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OBJECTIVE: Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett's oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling. DESIGN: We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. RESULTS: The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models. CONCLUSION: Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.
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Adenocarcinoma , Esófago de Barrett , Neoplasias Esofágicas , Humanos , Esófago de Barrett/patología , Estudio de Asociación del Genoma Completo , Neoplasias Esofágicas/patología , Adenocarcinoma/patologíaRESUMEN
BACKGROUND: Paclitaxel in combination with ramucirumab is the standard of care second-line therapy in gastro-esophageal adenocarcinoma (GEA). As the number of taxane pretreated patients in the perioperative or first-line setting is increasing, it is unknown whether these patients benefit from re-applying a taxane in using the combination of paclitaxel and ramucirumab. Furthermore, the rates of neurotoxicity with first-line FOLFOX or FLOT range from 30%-70%, making second-line taxane-containing therapy less suitable to a meaningful portion of patients. This patient group is likely to benefit from a taxane-free second-line chemotherapy regimen, such as FOLFIRI and ramucirumab (FOLFIRI-Ram). Therefore, the RAMIRIS phase III trial evaluates the effects of the regimen of FOLFIRI-Ram in the second-line treatment after a taxane-based chemotherapy in patients with advanced GEA. METHODS: The RAMIRIS trial is a randomized, open-label, multicenter phase II/III study comparing treatment of FOLFIRI-Ram (arm A) with paclitaxel and ramucirumab (arm B). The Phase II is already closed with 111 enrolled patients. In the phase III, 318 taxane-pretreated patients with advanced GEA will be recruited and randomized 1:1 to FOLFIRI (5-FU 2400 mg/m2 over 46 h i.v., irinotecan 180 mg/m2 i.v.; 5-FU 400 mg/m2 bolus; leucovorin 400 mg/m2 i.v.; on day 1 and 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm A) or paclitaxel 80 mg/m2 (days 1, 8, 15, q28) with ramucirumab 8 mg/kg every two weeks (Arm B). The primary endpoints are overall survival (OS) and objective overall response rate (ORR). Secondary endpoints are progression-free survival (PFS), disease control rate and safety and quality of life as assessed by EORTC-QLQ-C30 questionnaire. DISCUSSION: The already completed RAMIRIS phase II demonstrated feasibility and efficacy of FOLFIRI-Ram. Especially docetaxel-pretreated patients seemed to markedly benefit from FOLFIRI-Ram, with favorable response- and PFS rates and lower toxicity. This offers a rationale for the phase III trial. If the RAMIRIS III trial transfers and confirms the results, they will affect the current treatment guidelines, recommending the combination therapy of FOLFIRI-Ram for taxane-pretreated patients with advanced GEA. TRIAL REGISTRATION: NCT03081143 Date of registration: 13.11.2015.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina , Unión Esofagogástrica/patología , Fluorouracilo , Irinotecán , Leucovorina , Paclitaxel , Calidad de Vida , Neoplasias Gástricas/patología , RamucirumabRESUMEN
BACKGROUND: The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer. METHODS: The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life. Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy. DISCUSSION: MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy. TRIAL REGISTRATION: NCT02128243 (date of registration: 29-04-2014).
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Adenocarcinoma/tratamiento farmacológico , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/secundario , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/patología , Humanos , Quimioterapia de Mantención , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Gástricas/patologíaRESUMEN
Importance: Adding immune checkpoint inhibitors to chemotherapy has been associated with improved outcomes in metastatic esophagogastric adenocarcinoma, but treatment combinations and optimal patient selection need to be established. Objective: To investigate the efficacy and tolerability of the programmed cell death ligand 1 (PDL-1) inhibitor avelumab with paclitaxel plus ramucirumab. Design, Setting, and Participants: This multicenter, single-group, phase 2 nonrandomized controlled trial was conducted among patients with second-line metastatic esophagogastric adenocarcinoma. Patients pretreated with platinum plus fluoropyrimidine between April 2019 and November 2020 across 10 German centers (median follow-up, 27.4 months [95% CI 22.0-32.9 months]) were included. Data analysis was performed from January to December 2022. Interventions: Patients received ramucirumab at 8 mg/kg on days 1 and 15, avelumab at 10 mg/kg on days 1 and 15, and paclitaxel at 80 mg/m2 on days 1, 8, and 15 every 4 weeks. Main Outcomes and Measures: The prespecified primary end point was overall survival (OS) rate at 6 months, with the experimental therapy considered insufficiently active with an OS rate of 50% or less and a promising candidate with an OS rate of 65% or greater. Results: Of 60 enrolled patients, 59 patients (median [range] age, 64 [18-81] years; 47 males [70.7%]) were evaluable, including 30 patients with metastatic adenocarcinoma of the stomach and 29 patients with gastroesophageal junction. All patients were pretreated with platinum plus fluoropyrimidine, and 40 patients (67.8%) had received prior taxanes; 24 of 56 evaluable patients (42.9%) had a PDL-1 combined positive score (CPS) of 5 or greater, centrally assessed. The OS rate at 6 months was 71.2% (95% CI, 61.5%-83.7%). The median OS in the intention-to-treat population (59 patients) was 10.6 months (95% CI, 8.4-12.8 months) overall. Among patients assessable by central pathology, median OS was 9.4 months (95% CI, 7.2-11.7 months) in 32 patients with a PDL-1 CPS less than 5 and 14.0 months (95% CI, 6.0-22.1 months) in 24 patients with a PDL-1 CPS of 5 or greater (P = .25). Treatment was generally well tolerated, without unexpected toxicities. Patients with higher vs lower than median T cell repertoire richness showed an increased median OS of 20.4 months (95% CI, 7.7-33.0 months) compared with 8.3 months (95% CI, 3.7-12.9 months; hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .008). Patients with lower vs higher than median cell-free DNA burden had a median OS of 19.2 months (95% CI, 8.9-29.6 months) compared with 7.3 months (95% CI, 3.2-11.4 months; hazard ratio, 0.30; 95% CI, 0.16-0.59; P < .001). Conclusions and relevance: In this study, the combination of avelumab with paclitaxel plus ramucirumab showed favorable efficacy and tolerability in the second-line treatment for metastatic esophagogastric adenocarcinoma. A PDL-1 CPS score of 5 or greater, cell-free DNA level less than the median, and T cell repertoire richness greater than the median were associated with increased median OS. Trial Registration: ClinicalTrials.gov Identifier: NCT03966118.
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Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Ácidos Nucleicos Libres de Células , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/tratamiento farmacológico , Paclitaxel/uso terapéutico , Platino (Metal) , Ramucirumab , Femenino , Adolescente , Adulto Joven , Adulto , Anciano , Anciano de 80 o más AñosRESUMEN
Complete remission of BRAF V600E-driven ACC CUP by BRAF/MEK inhibition underscores importance of precision oncology.
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Proteínas Proto-Oncogénicas B-raf , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Mutación , Masculino , Femenino , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidoresRESUMEN
INTRODUCTION: The phase 2 RAMONA study demonstrated that second-line nivolumab ± ipilimumab immunotherapy was feasible and effective in older patients with advanced esophageal squamous cell cancer (ESCC). Here, we presented results from functional status (FS) and quality-of-life (QoL) analyses. MATERIALS AND METHODS: Patients aged ≥65 years with advanced ESCC and disease progression following first-line therapy were enrolled for study treatment with nivolumab ± ipilimumab. Geriatric assessments (GA) consisting of G8 and GoGo/SlowGo evaluation, and quality of life (QoL) assessments with EORTC QLQ-C30 questionnaires were conducted at baseline and during the treatment. A post hoc analysis was performed to compare therapy efficacy, toxicity, and QoL between age groups (≥70 years vs. <70 years) and functionality groups (G8 > 14 vs. ≤14 and GoGo vs. SlowGo). RESULTS: In 66 treated patients with a median age of 70.5 years, older patients had non-inferior overall survival and tumor response compared to younger patients, with no increased treatment-related adverse events. Fitter patients (G8 > 14, GoGo) had a clinically, yet not statistically significant, survival advantage than less fit patients (G8 ≤ 14, SlowGo) patients. Moreover, FS by G8 and GoGo/SlowGo significantly correlated with QoL. Overall, QoL was impaired at baseline but remained stable in all scales over the course of immunotherapy. DISCUSSION: The administration of nivolumab ± ipilimumab second-line immunotherapy in older patients with ESCC did not show age-dependent effects and maintained QoL. GA could identify functional deficits and limitations of QoL and should be implemented in the context of immunotherapy. CLINICALTRIALS: gov: NCT03416244.
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PURPOSE: Although participation in multidisciplinary tumor boards (MTBs) is an obligatory quality criterion for certification, there is scarce evidence, whether MTB recommendations are consistent with consensus guidelines and whether they are followed in clinical practice. Reasons of guideline and tumor board deviations are poorly understood so far. METHODS: MTB's recommendations from the weekly MTB for gastrointestinal cancers at the University Cancer Center Leipzig/Germany (UCCL) in 2020 were analyzed for their adherence to therapy recommendations as stated in National German guidelines and implementation within an observation period of 3 months. To assess adherence, an objective classification system was developed assigning a degree of guideline and tumor board adherence to each MTB case. For cases with deviations, underlying causes and influencing factors were investigated and categorized. RESULTS: 76% of MTBs were fully adherent to guidelines, with 16% showing deviations, mainly due to study inclusions and patient comorbidities. Guideline adherence in 8% of case discussions could not be determined, especially because there was no underlying guideline recommendation for the specific topic. Full implementation of the MTBs treatment recommendation occurred in 64% of all cases, while 21% showed deviations with primarily reasons of comorbidities and differing patient wishes. Significantly lower guideline and tumor board adherences were demonstrated in patients with reduced performance status (ECOG-PS ≥ 2) and for palliative intended therapy (p = 0.002/0.007). CONCLUSIONS: The assessment of guideline deviations and adherence to MTB decisions by a systematic and objective quality assessment tool could become a meaningful quality criterion for cancer centers in Germany.
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Neoplasias Gastrointestinales , Adhesión a Directriz , Humanos , AlemaniaRESUMEN
PURPOSE: Hematotoxicity is a common side-effect of cytotoxic gastrointestinal (GI) cancer therapies. An unsolved problem is to predict the individual risk therefore to decide on treatment adaptions. We applied an established biomathematical prediction model and primarily evaluated its predictive value in patients undergoing chemotherapy for GI cancers in curative intent. METHODS: In a prospective, observational multicenter study on patients with gastro-esophageal or pancreatic cancer (n = 28) receiving myelosuppressive adjuvant or neoadjuvant chemotherapy (FLO(T) or FOLFIRINOX), individual model parameters were learned based on patients' observed laboratory values during the first chemotherapy cycle and further external data resources. Grades of hematotoxicity of subsequent cycles were predicted by model simulation and compared with observed data. RESULTS: The most common high-grade hematological toxicity was neutropenia [19/28 patients (68%)]. For the FLO(T) regimen, individual grades of thrombocytopenia and leukopenia could be well predicted for cycles 2-4, as well as grades of neutropenia for cycle 2. Prediction accuracy for neutropenia in the third and fourth cycle differed by one toxicity grade on average. For the FOLFIRINOX-regimen, thrombocytopenia predictions showed a maximum deviation of one toxicity grade up to the end of therapy (8 cycles). Deviations of predictions were less than one degree on average up to cycle 4 for neutropenia, and up to cycle 6 for leukopenia. CONCLUSION: The biomathematical model showed excellent short-term and decent long-term prediction performance for all relevant hematological side effects associated with FLO(T)/FOLFIRINOX. Clinical utility of this precision-medicine approach needs to be further investigated in a larger cohort.
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Anemia , Neoplasias Gastrointestinales , Neutropenia , Neoplasias Pancreáticas , Trombocitopenia , Humanos , Neoplasias Pancreáticas/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios Prospectivos , Neutropenia/tratamiento farmacológico , Neutropenia/etiología , Trombocitopenia/inducido químicamente , Trombocitopenia/tratamiento farmacológico , Neoplasias Gastrointestinales/tratamiento farmacológico , Modelos TeóricosRESUMEN
Purpose: The Cancer Genome Atlas Research Network identified Epstein-Barr-Virus (EBV)-positive gastric cancer as a distinct molecular subtype. The prevalence is 8-9% and the histological examination shows pronounced lymphocytic infiltration, elevated levels of IFN-γ and consequently overexpression of PD-L1. The role of plasma EBV DNA load as a prognostic factor in patients with this cancer subtype is still to be defined. Methods and analysis: The present multicenter prospective observational study "EBV PRESAGE", involving German and Italian cancer centers, aims to evaluate the prognostic role of plasma EBV DNA in EBV-related gastric cancer (GC). The objective is to study the association between plasma EBV DNA load at different consecutive time points and the patient's prognosis. Every patient with a new diagnosis of gastric cancer (including gastroesophageal junction adenocarcinoma) will be screened for Epstein-Barr encoded small Region (EBER) on tissue biopsies using in situ hybridization (ISH). If EBER ISH is positive, blood analysis for plasma EBV DNA will be conducted. The plasma EBV quantitative analysis will be centralized, and extraction, detection, and quantification of EBV DNA in plasma samples will be performed using real-time PCR. Discussion: We hypothesized that plasma EBV DNA represents a non-invasive tool for monitoring EBV-related GC and might be valuable as a prognostic marker.
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PURPOSE: Pazopanib has promising antiangiogenetic activity in solid cancers. The investigator-initiated phase I/II trial evaluated the combination of Topotecan with Pazopanib in platinum-resistant or intermediate-sensitive recurrent ovarian cancer (ROC). METHODS: Patients (≥ 18 years) with first or second recurrence were enrolled in this multicentre open-label trial. Phase I analysed Topotecan 4 mg/m2 (day 1, 8, 15, ever 28 days) for six cycles to identify the maximum tolerated dose (MTD) of Pazopanib added in a dose-escalating scheme with 400 mg starting dose. The phase II analysed safety and efficacy aspects. For all patients with clinical remission a maintenance with Pazopanib until progression was allowed. This trial is registered with ClinicalTrials.gov, number NCT01600573. RESULTS: Between June 2012 and February 2017, 11 patients were enrolled in the phase I, and 50 patients in the phase II study. The MTD of Pazopanib was determined by 400 mg/daily. Haematological and liver toxicities determined the dose limiting toxicities (DLT) and the most common grade 3-4 adverse events: leucopenia (25%), neutropenia (22%), thrombocytopenia (19%), accumulation of cholestatic (20%) and hepatocellular damage (15%), which often caused dose modifications, but no new life-threatening events. Overall response was 16% and clinical benefit rate 68%. Median progression-free survival (PFS) was 3.5 months (95% CI 2.0-5.0). Due to early progression only 20% of the patients were able to start with maintenance treatment. CONCLUSION: The combination of pazopanib and weekly topotecan is feasible, resulting in a manageable haematological and liver toxicity, but despite its encouraging response rate, was not associated with a significant survival benefit.
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Leucopenia , Neoplasias Ováricas , Femenino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Leucopenia/inducido químicamente , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/etiología , Platino (Metal)/farmacología , Topotecan/uso terapéuticoRESUMEN
BACKGROUND: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. We assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population. METHODS: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03416244. FINDINGS: Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70·5 years [IQR 67·0-76·0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7·2 months (95% CI 5·7-12·4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0·0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment. INTERPRETATION: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment. FUNDING: Bristol Myers Squibb.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Células Epiteliales , Neoplasias Esofágicas/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Nivolumab/efectos adversosRESUMEN
OBJECTIVE: The study's aim was to determine to what extent total visceral adipose tissue (VAT) volume (VVAT-T ) measured from segmented VAT areas (AVAT ) on all axial computed tomography (CT) sections (thickness of 5 mm) between the diaphragm and pelvic floor can be predicted by the AVAT of commonly selected landmark sections in patients with overweight or obesity. METHODS: A total of 113 patients (31 females, 82 males) with images of full abdominopelvic coverage and proper image quality were included (BMI = 25.0-64.1 kg/m2 , 29.5 ± 4.9 kg/m2 ). Linear regression between AVAT and VVAT-T (reference) was used to determine approximate equations for VAT volume for all parameters (single sex, different anatomical landmarks or lumbar intervertebral disc spaces, one or five axial sections). Agreement was evaluated by the multivariate coefficient of determination and by the SD of the percentage difference (sd% ) between the estimated VAT volume on one or five sections and VVAT-T . RESULTS: The VVAT-T was 0.9 to 8.4 (3.8 ± 2.2) L for females and 2.7 to 11.7 (5.6 ± 2.1) L for males. Best agreement was found at L2-3 (sd% = 14.3%-15.5%) for females and at L1-2 or L2-3 (11.7%-12.4%) for males. Agreement at the umbilicus or the femoral heads was poor (20.2%-57.9%). Segmentation of one or five sections was substantially faster (11/70 seconds) than whole-abdomen processing (15 minutes). CONCLUSIONS: VVAT-T can be rapidly estimated by VAT segmentation of axial CT sections at sex-specific lumbar intervertebral disc spaces.
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Grasa Intraabdominal/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Femenino , Humanos , Masculino , Obesidad/diagnóstico por imagen , Sobrepeso/diagnóstico por imagenRESUMEN
BACKGROUND: Body fat and/or muscle composition influences prognosis in several cancer types. For advanced gastric and gastroesophageal junction cancer, we investigated which body composition parameters carry prognostic information beyond well-established clinical parameters using robust model selection strategy such that parameters identified can be expected to generalize and to be reproducible beyond our particular data set. Then we modelled how differences in these parameters translate into survival outcomes. METHODS: Fat and muscle parameters were measured on baseline computed tomography scans in 761 patients with advanced gastric or gastroesophageal junction cancer from the phase III EXPAND trial, undergoing first-line chemotherapy. Cox regression analysis for overall survival (OS) and progression-free survival (PFS) included body composition parameters and clinical prognostic factors. All continuous variables were entered linearly into the model as there was no evidence of non-linear prognostic impact. For transferability, the final model included only parameters that were picked by Bayesian information criterion model selection followed by bootstrap analysis to identify the most robust model. RESULTS: Muscle and fat parameters formed correlation clusters without relevant between-cluster correlation. Mean muscle attenuation (MA) clusters with the fat parameters. In multivariate analysis, MA was prognostic for OS (P < 0.0001) but not for PFS, while skeletal muscle index was prognostic for PFS (P = 0.02) but not for OS. Worse performance status Eastern Cooperative Oncology Group (ECOG 1/0), younger age (on a linear scale), and the number of metastatic sites were strong negative clinical prognostic factors for both OS and PFS. MA remained in the model for OS (P = 0.0001) following Bayesian information criterion model selection in contrast to skeletal muscle index that remained prognostic for PFS (P = 0.009). Applying stricter criteria for transferability, MA represented the only prognostic body composition parameter for OS, selected in >80% of bootstrap replicates. Finally, Cox model-derived survival curves indicated that large differences in MA translate into only moderate differences in expected OS in this cohort. CONCLUSIONS: Among body composition parameters, only MA has robust prognostic impact for OS. Data suggest that treatment approaches targeting muscle quality are unlikely to prolong OS noticeably on their own in advanced gastric cancer patients, indicating that multimodal approaches should be pursued in the future.
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Composición Corporal , Neoplasias Gástricas/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Neoplasias Gástricas/mortalidad , Análisis de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Dose reduction in obese cancer patients has been replaced by fully weight-based dosing recommendations. No data, however, are available on the effects of dose reduction in obese stage III colon cancer patients undergoing adjuvant chemotherapy. METHODS: Survival outcomes and toxicity data of obese (body mass index [BMI] ≥30 kg/m2), stage III colon cancer patients treated within the phase III PETACC 3 trial comparing leucovorin, 5-FU (LV5FU2) with LV5FU2 plus irinotecan were analysed retrospectively according to chemotherapy dosing at first infusion (i.e. fully weight-based dosed - versus dose-reduced group). Multivariate analyses on relapse free survival (RFS) and overall survival (OS) were conducted to adjust for baseline prognostic factors using Cox regression model. RESULTS: 13.4% (280 of 2094 patients) had a BMI ≥ 30 kg/m2, and 5.3% had both a BMI ≥ 30 kg/m2 and a body surface area (BSA) ≥2 m2. Dose reductions occurred in 16.1% of patients with a BMI ≥ 30 kg/m2 and 32.4% with BMI ≥ 30 kg/m2 and BSA ≥ 2 m2, respectively. In patients with BMI ≥ 30 kg/m2, multivariate analysis demonstrated a trend towards better RFS in the fully dosed compared to the dose-reduced group (Hazard ratio (HR): 0.69, 95% CI: 0.43-1.09; p = 0.11); however, there was no statistically significant difference in OS. In patients with BMI ≥ 30 kg/m2 and BSA ≥ 2 m2, multivariate analysis demonstrated better RFS in fully dosed compared with dose-reduced patients (HR: 0.48, 95% CI: 0.27-0.85; p = 0.01) and a strong trend towards better OS (HR: 0.53, 95% CI: 0.28-1.01; p = 0.052). This group comprised predominantly of men. CONCLUSIONS: Data support the recommendation of using fully dosed chemotherapy for the adjuvant treatment in obese patients with colon cancer.
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Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Colon/terapia , Recurrencia Local de Neoplasia/epidemiología , Obesidad/complicaciones , Adenocarcinoma/complicaciones , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Índice de Masa Corporal , Superficie Corporal , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/normas , Colectomía , Colon/patología , Colon/cirugía , Neoplasias del Colon/complicaciones , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Pronóstico , Estudios Retrospectivos , Factores Sexuales , Adulto JovenRESUMEN
INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) amplification is present in a subgroup of gastroo-esophageal cancers (GCs). HER2 inhibition with trastuzumab has shown to improve outcomes in advanced disease. Lapatinib ditosylate (LAP), a dual anti-epidermal growth factor receptor (EGFR) and anti-HER2 tyrosine kinase inhibitor with preclinical activity against GC, has been approved in HER2-positive breast cancer. We aimed to study the activity of LAP in HER2-amplified GC. MATERIALS AND METHODS: Patients (pts) with HER2-positive (gene amplification or increased copy numbers based on predefined criteria) advanced GC were randomly allocated 1:1 to receive LAP 1250mg per day 1-21 plus capecitabine (CAP) 2000mg/m(2) on days 1-14 of a 21-day cycle or LAP 1500mg monotherapy day 1-21 after having failed on a platinum-based first-line therapy. HER2 status was assessed centrally. The primary end-point was the objective response rate (ORR) as assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). We aimed to include 38 pts per arm to show an interesting response rate of ⩾20% in either of the two arms. RESULTS: 37 pts were enrolled (18 to LAP+CAP, 19 to LAP). Pts had received a median of three prior treatment lines. 12 pts in the LAP+CAP group (67%) and 12 pts in the LAP group (63%) had received prior trastuzumab. Only two pts (11.1%; 95% confidence interval (CI): 1.37-34.7), both in the LAP+CAP arm, achieved an objective response. The study was closed prematurely for futility. Median time to progression was 42 (95% CI: 38-61) days in the LAP group and 83 (95% CI: 42-86) days in the LAP+CAP group. Other secondary efficacy end-points (progression-free and overall survival) were comparable in the two treatment groups. Rates of diarrhoea were higher with LAP+CAP (61%; 95% CI: 35-83) compared to 26% (95% CI 9-51) with LAP mono, whereas other adverse events were mostly similar between the groups (18 [100%] versus 17 [90%]). DISCUSSION: Lapatinib showed insufficient activity in HER2-amplified pretreated advanced GC. The safety profile of LAP or LAP+CAP was as expected with some more toxicity in the combination arm. (ClinicalTrials.gov Identifier, NCT01145404).
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Esofágicas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Esquema de Medicación , Neoplasias Esofágicas/enzimología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Amplificación de Genes , Dosificación de Gen , Alemania , Humanos , Estimación de Kaplan-Meier , Lapatinib , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: We evaluated DNA polymorphisms in genes related to DNA repair, cell-cycle control and tumour microenvironment to determine possible associations with response and survival in neoadjuvant-treated gastric cancer patients. PATIENTS AND METHODS: One hundred and seventy eight patients who received platinum/5FU-based chemotherapy were genotyped for 10 polymorphisms in nine genes (ERCC1: Asn118Asn, C > T; ERCC1: 8092C > A; TP53: Arg72Pro, G < C; cyclinD1: Pro241Pro, G > A; STK15: Phe31Ile, A > T; VEGF: 936C > T; TNF-alpha: -308G > A; interleukin-1b (IL-1B): -511C >T; IL-1 receptor antagonist (IL-1RN): variable tandem repeat; IL-8: -251T>A). Genotypes were correlated with histopathological and clinical response and overall (OS) and progression-free survival (PFS). RESULTS: Only the cyclinD1 genotypes were associated with clinical response (P(x)(2)=0.044). Significantly worse survival rates were noted in patients homozygous for the G-allele as compared to patients with the AG or AA genotypes of the cyclinD1 polymorphism (OS: P(log-rank) = 0.024; PFS: P(log-rank)=0.007) and in patients homozygous for the short allele compared to all other genotypes at the IL-1RN polymorphic locus (OS: P(log-rank) = 0.026; PFS: P(log-rank) = 0.013). The combination of both unfavourable genotypes demonstrated strong prognostic relevance (OS: P(log-rank) = 0.006; PFS: P(log-rank) = 0.001). Multivariate analysis for OS in the group of completely resected patients (n = 139) revealed statistical significance for ypM (P < 0.001), histopathological response (P < 0.001) and the combined cyclinD1/IL-1RN genotypes (P = 0.043). CONCLUSION: The cyclinD1 and IL-1RN polymorphisms were associated with survival. The combination of specific cyclinD1 and IL-1RN genotypes showed a particular prognostic relevance and should be considered an independent prognostic marker for neoadjuvant-treated gastric cancer patients.