoma, only 15-20% present with resectable disease. Despite curative-intent resection, the prognosis remains poor with the majority of patients recurring, prompting the need for adjuvant therapy. Historical data support the use of adjuvant 5-fluorouracil (5-FU) or gemcitabine, but recent data suggest either gemcitabine plus capecitabine or modified FOLFIRINOX can improve overall survival when compared to gemcitabine alone. The use of adjuvant chemoradiation therapy remains controversial, primarily due to limitations in study design and mixed results of historical trials. The ongoing Radiation Therapy Oncology Group (RTOG)-0848 trial hopes to further define the role of adjuvant chemoradiation therapy. Intraoperative radiation therapy (IORT) and adjuvant immunotherapy represent additional possibilities to improve outcomes, but evidence supporting their use is limited. This article reviews adjuvant therapeutic strategies for resectable pancreatic adenocarcinoma, including chemotherapy, chemoradiation therapy, IORT and immunotherapy.
RESUMO
Prior studies examining the risk of second primary malignancy (SPM) after a first primary cancer generally have used large datasets such as the Surveillance, Epidemiology, and End Results (SEER) registry and excluded survivors of previous primaries and developers of synchronous primaries. The goal of this study was to provide a more complete representation of multiple cancer risk in squamous cell carcinoma of the anus (SCCA) patients. A single-institution retrospective study of 46 patients treated definitively for SCCA between January 2006 and July 2017 was conducted. Of the 46 patients, 18 (39%) had either a primary malignancy before SCCA (n=9) or SPM after an index SCCA (n=9). Six patients had ≥3 total malignancies. In our cohort, patients without SPMs tended to die from SCCA recurrence, while patients with SPMs were more likely to die from their SPM than from SCCA. Our study suggests that patients with SCCA are often either survivors of previous cancers or develop later malignancies. Several risk factors may play a role including HPV infection, HPV-related or treatment-related immunosuppression, somatic mutations due to chemotherapy, and genetic factors. Patients with SCCA require lifelong surveillance given their elevated risk of malignancy. Future work should focus on identifying genomic or immunologic factors that may predispose SCCA patients to develop multiple primary malignancies.