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Background: Effective surveillance strategies are required for patients diagnosed with oesophageal squamous cell carcinoma (OSCC) or adenocarcinoma (OAC) for whom chemoradiotherapy (CRT) is used as a potentially-curative, organ-sparing, alternative to surgery. In this study, we evaluated the safety, acceptability and tolerability of a non-endoscopic immunocytological device (the Cytosponge™) to assess treatment response following CRT. Methods: This multicentre, single-arm feasibility trial took place in 10 tertiary cancer centres in the UK. Patients aged at least 16 years diagnosed with OSCC or OAC, and who were within 4-16 weeks of completing definitive or neo-adjuvant CRT, were included. Participants were required to have a Mellow-Pinkas dysphagia score of 0-2 and be able to swallow tablets. All patients underwent a single Cytosponge™ assessment in addition to standard of care (which included post-treatment endoscopic evaluation with biopsy for patients undergoing definitive CRT; surgery for those who received neo-adjuvant CRT). The primary outcome was the proportion of consented, evaluable patients who successfully underwent Cytosponge™ assessment. Secondary and tertiary outcomes included safety, study consent rate, acceptance rate, the suitability of obtained samples for biomarker analysis, and the comparative efficacy of Cytosponge™ to standard histology (endoscopy and biopsy or post-resection specimen) in assessing for residual disease. The trial is registered with ClinicalTrials.gov, NCT03529669. Findings: Between 18th April 2018 and 16th January 2020, 41 (42.7%; 95% confidence interval (CI) 32.7-53.2) of 96 potentially eligible patients consented to participate. Thirty-nine (95.1%, 95% CI 83.5-99.4) successfully carried out the Cytosponge™ procedure. Of these, 37 (95%) would be prepared to repeat the procedure. There were only two grade 1 adverse events attributed to use of the Cytosponge™. Thirty-five (90%) of the completed Cytosponge™ samples were suitable for biomarker analysis; 29 (83%) of these were concordant with endoscopic biopsies, three (9%) had findings suggestive of residual cancer on Cytosponge™ not found on endoscopic biopsies, and three (9%) had residual cancer on endoscopic biopsies not detected by Cytosponge™. Interpretation: Use of the CytospongeTM is safe, tolerable, and acceptable for the assessment of treatment response following CRT in OAC and OSCC. Further evaluation of Cytosponge™ in this setting is warranted. Funding: Cancer Research UK, National Institute for Health Research, Medical Research Council.
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AIM: This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months. METHODS: NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m2 on Days 1, 15, and 29; capecitabine 625 mg/m2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m2 on Day 1, capecitabine 625 mg/m2 orally twice daily on Days 1-21) before CRT. Surgery was performed 6-8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression. RESULTS: Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24-0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29-1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression. CONCLUSIONS: OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component. CLINICAL TRIAL INFORMATION: EudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829.
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Adenocarcinoma/tratamento farmacológico , Capecitabina/uso terapêutico , Carboplatina/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Paclitaxel/uso terapêutico , Idoso , Capecitabina/farmacologia , Carboplatina/farmacologia , Feminino , Humanos , Masculino , Oxaliplatina/farmacologia , Paclitaxel/farmacologiaRESUMO
AIM: Enhanced prognostic models are required to improve risk stratification of patients with oesophageal cancer so treatment decisions can be optimised. The primary aim was to externally validate a published prognostic model incorporating PET image features. Transferability of the model was compared using only clinical variables. METHODS: This was a Transparent Reporting of a multivariate prediction model for Individual Prognosis Or Diagnosis (TRIPOD) type 3 study. The model was validated against patients treated with neoadjuvant chemoradiotherapy according to the Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS) trial regimen using pre- and post-harmonised image features. The Kaplan-Meier method with log-rank significance tests assessed risk strata discrimination. A Cox proportional hazards model assessed model calibration. Primary outcome was overall survival (OS). RESULTS: Between 2010 and 2015, 449 patients were included in the development (nâ¯=â¯302), internal validation (nâ¯=â¯101) and external validation (nâ¯=â¯46) cohorts. No statistically significant difference in OS between patient quartiles was demonstrated in prognostic models incorporating PET image features (X2â¯=â¯1.42, dfâ¯=â¯3, pâ¯=â¯0.70) or exclusively clinical variables (age, disease stage and treatment; X2â¯=â¯1.19, dfâ¯=â¯3, pâ¯=â¯0.75). The calibration slope ß of both models was not significantly different from unity (pâ¯=â¯0.29 and 0.29, respectively). Risk groups defined using only clinical variables suggested differences in OS, although these were not statistically significant (X2â¯=â¯0.71, dfâ¯=â¯2, pâ¯=â¯0.70). CONCLUSION: The prognostic model did not enable significant discrimination between the validation risk groups, but a second model with exclusively clinical variables suggested some transferable prognostic ability. PET harmonisation did not significantly change the results of model validation.
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Neoplasias Esofágicas/diagnóstico por imagem , Planejamento da Radioterapia Assistida por Computador/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: This retrospective cohort study developed a prognostic model incorporating PET texture analysis in patients with oesophageal cancer (OC). Internal validation of the model was performed. METHODS: Consecutive OC patients (n = 403) were chronologically separated into development (n = 302, September 2010-September 2014, median age = 67.0, males = 227, adenocarcinomas = 237) and validation cohorts (n = 101, September 2014-July 2015, median age = 69.0, males = 78, adenocarcinomas = 79). Texture metrics were obtained using a machine-learning algorithm for automatic PET segmentation. A Cox regression model including age, radiological stage, treatment and 16 texture metrics was developed. Patients were stratified into quartiles according to a prognostic score derived from the model. A p-value < 0.05 was considered statistically significant. Primary outcome was overall survival (OS). RESULTS: Six variables were significantly and independently associated with OS: age [HR =1.02 (95% CI 1.01-1.04), p < 0.001], radiological stage [1.49 (1.20-1.84), p < 0.001], treatment [0.34 (0.24-0.47), p < 0.001], log(TLG) [5.74 (1.44-22.83), p = 0.013], log(Histogram Energy) [0.27 (0.10-0.74), p = 0.011] and Histogram Kurtosis [1.22 (1.04-1.44), p = 0.017]. The prognostic score demonstrated significant differences in OS between quartiles in both the development (X2 143.14, df 3, p < 0.001) and validation cohorts (X2 20.621, df 3, p < 0.001). CONCLUSIONS: This prognostic model can risk stratify patients and demonstrates the additional benefit of PET texture analysis in OC staging. KEY POINTS: ⢠PET texture analysis adds prognostic value to oesophageal cancer staging. ⢠Texture metrics are independently and significantly associated with overall survival. ⢠A prognostic model including texture analysis can help risk stratify patients.
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Neoplasias Esofágicas/diagnóstico , Esôfago/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos RetrospectivosRESUMO
BACKGROUND AND STUDY AIMS: Several studies have suggested that a significant minority of esophageal cancers are missed at endoscopy The aim of this study was to estimate the proportion of esophageal cancers missed at endoscopy on a national level, and to investigate the relationship between miss rates and patient and tumor characteristics. PATIENTS AND METHODS: This retrospective, population-based, cohort study identified patients diagnosed with esophageal cancer between April 2011 and March 2012 in England, using two linked databases (National Oesophago-Gastric Cancer Audit and Hospital Episode Statistics). The main outcome was the rate of previous endoscopy within 3â-â36 months of cancer diagnosis. This was calculated for the overall cohort and by patient characteristics, including tumor site and disease stage. RESULTS: A total of 6943 new cases of esophageal cancer were identified, of which 7.8â% (95â% confidence interval 7.1â-â8.4) had undergone endoscopy in the 3â-â36 months preceding diagnosis. Of patients with stage 0/1 cancers, 34.0â% had undergone endoscopy in the 3â-â36 months before diagnosis compared with 10.0â% of stage 2 cancers and 4.5â% of stage 3/4 cancers. Of patients with stage 0/1 cancers, 22.1â% were diagnosed after ≥â3 endoscopies in the previous 3 years. Patients diagnosed with an upper esophageal lesion were more likely to have had an endoscopy in the previous 3â-â12 months (Pâ=â0.040). The most common diagnosis at previous endoscopy was an esophageal ulcer (48.2â% of investigations). CONCLUSION: Esophageal cancer may be missed at endoscopy in up to 7.8â% of patients who are subsequently diagnosed with cancer. Endoscopists should make a detailed examination of the whole esophageal mucosa to avoid missing subtle early cancers and lesions in the proximal esophagus. Patients with an esophageal cancer may be misdiagnosed as having a benign esophageal ulcer.
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Adenocarcinoma/patologia , Carcinoma de Células Escamosas/patologia , Diagnóstico Tardio/estatística & dados numéricos , Erros de Diagnóstico/estatística & dados numéricos , Neoplasias Esofágicas/patologia , Esofagoscopia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Bases de Dados Factuais , Inglaterra , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND: Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy.The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival. METHODS/DESIGN: SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio.During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further 120 patients into each arm and compare the overall survival of both groups.All patients randomised into Phase II will contribute to the Phase III comparison of overall survival. In addition to overall survival, Phase III of the study will also assess toxicity, health related quality of life and cost effectiveness. A detailed radiotherapy protocol and quality assurance procedure has been incorporated into this trial. TRIAL REGISTRATION: ISRCTN: ISRCTN47718479.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Anticorpos Monoclonais Humanizados , Cetuximab , Receptores ErbB/antagonistas & inibidores , HumanosRESUMO
BACKGROUND: This study aimed to assess the prognostic significance of endoluminal ultrasound-defined total length of disease and endoluminal ultrasound defined tumor volume (EDTV) in esophageal cancer. The hypothesis was that endoscopic ultrasound (EUS)-defined total length of disease and EDTV are both significant prognostic indicators and better predictors of outcome than endoscopic tumor length. METHODS: In this study, 174 consecutive patients (median age, 64 years and 128 months) underwent specialist EUS, and the maximum potential EDTV was calculated (pir(2) L, where r is the tumor thickness and L is the total length of disease) including proximal and distal lymph node metastases. Of the 174 patients, 104 underwent surgery (70 had neoadjuvant chemotherapy), 60 underwent definitive chemoradiotherapy, and 10 had palliative therapy. RESULTS: Survival was related to EUS T stage (p = 0.013), EUS N stage (p = 0.001), EUS M1a stage (p = 0.004), EUS disease length (<8 cm; p = 0.001), and EDTV (all patients <25 cm(3), p = 0.001; surgical patients <40 cm(3), p = 0.036). Forward conditional multivariate analysis showed three factors to be associated with survival: EUS N stage (hazard ratio [HR], 1.646; 95% confidence interval [CI], 1.041-2.602; p = 0.033), EUS M1a stage (HR, 2.702; 95% CI, 1.069-6.830; p = 0.036), and EDTV (HR, 2.702; 95% CI, 1.069-6.830; p = 0.025). Median and 2-year survival for EDTV <25 cm(3) versus >25 cm(3) was 43.4 months and 56%, respectively, compared with 23.5 months and 35%. CONCLUSIONS: In this study, EDTV based on total EUS-defined length of disease emerged as a new and important prognostic indicator for patients with esophageal cancer.
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Endossonografia/métodos , Neoplasias Esofágicas/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Distribuição de Qui-Quadrado , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Carga TumoralRESUMO
AIMS: The prognosis in surgically resected oesophageal carcinoma (OC) is dependent on the number of regional lymph nodes (LN) involved, but no guidance exists on how many LNs should be examined histopathologically to give a reliable pN status. The aim of this study was to determine whether the number of LNs examined after OC resection has a significant effect on the assessment of prognosis. METHODS AND RESULTS: Routinely generated pathology reports from 237 consecutive patients undergoing oesophagectomy for OC were examined and analysed in relation to survival. The main outcome measure was survival from date of diagnosis. Lymph node count (LNC) correlated strongly with survival; a plateau was reached after a count of 10. Median and 2-year survival was 30 months and 42%, respectively, if <10 nodes were examined (n = 88), compared with 51 months and 61% if >10 nodes were examined (P = 0.005). This effect was greatest in pN0 cases. The prognostic value of the absolute number of LN metastases (<4) and LN ratio (<0.4) was strongly dependent on a LNC of >10. CONCLUSIONS: These results demonstrate the importance of careful pathological examination and lymph node retrieval after OC resection. At least 10 nodes should be examined to designate an OC as pN0.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/patologia , Linfonodos/patologia , Adenocarcinoma/mortalidade , Carcinoma de Células Escamosas/mortalidade , Erros de Diagnóstico/prevenção & controle , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Endoscopic ultrasound (EUS) is known to detect smaller effusion volumes than computerised tomography (CT), yet the outcomes for patients diagnosed with oesophageal carcinoma and EUS-defined pleural, pericardial or ascitic fluid effusions (EDFE) are unknown. The aim of this study was to determine the outcome of multidisciplinary stage directed treatment for such patients. METHODS: Forty-nine (9.2%) out of a consecutive 527 patients diagnosed with oesophageal cancer from a single regional upper gastrointestinal (GI) cancer network were found to have evidence of EDFE undetected by CT. Thirty-nine (79.6%) patients had pleural effusions, eight (16.3%) pericardial effusions, and two (4.1%) ascites. RESULTS: Twelve (24.4%) underwent surgery, 3 (6.1%) received neoadjuvant chemotherapy without subsequent surgery, 12 (24.5%) received definitive chemoradiotherapy (dCRT), and 22 (44.9%) received palliative treatment. Survival in patients with EDFE was significantly shorter (median and 2-year survival 15.6 months and 24%, respectively) when compared with patients without EDFE (26.7 months and 40%, respectively, p = 0.001), and was unrelated to EDFE type (p = 0.192). Two-year survival after oesophagectomy with or without neoadjuvant therapy was 45% in patients with EDFE compared with 42% in patients without EDFE (p = 0.668). CONCLUSIONS: EDFE was an important adverse prognostic indicator, but patients deemed to have operable tumours should still be treated with radical intent.
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Líquido Ascítico/diagnóstico por imagem , Endossonografia , Neoplasias Esofágicas/diagnóstico por imagem , Derrame Pericárdico/diagnóstico por imagem , Derrame Pleural/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Estatísticas não Paramétricas , Taxa de Sobrevida , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To determine the influence of deprivation on outcomes for patients with oesophageal cancer. MATERIAL AND METHODS: A total of 1196 consecutive patients with oesophageal carcinoma presenting to a regional multidisciplinary team between 1 January 1998 and 31 August 2005 were studied prospectively and deprivation scores calculated using the Indices of Multiple Deprivation (IMD) of the National Assembly for Wales. The patients were subdivided into quintiles for analysis. RESULTS: Inhabitants of the most deprived areas (quintile 5) were younger at presentation (median age 67 years versus 70 years, p = 0.01) and were more likely to have squamous cell carcinomas (SCCs) (p = 0.002) in comparison with patients from the least deprived areas (quintile 1). Stage of disease and morbidity did not correlate with deprivation quintile, but operative mortality was greater in quintile 1 versus 5 (1.9% versus 5.8%, p = 0.281). Overall 5-year survival for those patients undergoing oesophagectomy was unrelated to deprivation quintile (1 versus 5, 24% versus 33%, p = 0.8246), but was lower following definitive chemoradiotherapy (dCRT) for the least deprived quintiles (1, 2 & 3 versus 4 & 5, 35% versus 16%, p = 0.0272). CONCLUSIONS: Although deprivation was associated with younger age, SCC and a trend towards higher operative mortality, survival after diagnosis and oesophagectomy were unrelated to deprivation.
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Neoplasias Esofágicas/economia , Fatores Socioeconômicos , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Equipe de Assistência ao Paciente , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento , País de GalesRESUMO
BACKGROUND: The Intergroup 0116 randomized study showed that postoperative 5-fluorouracil-based chemoradiotherapy improved locoregional control and overall survival in patients with gastric cancer. We hypothesized that these results could be improved further by using a more effective, intensified, and convenient chemotherapy schedule. Therefore, this Phase I-II dose-escalation study was performed to determine the maximal tolerated dose and toxicity profile of postoperative radiotherapy combined with concurrent capecitabine. PATIENTS AND METHODS: After recovery from surgery for adenocarcinoma of the gastroesophageal junction or stomach, all patients were treated with capecitabine monotherapy, 1,000 mg/m2 twice daily for 2 weeks. After a 1-week treatment-free interval, patients received capecitabine (650-1,000 mg/m2 orally twice daily 5 days/week) in a dose-escalation schedule combined with radiotherapy on weekdays for 5 weeks. Radiotherapy was delivered to a total dose of 45 Gy in 25 fractions to the gastric bed, anastomoses, and regional lymph nodes. RESULTS: Sixty-six patients were treated accordingly. Two patients went off study before or shortly after the start of chemoradiotherapy because of progressive disease. Therefore, 64 patients completed treatment as planned. During the chemoradiotherapy phase, 4 patients developed four items of Grade III dose-limiting toxicity (3 patients in Dose Level II and 1 patient in Dose Level IV). The predefined highest dose of capecitabine, 1,000 mg/m2 twice daily orally, was tolerated well and, therefore, considered safe for further clinical evaluation. CONCLUSIONS: This Phase I-II study shows that intensified chemoradiotherapy with daily capecitabine is feasible in postoperative patients with gastroesophageal junction and gastric cancer.