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1.
Br J Surg ; 111(2)2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38387083

RESUMO

BACKGROUND: This study evaluated the association of pathological tumour response (tumour regression grade, TRG) and a novel scoring system, combining both TRG and nodal status (TRG-ypN score; TRG1-ypN0, TRG>1-ypN0, TRG1-ypN+ and TRG>1-ypN+), with recurrence patterns and survival after multimodal treatment of oesophageal adenocarcinoma. METHODS: This Dutch nationwide cohort study included patients treated with neoadjuvant chemoradiotherapy followed by oesophagectomy for distal oesophageal or gastro-oesophageal junctional adenocarcinoma between 2007 and 2016. The primary endpoint was the association of Mandard score and TRG-ypN score with recurrence patterns (rate, location, and time to recurrence). The secondary endpoint was overall survival. RESULTS: Among 2746 inclusions, recurrence rates increased with higher Mandard scores (TRG1 30.6%, TRG2 44.9%, TRG3 52.9%, TRG4 61.4%, TRG5 58.2%; P < 0.001). Among patients with recurrent disease, the distribution (locoregional versus distant) was the same for the different TRG groups. Patients with TRG1 developed more brain recurrences (17.7 versus 9.8%; P = 0.001) and had a longer mean overall survival (44 versus 35 months; P < 0.001) than those with TRG>1. The TRG>1-ypN+ group had the highest recurrence rate (64.9%) and worst overall survival (mean 27 months). Compared with the TRG>1-ypN0 group, patients with TRG1-ypN+ had a higher risk of recurrence (51.9 versus 39.6%; P < 0.001) and worse mean overall survival (33 versus 41 months; P < 0.001). CONCLUSION: Improved tumour response to neoadjuvant therapy was associated with lower recurrence rates and higher overall survival rates. Among patients with recurrent disease, TRG1 was associated with a higher incidence of brain recurrence than TRG>1. Residual nodal disease influenced prognosis more negatively than residual disease at the primary tumour site.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Humanos , Prognóstico , Estudos de Coortes , Intervalo Livre de Doença , Terapia Combinada
2.
BJU Int ; 131(2): 244-252, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35861125

RESUMO

OBJECTIVES: To investigate the role of specialised genitourinary multidisciplinary team meetings (MDTMs) in decision-making and identify factors that influence the probability of receiving a treatment plan with curative intent for patients with muscle invasive bladder cancer (MIBC). PATIENTS AND METHODS: Data relating to patients with cT2-4aN0/X-1 M0 urothelial cell carcinoma, diagnosed between November 2017 and October 2019, were selected from the nationwide, population-based Netherlands Cancer Registry ('BlaZIB study'). Curative treatment options were defined as radical cystectomy (RC) with or without neoadjuvant chemotherapy, chemoradiation or brachytherapy. Multilevel logistic regression analyses were used to examine the association between MDTM factors and curative treatment advice and how this advice was followed. RESULTS: Of the 2321 patients, 2048 (88.2%) were discussed in a genitourinary MDTM. Advanced age (>80 years) and poorer World Health Organization performance status (score 1-2 vs 0) were associated with no discussion (P < 0.001). Being discussed was associated with undergoing treatment with curative intent (odds ratio [OR] 3.0, 95% confidence interval [CI] 1.9-4.9), as was the involvement of a RC hospital (OR 1.70, 95% CI 1.09-2.65). Involvement of an academic centre was associated with higher rates of bladder-sparing treatment (OR 2.05, 95% CI 1.31-3.21). Patient preference was the main reason for non-adherence to treatment advice. CONCLUSIONS: For patients with MIBC, the probability of being discussed in a MDTM was associated with age, performance status and receiving treatment with curative intent, especially if a representative of a RC hospital was present. Future studies should focus on the impact of MDTM advice on survival data.


Assuntos
Neoplasias da Bexiga Urinária , Humanos , Idoso de 80 Anos ou mais , Neoplasias da Bexiga Urinária/cirurgia , Bexiga Urinária/patologia , Cistectomia , Terapia Neoadjuvante , Equipe de Assistência ao Paciente , Invasividade Neoplásica
3.
J Appl Clin Med Phys ; 24(4): e13864, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36565168

RESUMO

BACKGROUND AND PURPOSE: For accurate pre-operative gastric radiotherapy, intrafractional changes must be taken into account. The aim of this study is to quantify local gastric deformations and compare these deformations with respiratory-induced displacement. MATERIALS AND METHODS: Coronal 2D MRI scans (15-16 min; 120 repetitions of 25-27 interleaved slices) were obtained for 18 healthy volunteers. A deep-learning network was used to auto-segment the stomach. To separate out respiratory-induced displacements, auto-segmentations were rigidly shifted in superior-inferior (SI) direction to align the centre of mass (CoM) within every slice. From these shifted auto-segmentations, 3D iso-probability surfaces (isosurfaces) were established: a reference surface for POcc  = 0.50 and 50 other isosurfaces (from POcc  = 0.01 to 0.99), with POcc indicating the probability of occupation by the stomach. For each point on the reference surface, distances to all isosurfaces were determined and a cumulative Gaussian was fitted to this probability-distance dataset to obtain a standard deviation (SDdeform ) expressing local deformation. For each volunteer, we determined median and 98th percentile of SDdeform over the reference surface and compared these with the respiratory-induced displacement SDresp , that is, the SD of all CoM shifts (paired Wilcoxon signed-rank, α = 0.05). RESULTS: Larger deformations were mostly seen in the antrum and pyloric region. Median SDdeform (range, 2.0-2.9 mm) was smaller than SDresp (2.7-8.8 mm) for each volunteer (p < 0.00001); 98th percentile of SDdeform (3.2-7.3 mm) did not significantly differ from SDresp (p = 0.13). CONCLUSION: Locally, gastric deformations can be large. Overall, however, these deformations are limited compared to respiratory-induced displacement. Therefore, unless respiratory motion is considerably reduced, the need to separately include these deformation uncertainties in the treatment margins may be limited.


Assuntos
Imageamento por Ressonância Magnética , Humanos , Movimento (Física)
4.
Cancer Sci ; 113(3): 1038-1046, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34986523

RESUMO

Data on treatment and survival of patients with advanced unresectable esophageal squamous cell carcinoma (ESCC) from Western populations are limited. Here we describe treatment and survival in patients with advanced unresectable ESCC: patients with cT4b disease without metastases (cT4b), metastases limited to the supraclavicular lymph nodes (SCLNM) or distant metastatic ESCC at the population level. All patients with unresectable (cT4b) or synchronous metastatic ESCC at primary diagnosis (2015-2018) or patients with metachronous metastases after primary non-metastatic diagnosis in 2015-2016 were selected from the Netherlands Cancer Registry. Fifteen percent of patients had cT4b disease (n = 146), 12% SCLNM (n = 118) and 72% distant metastases (n = 681). Median overall survival (OS) time was 6.3, 11.2, and 4.4 months in patients with cT4b, SCLNM, and distant metastases, respectively (P < .001). Multivariable Cox regression showed that patients with cT4b (hazard ratio 1.44, 95% CI 1.04-1.99) and patients with distant metastases (hazard ratio 1.42, 95% CI 1.12-1.80) had a worse survival time compared with patients with SCLNM. Among patients who received chemoradiotherapy and/or underwent resection (primary tumor and/or metastases), median OS was 11.9, 16.1, and 14.0 months in patients with cT4b, SCLNM, and distant metastases, respectively (P = .76). Patients with SCLNM had a better survival time compared with patients with cT4b and patients with distant metastases. Survival of patients with advanced unresectable ESCC in clinical practice was poor, even in patients treated with curative intent.


Assuntos
Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Carcinoma de Células Escamosas do Esôfago/mortalidade , Carcinoma de Células Escamosas do Esôfago/terapia , Idoso , Quimiorradioterapia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Pneumonectomia , Sistema de Registros , Estudos Retrospectivos , Taxa de Sobrevida
5.
Ann Surg ; 276(5): 806-813, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35880759

RESUMO

OBJECTIVE: This study investigated the patterns, predictors, and survival of recurrent disease following esophageal cancer surgery. BACKGROUND: Survival of recurrent esophageal cancer is usually poor, with limited prospects of remission. METHODS: This nationwide cohort study included patients with distal esophageal and gastroesophageal junction adenocarcinoma and squamous cell carcinoma after curatively intended esophagectomy in 2007 to 2016 (follow-up until January 2020). Patients with distant metastases detected during surgery were excluded. Univariable and multivariable logistic regression were used to identify predictors of recurrent disease. Multivariable Cox regression was used to determine the association of recurrence site and treatment intent with postrecurrence survival. RESULTS: Among 4626 patients, 45.1% developed recurrent disease a median of 11 months postoperative, of whom most had solely distant metastases (59.8%). Disease recurrences were most frequently hepatic (26.2%) or pulmonary (25.1%). Factors significantly associated with disease recurrence included young age (≤65 y), male sex, adenocarcinoma, open surgery, transthoracic esophagectomy, nonradical resection, higher T-stage, and tumor positive lymph nodes. Overall, median postrecurrence survival was 4 months [95% confidence interval (95% CI): 3.6-4.4]. After curatively intended recurrence treatment, median survival was 20 months (95% CI: 16.4-23.7). Survival was more favorable after locoregional compared with distant recurrence (hazard ratio: 0.74, 95% CI: 0.65-0.84). CONCLUSIONS: This study provides important prognostic information assisting in the surveillance and counseling of patients after curatively intended esophageal cancer surgery. Nearly half the patients developed recurrent disease, with limited prospects of survival. The risk of recurrence was higher in patients with a higher tumor stage, nonradical resection and positive lymph node harvest.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Adenocarcinoma/patologia , Estudos de Coortes , Esofagectomia , Humanos , Metástase Linfática , Masculino , Recidiva Local de Neoplasia/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
6.
Br J Surg ; 109(12): 1312-1318, 2022 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-36036665

RESUMO

BACKGROUND: Patients with different ethnic and genetic backgrounds may respond differently to anticancer therapies. This study aimed to assess whether patients with oesophageal squamous cell carcinoma (OSCC) treated with neoadjuvant chemoradiotherapy (nCRT) in East Asia had an inferior pathological response compared with patients treated in Northwest Europe. METHODS: Patients with OSCC who underwent nCRT according to the CROSS regimen (carboplatin and paclitaxel with concurrent 41.4 Gy radiotherapy) followed by oesophagectomy between June 2012 and April 2020 were identified from East Asian and Dutch databases. The primary outcome was pCR, defined as ypT0 N0. Groups were compared using propensity score matching, adjusting for sex, Charlson Co-morbidity Index score, tumour location, cT and cN categories, interval between nCRT and surgery, and number of resected lymph nodes. RESULTS: Of 725 patients identified, 133 remained in each group after matching. A pCR was achieved in 37 patients (27.8 per cent) in the Asian database and 58 (43.6 per cent) in the Dutch database (P = 0.010). The rate of ypT1-4 was higher in Asian than Dutch data (66.2 and 49.6 per cent; P = 0.004). The ypN1-3 rate was 44.4 per cent in the Asian and 33.1 per cent in the Dutch data set. Clear margins were achieved in 92.5 per cent of Asian and 95.5 per cent of Dutch patients. CONCLUSION: Regional differences in responses to CROSS nCRT for oesophageal cancer were apparent, the origin of which will need evaluation.


Assuntos
Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Terapia Neoadjuvante , Carcinoma de Células Escamosas do Esôfago/cirurgia , Esofagectomia/efeitos adversos , Neoplasias Esofágicas/patologia , Carboplatina , Quimiorradioterapia , Resultado do Tratamento
7.
Acta Oncol ; 61(7): 849-855, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35651320

RESUMO

INTRODUCTION: The recent POLDER trial investigated the effects of external beam radiotherapy (EBRT) on dysphagia caused by incurable oesophageal cancer. An estimated life expectancy of minimally three months was required for inclusion. However, nearly one-third of the included patients died within three months. The aim of this study was to investigate if the use of prediction models could have improved the physician's estimation of the patient's survival. METHODS: Data from the POLDER trial (N = 110) were linked to the Netherlands Cancer Registry to retrieve patient, tumour, and treatment characteristics. Two published prediction models (the SOURCE model and Steyerberg model) were used to predict three-month survival for all patients included in the POLDER trial. Predicted survival probabilities were dichotomised and the accuracy, sensitivity, specificity, and the area under the curve (AUC) were used to evaluate the predictive performance. RESULTS: The SOURCE and Steyerberg model had an accuracy of 79% and 64%, and an AUC of 0.76 and 0.60 (p = .017), respectively. The SOURCE model had higher specificity across survival cut-off probabilities, the Steyerberg model had a higher sensitivity beyond the survival probability cut-off of 0.7. Using optimal cut-off probabilities, SOURCE would have wrongfully included 16/110 patients into the POLDER and Steyerberg 34/110. CONCLUSION: The SOURCE model was found to be a more useful decision aid than the Steyerberg model. Results showed that the SOURCE model could be used for three-month survival predictions for patients that are considered for palliative treatment of dysphagia caused by oesophageal cancer in addition to clinicians' judgement.


Assuntos
Transtornos de Deglutição , Neoplasias Esofágicas , Área Sob a Curva , Técnicas de Apoio para a Decisão , Transtornos de Deglutição/etiologia , Transtornos de Deglutição/radioterapia , Neoplasias Esofágicas/complicações , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/radioterapia , Humanos , Países Baixos/epidemiologia , Cuidados Paliativos/métodos , Taxa de Sobrevida
8.
Proc Natl Acad Sci U S A ; 116(6): 2237-2242, 2019 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-30670657

RESUMO

Esophageal adenocarcinoma (EAC) has a dismal prognosis, and survival benefits of recent multimodality treatments remain small. Cancer-associated fibroblasts (CAFs) are known to contribute to poor outcome by conferring therapy resistance to various cancer types, but this has not been explored in EAC. Importantly, a targeted strategy to circumvent CAF-induced resistance has yet to be identified. By using EAC patient-derived CAFs, organoid cultures, and xenograft models we identified IL-6 as the stromal driver of therapy resistance in EAC. IL-6 activated epithelial-to-mesenchymal transition in cancer cells, which was accompanied by enhanced treatment resistance, migratory capacity, and clonogenicity. Inhibition of IL-6 restored drug sensitivity in patient-derived organoid cultures and cell lines. Analysis of patient gene expression profiles identified ADAM12 as a noninflammation-related serum-borne marker for IL-6-producing CAFs, and serum levels of this marker predicted unfavorable responses to neoadjuvant chemoradiation in EAC patients. These results demonstrate a stromal contribution to therapy resistance in EAC. This signaling can be targeted to resensitize EAC to therapy, and its activity can be measured using serum-borne markers.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Fibroblastos Associados a Câncer/metabolismo , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Interleucina-6/metabolismo , Tolerância a Radiação , Células Estromais/metabolismo , Adenocarcinoma/terapia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Transição Epitelial-Mesenquimal/genética , Neoplasias Esofágicas/terapia , Humanos , Camundongos , Técnicas de Cultura de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
9.
J Natl Compr Canc Netw ; 19(4): 403-410, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33636694

RESUMO

BACKGROUND: Personalized prediction of treatment outcomes can aid patients with cancer when deciding on treatment options. Existing prediction models for esophageal and gastric cancer, however, have mostly been developed for survival prediction after surgery (ie, when treatment has already been completed). Furthermore, prediction models for patients with metastatic cancer are scarce. The aim of this study was to develop prediction models of overall survival at diagnosis for patients with potentially curable and metastatic esophageal and gastric cancer (the SOURCE study). METHODS: Data from 13,080 patients with esophageal or gastric cancer diagnosed in 2015 through 2018 were retrieved from the prospective Netherlands Cancer Registry. Four Cox proportional hazards regression models were created for patients with potentially curable and metastatic esophageal or gastric cancer. Predictors, including treatment type, were selected using the Akaike information criterion. The models were validated with temporal cross-validation on their C-index and calibration. RESULTS: The validated model's C-index was 0.78 for potentially curable gastric cancer and 0.80 for potentially curable esophageal cancer. For the metastatic models, the c-indices were 0.72 and 0.73 for esophageal and gastric cancer, respectively. The 95% confidence interval of the calibration intercepts and slopes contain the values 0 and 1, respectively. CONCLUSIONS: The SOURCE prediction models show fair to good c-indices and an overall good calibration. The models are the first in esophageal and gastric cancer to predict survival at diagnosis for a variety of treatments. Future research is needed to demonstrate their value for shared decision-making in clinical practice.


Assuntos
Neoplasias Esofágicas , Neoplasias Gástricas , Tomada de Decisão Compartilhada , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Humanos , Modelos Teóricos , Metástase Neoplásica , Países Baixos , Estudos Prospectivos , Sistema de Registros , Projetos de Pesquisa , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/terapia , Análise de Sobrevida
10.
Acta Oncol ; 60(4): 497-504, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33491513

RESUMO

BACKGROUND: With increasing interest in organ-preserving strategies for potentially curable esophageal cancer, real-world data is needed to understand the impact of pathological tumor response after neoadjuvant chemoradiotherapy (CRT) on patient outcome. The objective of this study is to assess the association between pathological tumor response following CROSS neoadjuvant CRT and long-term overall survival (OS) in a nationwide cohort. MATERIAL AND METHODS: All patients diagnosed in the Netherlands with potentially curable esophageal cancer between 2009 and 2017, and treated with neoadjuvant CRT followed by esophagectomy were included. Through record linkage with the nationwide Dutch Pathology Registry (PALGA), pathological data were obtained. The primary outcome was pathological tumor response based on ypTNM, classified into pathological complete response (ypT0N0) and incomplete responders (ypT0N+, ypT+N0, and ypT+N+). Multivariable logistic and Cox regression models were used to identify predictors of pathological complete response (pCR) and survival. RESULTS: A total of 4946 patients were included. Overall, 24% achieved pCR, with 19% in adenocarcinoma and 42% in squamous cell carcinoma. Patients with pCR had a better estimated 5-year OS compared to incomplete responders (62% vs. 38%, p< .001). Of the patients with incomplete response, ypT+N+ patients (32% of total population) had the lowest estimated 5-year OS rate, followed by ypT0N+ and ypT+ N0 (22%, 47%, and 49%, respectively, p< .001). Adenocarcinoma, well to moderate differentiation, cT3-4, cN+, signet ring cell differentiation and lymph node yield (≥15) were associated with lower likelihood of pCR. CONCLUSION: In this population-based study, pathological tumor response based on the ypTNM-stage was associated with different prognostic subgroups. A quarter of patients achieved ypT0N0 with favorable long-term survival, while one-third had an ypT+N+ response with very poor survival. The association between pathological tumor response and long-term survival could help in more accurate assessments of individual prognosis and treatment decisions.


Assuntos
Neoplasias Esofágicas , Terapia Neoadjuvante , Quimiorradioterapia , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/terapia , Esofagectomia , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
11.
Cancer ; 126(3): 628-639, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31730712

RESUMO

BACKGROUND: Although testicular cancer (TC) treatment has been associated with severe late morbidities, including second malignant neoplasms (SMNs) and ischemic heart disease (IHD), cause-specific excess mortality has been rarely studied among patients treated in the platinum era. METHODS: In a large, multicenter cohort including 6042 patients with TC treated between 1976 and 2006, cause-specific mortality was compared with general population mortality rates. Associations with treatment were assessed with proportional hazards analysis. RESULTS: With a median follow-up of 17.6 years, 800 patients died; 40.3% of these patients died because of TC. The cumulative mortality was 9.6% (95% confidence interval [CI], 8.5%-10.7%) 25 years after TC treatment. In comparison with general population mortality rates, patients with nonseminoma experienced 2.0 to 11.6 times elevated mortality from lung, stomach, pancreatic, rectal, and kidney cancers, soft-tissue sarcomas, and leukemia; 1.9-fold increased mortality (95% CI, 1.3-2.8) from IHD; and 3.9-fold increased mortality (95% CI, 1.5-8.4) from pneumonia. Seminoma patients experienced 2.5 to 4.6 times increased mortality from stomach, pancreatic, bladder cancer and leukemia. Radiotherapy and chemotherapy were associated with 2.1 (95% CI, 1.8-2.5) and 2.5 times higher SMN mortality (95% CI, 2.0-3.1), respectively, in comparison with the general population. In a multivariable analysis, patients treated with platinum-containing chemotherapy had a 2.5-fold increased hazard ratio (HR; 95% CI, 1.8-3.5) for SMN mortality in comparison with patients without platinum-containing chemotherapy. The HR for SMN mortality increased 0.29 (95% CI, 0.19-0.39) per 100 mg/m2 platinum dose administered (Ptrend  < .001). IHD mortality was increased 2.1-fold (95% CI, 1.5-4.2) after platinum-containing chemotherapy in comparison with patients without platinum exposure. CONCLUSIONS: Platinum-containing chemotherapy is associated with a dose-dependent increase in the risk of SMN mortality.


Assuntos
Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/mortalidade , Neoplasias Testiculares/tratamento farmacológico , Neoplasias Testiculares/mortalidade , Adulto , Antineoplásicos/uso terapêutico , Causas de Morte , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/patologia , Segunda Neoplasia Primária/radioterapia , Platina/uso terapêutico , Modelos de Riscos Proporcionais , Fatores de Risco , Sobrevivência , Neoplasias Testiculares/patologia , Neoplasias Testiculares/radioterapia , Adulto Jovem
12.
Acta Oncol ; 59(8): 895-903, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32319845

RESUMO

Background: Proximal esophageal cancer (EC) is commonly treated with definitive chemoradiation (CRT). The radiation dose and type of chemotherapy backbone are still under debate. The objective of this study was to compare the treatment outcomes of contemporary CRT regimens.Material and Methods: In this retrospective observational cohort study, we included patients with locally advanced squamous cell cancer of the proximal esophagus, from 11 centers in the Netherlands, treated with definitive CRT between 2004 and 2014. Each center had a preferential CRT regimen, based on cisplatin (Cis) or carboplatin-paclitaxel (CP) combined with low (≤50.4 Gy) or high (>50.4 Gy) dose radiotherapy (RT). Differences in overall survival (OS) between CRT regimens were assessed using a fully adjusted Cox proportional hazards and propensity score (PS) weighted model. Safety profiles were compared using a multilevel logistic regression model.Results: Two hundred patients were included. Fifty-four, 39, 95, and 12 patients were treated with Cis-low-dose RT, Cis-high-dose RT, CP-low-dose RT, and CP-high-dose RT, respectively. Median follow-up was 62.6 months (95% CI: 47.9-77.2 months). Median OS (21.9 months; 95% CI: 16.9-27.0 months) was comparable between treatment groups (logrank p = .88), confirmed in the fully adjusted and PS weighted model (p > .05). Grades 3-5 acute adverse events were less frequent in patients treated with CP-low-dose RT versus Cis-high-dose RT (OR 3.78; 95% CI: 1.31-10.87; p = .01). The occurrence of grades 3-5 late toxicities was not different between treatment groups.Conclusion: Our study was unable to demonstrate a difference in OS between the CRT regimens, probably related to the relatively small sample size. Based on the superior safety profile, carboplatin and paclitaxel-based CRT regimens are preferred in patients with locally advanced proximal EC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/métodos , Neoplasias Esofágicas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos , Paclitaxel/administração & dosagem , Pontuação de Propensão , Modelos de Riscos Proporcionais , Dosagem Radioterapêutica , Estudos Retrospectivos , Resultado do Tratamento
13.
Int J Cancer ; 145(10): 2792-2803, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31018252

RESUMO

Multimodality treatment has advanced the outcome of esophageal adenocarcinoma (EAC), but overall survival remains poor. Therapeutic pressure activates effective resistance mechanisms and we characterized these mechanisms in response to the currently used neoadjuvant treatment against EAC: carboplatin, paclitaxel and radiotherapy. We developed an in vitro approximation of this regimen and applied it to primary patient-derived cultures. We observed a heterogeneous epithelial-to-mesenchymal (EMT) response to the high therapeutic pressure exerted by chemoradiation. We found EMT to be initiated by the autocrine production and response to transforming growth factor beta (TGF-ß) of EAC cells. Inhibition of TGF-ß ligands effectively abolished chemoradiation-induced EMT. Assessment of TGF-ß serum levels in EAC patients revealed that high levels after neoadjuvant treatment predicted the presence of fluorodeoxyglucose uptake in lymph nodes on the post-chemoradiation positron emission tomography-scan. Our study shows that chemoradiation contributes to resistant metastatic disease in EAC patients by inducing EMT via autocrine TGF-ß production. Monitoring TGF-ß serum levels during treatment could identify those patients at risk of developing metastatic disease, and who would likely benefit from TGF-ß targeting therapy.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Neoplasias Esofágicas/terapia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Adenocarcinoma/sangue , Adenocarcinoma/mortalidade , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/farmacologia , Carboplatina/uso terapêutico , Linhagem Celular Tumoral , Quimiorradioterapia/métodos , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Transição Epitelial-Mesenquimal/efeitos da radiação , Mucosa Esofágica/diagnóstico por imagem , Mucosa Esofágica/patologia , Neoplasias Esofágicas/sangue , Neoplasias Esofágicas/mortalidade , Esofagectomia , Feminino , Fluordesoxiglucose F18 , Humanos , Estimativa de Kaplan-Meier , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Tomografia por Emissão de Pósitrons , Cultura Primária de Células , Intervalo Livre de Progressão , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/efeitos da radiação , Fator de Crescimento Transformador beta/sangue , Fator de Crescimento Transformador beta/metabolismo , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Gastroenterology ; 155(3): 784-798, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885883

RESUMO

BACKGROUND & AIMS: Immune checkpoint inhibition may affect growth or progression of highly aggressive cancers, such as esophageal adenocarcinoma (EAC). We investigated the regulation of expression of major histocompatibility complex, class 1 (MHC-I) proteins (encoded by HLA-A, HLA-B, and HLA-C) and the immune response to EACs in patient samples. METHODS: We performed quantitative polymerase chain reaction array analyses of OE33 cells and OE19 cells, which express different levels of the ATP binding cassette subfamily B member 1 (TAP1) and TAP2, required for antigen presentation by MHC-I, to identify microRNAs (miRNAs) that regulate their expression. We performed luciferase assays to validate interactions between miRNAs and potential targets. We overexpressed candidate miRNAs in OE33, FLO-1, and OACP4 C cell lines and performed quantitative polymerase chain reaction, immunoblot, and flow cytometry analyses to identify changes in messenger RNA (mRNA) and protein expression; we studied the effects of cytotoxic T cells. We performed miRNA in situ hybridization, RNA-sequencing, and immunohistochemical analyses of tumor tissues from 51 untreated patients with EAC in the Netherlands. Clinical and survival data were collected for patients, and EAC subtypes were determined. RESULTS: We found OE19 cells to have increased levels of 7 miRNAs. Of these, we found binding sites for miRNA 125a (MIR125a)-5p in the 3' untranslated region of the TAP2 mRNA and binding sites for MIR148a-3p in 3' untranslated regions of HLA-A, HLA-B, and HLA-C mRNAs. Overexpression of these miRNAs reduced expression of TAP2 in OE33, FLO-1, and OACP4 C cells, and reduced cell-surface levels of MHC-I. OE33 cells that expressed the viral peptide BZLF1 were killed by cytotoxic T cells, whereas OE33 that overexpressed MIR125a-5p or MIR 148a along with BZLF1 were not. In EAC and nontumor tissues, levels of MIR125a-5p correlated inversely with levels of TAP2 protein. High expression of TAP1 by EAC correlated with significantly shorter overall survival times of patients. EACs that expressed high levels of TAP1 and genes involved in antigen presentation also expressed high levels of genes that regulate the adaptive immune response, PD-L1, PD-L2, and IDO1; these EACs had a poor response to neoadjuvant chemoradiotherapy and associated with shorter overall survival times of patients. CONCLUSIONS: In studies of EAC cell lines and tumor tissues, we found increased levels of MIR125a-5p and MIR148a-3p to reduce levels of TAP2 and MHC-I, required for antigen presentation. High expression of MHC-I molecules by EAC correlated with markers of an adaptive immune response and significantly shorter overall survival times of patients.


Assuntos
Imunidade Adaptativa/genética , Adenocarcinoma/imunologia , Proteínas de Ligação a DNA/imunologia , Neoplasias Esofágicas/imunologia , MicroRNAs/fisiologia , Fatores de Transcrição/imunologia , Regiões 3' não Traduzidas/imunologia , Membro 3 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/imunologia , Adenocarcinoma/genética , Linhagem Celular Tumoral , Neoplasias Esofágicas/genética , Humanos , MicroRNAs/imunologia
15.
Acta Oncol ; 58(6): 943-950, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30905243

RESUMO

Objective: Delineation variation of esophageal tumors remains a large source of geometric uncertainty. In the present study, we investigated the inter- and intra-observer variation in esophageal gross tumor volume (GTV) delineation and the impact of endoscopically implanted fiducial markers on these variations. Material/Methods: Ten esophageal cancer patients with at least two markers endoscopically implanted at the cranial and caudal tumor borders and visible on the planning computed tomography (pCT) were included in this study. Five dedicated gastrointestinal radiation oncologists independently delineated GTVs on the pCT without markers and with markers. The GTV was first delineated on pCTs where markers were digitally removed and next on the original pCT with markers. Both delineation series were executed twice to determine intra-observer variation. For both the inter- and intra-observer analyses, the generalized conformity index (CIgen), and the standard deviation (SD) of the distances between delineated surfaces (i.e., overall, longitudinal, and radial SDs) were calculated. Linear mixed-effect models were used to compare the without and with markers series (α = 0.05). Results: Both the inter- and intra-observer CIgen were significantly larger in the series with markers than in the series without markers (p < .001). For the series without markers vs. with markers, the inter-observer overall SD, longitudinal SD, and radial SD was 0.63 cm vs. 0.22 cm, 1.44 cm vs. 0.42 cm, and 0.26 cm vs. 0.18 cm, respectively (p < .05); moreover, the intra-observer overall SD, longitudinal SD, and radial SD was 0.45 cm vs. 0.26 cm, 1.10 cm vs. 0.41 cm, and 0.22 cm vs. 0.15 cm, respectively (p < .05). Conclusion: The presence of markers at the cranial and caudal tumor borders significantly reduced both inter- and intra-observer GTV delineation variation, especially in the longitudinal direction. Our results endorse the use of markers in GTV delineation for esophageal cancer patients.


Assuntos
Adenocarcinoma/radioterapia , Carcinoma de Células Escamosas/radioterapia , Neoplasias Esofágicas/radioterapia , Marcadores Fiduciais , Variações Dependentes do Observador , Radioterapia/normas , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Planejamento da Radioterapia Assistida por Computador/métodos , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios X/métodos
16.
Lancet Oncol ; 19(7): 965-974, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29861116

RESUMO

BACKGROUND: After neoadjuvant chemoradiotherapy for oesophageal cancer, roughly half of the patients with squamous cell carcinoma and a quarter of those with adenocarcinoma have a pathological complete response of the primary tumour before surgery. Thus, the necessity of standard oesophagectomy after neoadjuvant chemoradiotherapy should be reconsidered for patients who respond sufficiently to neoadjuvant treatment. In this study, we aimed to establish the accuracy of detection of residual disease after neoadjuvant chemoradiotherapy with different diagnostic approaches, and the optimal combination of diagnostic techniques for clinical response evaluations. METHODS: The preSANO trial was a prospective, multicentre, diagnostic cohort study at six centres in the Netherlands. Eligible patients were aged 18 years or older, had histologically proven, resectable, squamous cell carcinoma or adenocarcinoma of the oesophagus or oesophagogastric junction, and were eligible for potential curative therapy with neoadjuvant chemoradiotherapy (five weekly cycles of carboplatin [area under the curve 2 mg/mL per min] plus paclitaxel [50 mg/m2 of body-surface area] combined with 41·4 Gy radiotherapy in 23 fractions) followed by oesophagectomy. 4-6 weeks after completion of neoadjuvant chemoradiotherapy, patients had oesophagogastroduodenoscopy with biopsies and endoscopic ultrasonography with measurement of maximum tumour thickness. Patients with histologically proven locoregional residual disease or no-pass during endoscopy and without distant metastases underwent immediate surgical resection. In the remaining patients a second clinical response evaluation was done (PET-CT, oesophagogastroduodenoscopy with biopsies, endoscopic ultrasonography with measurement of maximum tumour thickness, and fine-needle aspiration of suspicious lymph nodes), followed by surgery 12-14 weeks after completion of neoadjuvant chemoradiotherapy. The primary endpoint was the correlation between clinical response during clinical response evaluations and the final pathological response in resection specimens, as shown by the proportion of tumour regression grade (TRG) 3 or 4 (>10% residual carcinoma in the resection specimen) residual tumours that was missed during clinical response evaluations. This study was registered with the Netherlands Trial Register (NTR4834), and has been completed. FINDINGS: Between July 22, 2013, and Dec 28, 2016, 219 patients were included, 207 of whom were included in the analyses. Eight of 26 TRG3 or TRG4 tumours (31% [95% CI 17-50]) were missed by endoscopy with regular biopsies and fine-needle aspiration. Four of 41 TRG3 or TRG4 tumours (10% [95% CI 4-23]) were missed with bite-on-bite biopsies and fine-needle aspiration. Endoscopic ultrasonography with maximum tumour thickness measurement missed TRG3 or TRG4 residual tumours in 11 of 39 patients (28% [95% CI 17-44]). PET-CT missed six of 41 TRG3 or TRG4 tumours (15% [95% CI 7-28]). PET-CT detected interval distant histologically proven metastases in 18 (9%) of 190 patients (one squamous cell carcinoma, 17 adenocarcinomas). INTERPRETATION: After neoadjuvant chemoradiotherapy for oesophageal cancer, clinical response evaluation with endoscopic ultrasonography, bite-on-bite biopsies, and fine-needle aspiration of suspicious lymph nodes was adequate for detection of locoregional residual disease, with PET-CT for detection of interval metastases. Active surveillance with this combination of diagnostic modalities is now being assessed in a phase 3 randomised controlled trial (SANO trial; Netherlands Trial Register NTR6803). FUNDING: Dutch Cancer Society.


Assuntos
Quimiorradioterapia/métodos , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/terapia , Neoplasia Residual/mortalidade , Neoplasia Residual/terapia , Área Sob a Curva , Biópsia por Agulha Fina , Estudos de Coortes , Intervalo Livre de Doença , Endossonografia/métodos , Neoplasias Esofágicas/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/patologia , Estadiamento de Neoplasias , Neoplasia Residual/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Estudos Prospectivos , Medição de Risco , Taxa de Sobrevida
17.
Br J Cancer ; 119(7): 901-907, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30297773

RESUMO

BACKGROUND: While the risk of diabetes is increased following radiation exposure to the pancreas among childhood cancer survivors, its association among testicular cancer (TC) survivors has not been investigated. METHODS: Diabetes risk was studied in 2998 1-year TC survivors treated before 50 years of age with orchidectomy with/without radiotherapy between 1976 and 2007. Diabetes incidence was compared with general population rates. Treatment-specific risk of diabetes was assessed using a case-cohort design. RESULTS: With a median follow-up of 13.4 years, 161 TC survivors were diagnosed with diabetes. Diabetes risk was not increased compared to general population rates (standardised incidence ratios (SIR): 0.9; 95% confidence interval (95% CI): 0.7-1.1). Adjusted for age, para-aortic radiotherapy was associated with a 1.66-fold (95% CI: 1.05-2.62) increased diabetes risk compared to no radiotherapy. The excess hazard increased with 0.31 with every 10 Gy increase in the prescribed radiation dose (95% CI: 0.11-0.51, P = 0.003, adjusted for age and BMI); restricted to irradiated patients the excess hazard increased with 0.33 (95% CI: -0.14 to 0.81, P = 0.169) with every 10 Gy increase in radiation dose. CONCLUSION: Compared to surgery only, para-aortic irradiation is associated with increased diabetes risk among TC survivors.


Assuntos
Diabetes Mellitus/epidemiologia , Radioterapia/efeitos adversos , Neoplasias Testiculares/radioterapia , Neoplasias Testiculares/cirurgia , Adulto , Sobreviventes de Câncer/estatística & dados numéricos , Estudos de Coortes , Diabetes Mellitus/etiologia , Relação Dose-Resposta à Radiação , Humanos , Incidência , Masculino , Orquiectomia , Resultado do Tratamento
18.
Ann Surg ; 267(2): 303-310, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-27811508

RESUMO

OBJECTIVE: The aim of this article was to study the influence of hospital of diagnosis on the probability of receiving curative treatment and its impact on survival among patients with esophageal cancer (EC). BACKGROUND: Although EC surgery is centralized in the Netherlands, the disease is often diagnosed in hospitals that do not perform this procedure. METHODS: Patients with potentially curable esophageal or gastroesophageal junction tumors diagnosed between 2005 and 2013 who were potentially curable (cT1-3,X, any N, M0,X) were selected from the Netherlands Cancer Registry. Multilevel logistic regression was performed to examine the probability to undergo curative treatment (resection with or without neoadjuvant treatment, definitive chemoradiotherapy, or local tumor excision) according to hospital of diagnosis. Effects of variation in probability of undergoing curative treatment among these hospitals on survival were investigated by Cox regression. RESULTS: All 13,017 patients with potentially curable EC, diagnosed in 91 hospitals, were included. The proportion of patients receiving curative treatment ranged from 37% to 83% and from 45% to 86% in the periods 2005-2009 and 2010-2013, respectively, depending on hospital of diagnosis. After adjustment for patient- and hospital-related characteristics these proportions ranged from 41% to 77% and from 50% to 82%, respectively (both P < 0.001). Multivariable survival analyses showed that patients diagnosed in hospitals with a low probability of undergoing curative treatment had a worse overall survival (hazard ratio = 1.13, 95% confidence interval 1.06-1.20; hazard ratio = 1.15, 95% confidence interval 1.07-1.24). CONCLUSIONS: The variation in probability of undergoing potentially curative treatment for EC between hospitals of diagnosis and its impact on survival indicates that treatment decision making in EC may be improved.


Assuntos
Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Hospitais/estatística & dados numéricos , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Países Baixos/epidemiologia , Probabilidade , Modelos de Riscos Proporcionais , Sistema de Registros , Resultado do Tratamento
19.
Ann Surg ; 267(5): 892-897, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-28350565

RESUMO

OBJECTIVE: To compare overall survival in patients with esophageal adenocarcinoma who underwent transhiatal esophagectomy (THE) with limited lymphadenectomy or transthoracic esophagectomy (TTE) with extended lymphadenectomy with or without neoadjuvant chemoradiotherapy (nCRT). BACKGROUND: The application of neoadjuvant therapy might change the association between the extent of lymphadenectomy and survival in patients with esophageal adenocarcinoma. This may influence the choice of surgical approach in patients treated with nCRT. METHODS: Patients with potentially curable subcarinal esophageal adenocarcinoma treated with surgery alone or nCRT followed by surgery in 7 centers were included. The effect of surgical approach on overall survival, differentiated by the addition or omission of nCRT, was analyzed using a multivariable Cox regression model that included well-known prognostic factors and factors that might have influenced the choice of surgical approach. RESULTS: In total, 701 patients were included, of whom 318 had TTE with extended lymphadenectomy and 383 had THE with limited lymphadenectomy. TTE had differential effects on survival (P for interaction = 0.02), with a more favorable prognostic effect in patients who were treated with surgery alone [hazard ratio (HR) = 0.77, 95% confidence interval (CI) 0.58-1.03]. This association was statistically significant in a subgroup of patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 0.62, 95% CI 0.43-0.90). The favorable prognostic effect of TTE over THE was absent in the nCRT and surgery group (HR = 1.16, 95% CI 0.80-1.66) and in the subgroup of nCRT patients with 1 to 8 positive lymph nodes in the resection specimen (HR = 1.00, 95% CI 0.61-1.68). CONCLUSIONS: Compared to surgery alone, the addition of nCRT may reduce the need for TTE with extended lymphadenectomy to improve long-term survival in patients with esophageal adenocarcinoma.


Assuntos
Adenocarcinoma/terapia , Neoplasias Esofágicas/terapia , Esofagectomia/métodos , Estadiamento de Neoplasias , Adenocarcinoma/diagnóstico , Adenocarcinoma/mortalidade , Idoso , Quimiorradioterapia Adjuvante , Intervalo Livre de Doença , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Países Baixos/epidemiologia , Tomografia por Emissão de Pósitrons , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia
20.
BMC Cancer ; 18(1): 877, 2018 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-30200910

RESUMO

BACKGROUND: Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy. METHODS: In this multicentre phase II non-comparative study, patients with clinical stage IB-IIIC (TNM 8th edition) resectable gastric adenocarcinoma are randomised between: (1) 4 cycles of docetaxel+oxaliplatin+capecitabine (DOC), (2) 2 cycles of DOC followed by chemoradiotherapy (45Gy in combination with weekly paclitaxel and carboplatin) or (3) chemoradiotherapy. Primary endpoint is event-free survival, 1 year after randomisation (events are local and/or regional recurrence or progression, distant recurrence, or death from any cause). Secondary endpoints include: toxicity, surgical outcomes, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival, and health related quality of life. Exploratory endpoints include translational studies on predictive and prognostic biomarkers. DISCUSSION: The aim of this study is to select the most promising among three preoperative treatment arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the standard therapy in a phase III trial. TRIAL REGISTRATION: clinicaltrials.gov NCT02931890 ; registered 13 October 2016. Date of first enrolment: 21 December 2017.


Assuntos
Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Gastrectomia , Terapia Neoadjuvante , Neoplasias Gástricas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia Adjuvante/métodos , Quimioterapia Adjuvante/métodos , Terapia Combinada , Feminino , Seguimentos , Gastrectomia/métodos , Humanos , Masculino , Terapia Neoadjuvante/métodos , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Qualidade de Vida , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Resultado do Tratamento
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