RESUMO
5-Fluorouracil (5-FU) is widely used in gastric cancer treatment, yet 5-FU resistance remains an important clinical challenge. We established a model based on five long noncoding RNAs (lncRNA) to effectively assess the prognosis of gastric cancer patients; among them, lncRNA OVAAL was markedly upregulated in gastric cancer and associated with poor prognosis and 5-FU resistance. In vitro and in vivo assays confirmed that OVAAL promoted proliferation and 5-FU resistance of gastric cancer cells. Mechanistically, OVAAL bound with pyruvate carboxylase (PC) and stabilized PC from HSC70/CHIP-mediated ubiquitination and degradation. OVAAL knockdown reduced intracellular levels of oxaloacetate and aspartate, and the subsequent pyrimidine synthesis, which could be rescued by PC overexpression. Moreover, OVAAL knockdown increased sensitivity to 5-FU treatment, which could be reversed by PC overexpression or repletion of oxaloacetate, aspartate, or uridine. OVAAL overexpression enhanced pyrimidine synthesis to promote proliferation and 5-FU resistance of gastric cancer cells, which could be abolished by PC knockdown. Thus, OVAAL promoted gastric cancer cell proliferation and induced 5-FU resistance by enhancing pyrimidine biosynthesis to antagonize 5-FU induced thymidylate synthase dysfunction. Targeting OVAAL-mediated nucleotide metabolic reprograming would be a promising strategy to overcome chemoresistance in gastric cancer.
Assuntos
RNA Longo não Codificante , Neoplasias Gástricas , Ácido Aspártico/farmacologia , Ácido Aspártico/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Nucleotídeos/farmacologia , Nucleotídeos/uso terapêutico , Oxaloacetatos/farmacologia , Oxaloacetatos/uso terapêutico , Piruvato Carboxilase/genética , RNA Longo não Codificante/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismoRESUMO
OBJECTIVE: The aim of this study was to assess the cost-effectiveness of pressurized intraperitoneal aerosol chemotherapy with low-dose cisplatin and doxorubicin (PIPAC C/D) for the treatment of advanced gastric cancer. METHODS: A Partitioned Survival Model followed by state transition Markov model was developed to estimate the costs and effectiveness of the use of PIPAC C/D versus palliative chemotherapy in the UK. The intervention was assessed at two different levels of care, including upfront therapy (PIPAC C/D plus Oxaliplatin in combination with Capecitabine (XELOX) chemotherapy versus first-line chemotherapy alone) and second-line therapy (PIPAC C/D alone versus second-line chemotherapy (ramucirumab monotherapy)). Data from multiple sources, including published literature and UK-based databases, were used to inform the economic model. RESULTS: For the upfront therapy analysis, the estimated total costs in the intervention and comparator arms were £32,606 (SD: £3877) and £17,844 (SD: £920), respectively. PIPAC C/D plus XELOX led to an increase of 0.46 in quality-adjusted life-years (QALYs) gained. The incremental cost per QALY gained was £31,868. For the second-line therapy analysis, the use of PIPAC C/D led to an increase of 0.19 in QALYs and a £21,474 reduction in costs, meaning the intervention was a dominant strategy. CONCLUSIONS: The cost-effectiveness results for the upfront therapy analysis indicate that PIPAC C/D plus chemotherapy is a cost-effective strategy. Additionally, PIPAC C/D alone as a second-line therapy has the potential to reduce costs and improve clinical outcomes for patients with advanced gastric cancer with peritoneal metastasis.
Assuntos
Aerossóis , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Capecitabina/uso terapêutico , Carcinoma/tratamento farmacológico , Oxaloacetatos/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/secundário , Cisplatino/administração & dosagem , Análise Custo-Benefício , Doxorrubicina/administração & dosagem , Humanos , Injeções Intraperitoneais , Laparoscopia , Neoplasias Peritoneais/secundário , Anos de Vida Ajustados por Qualidade de Vida , Reino UnidoRESUMO
OBJECTIVE: The aim of this study was to compare the clinical efficacy of neoadjuvant chemoradiotherapy (NACRT) combined with postoperative adjuvant XELOX (Oxaliplatin +Capecitabine) chemotherapy and postoperative adjuvant chemotherapy (ACT) with XELOX for local advanced gastric cancer (LAGC). METHODS: In this prospectively randomized trial, we investigated the effect of NACRT combined with postoperative ACT for LAGC. 60 patients were randomly divided into NACRT group and ACT group, with 30 patients in each group. Patients in NACRT group were given three-dimensional conformal radiotherapy (45 Gy/1.8 Gy/f) accompanied by synchronous XELOX of two cycles, followed by surgery, and then postoperative adjuvant XELOX chemotherapy of four cycles was performed. Patients in ACT group received surgery in advance, and then XELOX chemotherapy of six cycles was given. RESULTS: The objective response rate of NACRT was 76.7%. The overall incidence of postoperative complications in NACRT group was not significantly different from that in ACT group (23.1% vs 30.0%, p = 0.560). The 1 year, 2 years, and 3 years progression-free survival (PFSï¼and overall survival (OS) in NACRT and ACT groups were 80.0% vs 56.7%, 73.3% vs 46.7%, 60.0% vs 33.3%, and 86.7% vs 80.0%, 76.7% vs 66.7%, 63.3% vs 50.0%, respectively. Patients in NACRT group showed a significantly higher R0 resection rate (84.6% vs 56.7%, p = 0.029),lower loco-regional recurrence rate (36.7% vs 11.5%, p = 0.039), longer PFS (p = 0.019) and freedom from locoregional progression(FFLP) (p = 0.004) than patients in ACT group, while there was no difference in OS (p = 0.215) and in toxicity incidence (p > 0.05). CONCLUSIONS: NACRT combined with postoperative adjuvant XELOX chemotherapy can improve R0 resection rate, reduce loco-regional recurrence, prolong PFS and FFLP without increasing the incidence of postoperative complications in patients with LAGC. ADVANCES IN KNOWLEDGE: Compared with postoperative adjuvant chemotherapy, locally advanced gastric cancer patients may benefit from neoadjuvant chemoradiotherapy, and toxicity associated with chemoradiotherapy was tolerant and manageable.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Oxaloacetatos/uso terapêutico , Radioterapia Conformacional , Neoplasias Gástricas/terapia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Período Pós-Operatório , Estudos Prospectivos , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Resultado do TratamentoRESUMO
BACKGROUND: A combination of fluoropyrimidines and platinum is widely accepted as the standard first-line treatment for advanced gastric and gastroesophageal adenocarcinomas. However, the benefit compared with platinum-free chemotherapeutic regimens remains controversial. We compared the efficacy and safety of capecitabine with oxaliplatin or docetaxel, as first-line therapy in advanced gastric cancer. METHODS: Eligible patients were randomly assigned to receive either capecitabine and oxaliplatin (XELOX) (capecitabine 1,000âmg/m2; twice daily for 14âdays with oxaliplatin 130âmg/m2 on day 1, every 21âdays), or DX (capecitabine 1,000âmg/m2; twice daily for 14âdays with docetaxel 75âmg/m2 on day 1, every 21âdays). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), progression-free survival, overall survival, and prespecified safety endpoints. RESULTS: Ninety patients were enrolled in the West China Hospital from April 2012 to August 2016; a total of 83 and 66 patients were eligible for safety and efficacy analyses, respectively. Between the XELOX and DX groups, ORR (24.2% vs 24.2%, pâ=â1.000), DCR (90.9% vs 75.8%, pâ=â0.099), progression-free survival (6.1m vs 4.1m, pâ=â0.346), and overall survival (8.8m vs 9.0m, pâ=â0.973) were similar. There was no significant difference in toxicity between the two regimens. The frequent grade 3 or higher toxicities in the XELOX and DX groups were peripheral neuropathy and hematological toxicity, respectively. Toxicity was tolerable; no treatment-related deaths occurred in either group. CONCLUSIONS: The DX regimen was not superior to XELOX, but instead, similar. The platinum-containing regimen remains the preferred first-line option for advanced gastric and gastroesophageal adenocarcinomas, and DX might be considered as an alternative for patients unsuitable for platinum-containing chemotherapy.
Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Docetaxel/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Oxaliplatina/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaloacetatos/uso terapêutico , Intervalo Livre de Progressão , Neoplasias Gástricas/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Second-line (2L) treatments for advanced pancreatic ductal adenocarcinoma (PDAC) achieve a modest benefit at the expense of potential toxicity. In the absence of predictive factors of response, the identification of prognostic factors could help in the therapeutic decisions-making. The purpose of this study was to assess the prognostic factors associated with shorter survival in patients with advanced PDAC who received 2L treatment. METHODS: We conducted a single institution retrospective study, which included all patients with advanced PDAC who received 2L treatment between September 2006 and February 2020 at La Paz University Hospital, Madrid (Spain). Significant variables in the logistic regression model were used to create a prognostic score. RESULTS: We included 108 patients. The median overall survival (OS) was 5.10 months (95%CI 4.02-6.17). In the multivariate analysis, time to progression (TTP) shorter than 4 months after first-line treatment (OR 4.53 [95%CI 1.28-16.00] p = 0.01), neutrophil-to-lymphocyte ratio (NLR) greater than 3 at the beginning of 2L (OR 9.07 [95%CI 1.82-45.16] p = 0.01) and CA-19.9 level higher than the upper limit of normal at the beginning of 2L (OR 7.83 [95%CI 1.30-49.97] p = 0.02) were independently associated with OS shorter than 3 months. The prognostic score classified patients into three prognostic groups (good, intermediate and poor) with significant differences in OS (p < 0.001). CONCLUSIONS: TTP shorter than 4 months after first-line treatment, NLR greater than 3 and CA-19.9 level higher than the upper limit of normal at the beginning of 2L were associated with shorter overall survival. We developed a prognostic score that classifies patients with advanced PDAC into three prognostic groups after progression to the first-line. This score could help in the decision-making for 2L treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Glicosídicos Associados a Tumores/sangue , Capecitabina/uso terapêutico , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Tomada de Decisão Clínica , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Modelos Logísticos , Linfócitos/citologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Oxaliplatina/uso terapêutico , Oxaloacetatos/uso terapêutico , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , GencitabinaRESUMO
BACKGROUND: The trial hypothesis was that, in a resource-constrained situation, short-course radiotherapy would improve treatment compliance compared with conventional chemoradiotherapy for locally advanced rectal cancer, without compromising oncological outcomes. METHODS: In this open-label RCT, patients with cT3, cT4 or node-positive non-metastatic rectal cancer were allocated randomly to 5 × 5 Gy radiotherapy and two cycles of XELOX (arm A) or chemoradiotherapy with concurrent capecitabine (arm B), followed by total mesorectal excision in both arms. All patients received a further six cycles of adjuvant chemotherapy with the XELOX regimen. The primary endpoint was treatment compliance, defined as the ability to complete planned treatment, including neoadjuvant radiochemotherapy, surgery, and adjuvant chemotherapy to a dose of six cycles. RESULTS: Of 162 allocated patients, 140 were eligible for analysis: 69 in arm A and 71 in arm B. Compliance with planned treatment (primary endpoint) was greater in arm A (63 versus 41 per cent; P = 0.005). The incidence of acute toxicities of neoadjuvant therapy was similar (haematological: 28 versus 32 per cent, P = 0.533; gastrointestinal: 14 versus 21 per cent, P = 0.305; grade III-IV: 2 versus 4 per cent, P = 1.000). Delays in radiotherapy were less common in arm A (9 versus 45 per cent; P < 0.001), and overall times for completion of neoadjuvant treatment were shorter (P < 0.001). The rates of R0 resection (87 versus 90 per cent; P = 0.554), sphincter preservation (32 versus 35 per cent; P = 0.708), pathological complete response (12 versus 10 per cent; P = 0.740), and overall tumour downstaging (75 versus 75 per cent; P = 0.920) were similar. Downstaging of the primary tumour (ypT) was more common in arm A (P = 0.044). There was no difference in postoperative complications between trial arms (P = 0.838). CONCLUSION: Reduced treatment delays and a higher rate of compliance were observed with treatment for short-course radiotherapy with consolidation chemotherapy, with no difference in early oncological surgical outcomes. In time- and resource-constrained rectal cancer units in developing countries, short-course radiotherapy should be the standard of care.
Assuntos
Quimiorradioterapia/métodos , Quimioterapia de Consolidação , Fracionamento da Dose de Radiação , Neoplasias Retais/terapia , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenocarcinoma/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Países em Desenvolvimento , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Oxaloacetatos/uso terapêutico , Cooperação do Paciente , Estudos Prospectivos , Neoplasias Retais/mortalidade , Neoplasias Retais/patologiaRESUMO
Limited studies have been reported about the function of low level of microsatellite instability (MSI-L) in cancer. The aim of our study is to unveil the prognostic role of MSI-L in gastric cancer (GC). One hundred nine patients with locally advanced GC (T3-4a, N+, M0) who underwent neoadjuvant chemotherapy plus gastrectomy with extended (D2) lymph node dissection were collected. Clinicopathological characteristics, tumour regression score, disease-free survival (DFS), and overall survival (OS) were analysed and correlated with the MSI status. The MSI status of 96 patients was identified (7 (7.3%) with MSI-H, 12 (12.5%) with MSI-L, and 77 (80.2%) with MSS). MSI-L was significantly correlated with perineural invasion (P = 0.009) and decreased MUC5AC expression (P = 0.042). Poor response to neoadjuvant chemotherapy in MSI-L patients (83.3% assessed as poor response) was observed (P = 0.501). Compared with patients with MSS tumours, patients with MSI-L tumours showed poor DFS (P = 0.018) with a hazard ratio (HR) of 2.839 (95% CI 1.131-7.124, P = 0.026) from multivariable cox regression analysis. However, this was not associated with OS (P = 0.063). MSI-L is an independent poor prognostic biomarker for the locally advanced gastric cancer treated with neoadjuvant chemotherapy. Further studies with larger sample sizes are needed for validation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Capecitabina/uso terapêutico , Gastrectomia , Excisão de Linfonodo , Instabilidade de Microssatélites , Terapia Neoadjuvante , Oxaloacetatos/uso terapêutico , Neoplasias Gástricas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Gastrectomia/efeitos adversos , Gastrectomia/mortalidade , Humanos , Excisão de Linfonodo/efeitos adversos , Excisão de Linfonodo/mortalidade , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Oxaloacetatos/efeitos adversos , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Neoplasias Gástricas/genética , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de TempoRESUMO
OBJECTIVES: First-line regimens in the treatment of metastatic colorectal cancer (mCRC) combine a fluoropyrimidine with oxaliplatin (FOLFOX/XELOX) or irinotecan (FOLFIRI). There is limited efficacy data to guide the selection of one treatment over the other. This study investigated whether mutations affecting DNA damage response (DDR) could differentially influence the response to oxaliplatin and irinotecan-containing regimens. METHODS: We retrospectively analyzed 49 patients with mCRC for whom treatment outcomes and results of comprehensive genomic profiling of tumors were available. Specimens with at least 1 pathogenic mutation involving BRCA1, BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, or RAD54L were classified as DDR-mutated, while those without mutations were DDR-wild-type (WT). We compared the overall survival (OS), disease control rate, and response rate (RR) between the DDR-mutated and DDR-WT groups. RESULTS: DDR mutations occurred in 11 patients (22%). First-line treatment with an oxaliplatin-containing regimen was administered to 33 patients (31 FOLFOX, 2 XELOX), while 16 patients received FOLFIRI. Among DDR-mutated cases, first-line treatment with FOLFOX/XELOX correlated with a statistically significant improvement in median OS compared with FOLFIRI (3.4 vs.1.8 y; P=0.042) and numerically higher RR (50% vs. 33%; P=0.58). No significant difference in OS (2.4 vs. 2.5 y; P=0.42), RR, disease control rate was observed between the 2 regimens in patients with DDR-WT tumors. CONCLUSIONS: Mutations in DDR genes were present in 22% of patients with mCRC. In patients with DDR-mutated tumors, initial treatment with FOLFOX/XELOX correlated with improved OS and a numerically higher RR compared with FOLFIRI.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Reparo do DNA/genética , Adulto , Idoso , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Reparo do DNA/efeitos dos fármacos , Feminino , Fluoruracila/uso terapêutico , Humanos , Irinotecano/administração & dosagem , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/administração & dosagem , Oxaloacetatos/uso terapêutico , Resultado do TratamentoRESUMO
ABSTRACT: Maintenance treatment after first-line chemotherapy for patients with metastatic colorectal cancer (mCRC) is a priority strategy. However, which medicine is chosen is controversial. This study aimed to determine the efficacy and safety of maintenance treatment with metronomic capecitabine vs observation.In this randomized controlled trial, patients who completed 18 weeks of induction chemotherapy with XELOX and achieved disease control were randomly assigned centrally (1:1) to receive maintenance therapy with metronomic chemotherapy or observation until disease progression. The primary endpoint was progression-free survival from randomization; secondary endpoints included overall survival and safety. Analyses were performed by intention to treat.Between January 1st, 2017 and December 31th 2018, 48 patients were enrolled and randomly assigned to receive maintenance treatment with metronomic capecitabine (nâ=â25) or only observation (nâ=â23). The median progression-free survival in the metronomic capecitabine group was 5.66 (95% confidence interval [CI] 5.25-6.07) months vs 3.98 (95%CI 3.71-4.24) months in the observation group (hazard ratio 0.11, 95% [CI] 0.04-0.26, Pâ=â.000). There was no statistically significant difference in median overall survival: 23.82 (95% CI 22.38-25.25) months in the metronomic capecitabine group vs 21.81 (95% CI 20.23-23.38) months in the observation group (hazard ratio 0.49, 95% CI 0.21-1.11, Pâ=â.087). Subgroup analyses were generally consistent with the primary finding. Similar safety profiles were observed in both arms. The most frequent adverse events in metronomic capecitabine group included neutropenia, diarrhea, hand-foot skin reaction, and mucositis.Maintenance therapy with metronomic capecitabine can be considered an alternative option following first-line chemotherapy of XELOX in patients with metastatic colorectal cancer with controlled toxicities.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Oxaloacetatos/uso terapêutico , Administração Metronômica , Idoso , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/administração & dosagem , Capecitabina/efeitos adversos , Neoplasias Colorretais/patologia , Feminino , Humanos , Quimioterapia de Indução , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Oxaloacetatos/administração & dosagem , Oxaloacetatos/efeitos adversos , Intervalo Livre de ProgressãoRESUMO
BACKGROUND: Tumor budding (Bd) has been demonstrated to be a promising prognostic factor in many carcinomas and in gastric cancer. It may represent an optimal additional parameter that is helpful for risk stratification in gastric adenocarcinoma. Hence, the present research was designed to predict the survival outcomes of gastric cancer in Vietnam, applying the tumor budding criteria of the International Tumor Budding Consensus Conference (ITBCC) 2016. METHODS: The present study was conducted on 109 gastric cancer patients who underwent surgery but did not receive neo-adjuvant chemotherapy from 2012 to 2015. The patients' clinicopathological features were recorded. Bd was evaluated according to the 2016 ITBCC criteria and classified as Bd1 (0-4 buds), Bd2 (5-9 buds), and Bd3 (≥10 buds) grades, in addition to being categorized into 2 main Bd groups: low (<10 buds) and high (≥10 buds) Bd. Kaplan-Meier and log-rank models were applied to analyze survival proportions. RESULTS: Of all the patients, 22.9% were classified as Bd1, 31.2% as Bd2, and 45.9% as Bd3 grades. Furthermore, 54.1% patients were categorized into the low and 45.9% into the high Bd groups. Patients with Bd1 and Bd2 grades (the low Bd group) exhibited the best prognosis, with 5-year overall survival (OS) rates of 85.7%, 90.8%, and90.3%, respectively. Patients with Bd3 grade (the high Bd group exhibited the worst prognosis, and none of them lived for 5 years (p < 0.001). Similar to OS rates, disease-free survival (DFS) rates markedly reduced from the Bd1 to Bd3 grade: Bd1, 95.0%; Bd2, 84.7%; and Bd3, 0% (p < 0.001). CONCLUSION: Patients with different gastric cancer Bd grades exhibited significantly different OS and DFS rates. The present study findings suggest that the ITBCC criteria can be used to stratify Bd for the treatment and prognosis of gastric cancer patients in Vietnam.
Assuntos
Carcinoma/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Neoplasias Gástricas/mortalidade , Estômago/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Carcinoma/patologia , Carcinoma/terapia , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Feminino , Seguimentos , Gastrectomia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Oxaloacetatos/uso terapêutico , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Estômago/cirurgia , Neoplasias Gástricas/patologia , Neoplasias Gástricas/terapia , Vietnã/epidemiologiaRESUMO
Importance: In the pivotal Bevacizumab-Avastin Adjuvant (AVANT) trial, patients with high-risk stage II colon cancer (CC) had 5-year and 10-year overall survival (OS) rates of 88% and 75%, respectively, with adjuvant fluorouracil and oxaliplatin-based chemotherapy; however, the trial did not demonstrate a disease-free survival (DFS) benefit of adding bevacizumab to oxaliplatin-based chemotherapy in stage III CC and suggested a detrimental effect on OS. The Long-term Survival AVANT (S-AVANT) study was designed to collect extended follow-up for patients in the AVANT trial. Objective: To explore the efficacy of adjuvant bevacizumab combined with oxaliplatin-based chemotherapy in patients with high-risk, stage II CC. Design, Setting, and Participants: This prespecified secondary end point analysis of the AVANT and S-AVANT studies included 573 patients with curatively resected high-risk stage II CC and at least 1 of the following criteria: stage T4, bowel obstruction or perforation, blood and/or lymphatic vascular invasion and/or perineural invasion, age younger than 50 years, or fewer than 12 nodes analyzed. The AVANT study was a multicenter randomized stage 3 clinical trial. Data were collected from December 2004 to February 2019, and data for this study were analyzed from March to September 2019. Intervention: Patients were randomly assigned to receive 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4), FOLFOX4 with bevacizumab, or capecitabine and oxaliplatin (XELOX) with bevacizumab. Main Outcomes and Measures: The primary end points of this secondary analysis were DFS and OS in patients with high-risk stage II CC. Results: The AVANT study included 3451 patients, of whom 573 (16.6%) had high-risk stage II CC (192 [33.5%] randomized to FOLFOX4 group; 194 [33.9%] randomized to FOLFOX4 with bevacizumab group; 187 [32.6%] randomized to XELOX with bevacizumab group). With a median (interquartile range) age of 57.0 (47.2-65.7) years, the study population comprised 325 men (56.7%) and 248 women (43.3%). After a median (interquartile range) follow-up of 6.9 (6.1-11.3) years, the 3-year DFS and 5-year OS rates were 88.2% (95% CI, 83.7%-93.0%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 group, 86.6% (95% CI, 81.8%-91.6%) and 89.7% (95% CI, 85.4%-94.2%) in the FOLFOX4 with bevacizumab group, and 86.7% (95% CI, 81.8%-91.8%) and 93.2% (95% CI, 89.6%-97.0%) in the XELOX with bevacizumab group, respectively. The DFS hazard ratio was 0.94 (95% CI, 0.59-1.48; P = .78) for FOLFOX4 with bevacizumab vs FOLFOX4 and 1.07 (95% CI, 0.69-1.67; P = .76) for XELOX with bevacizumab vs FOLFOX4. The OS hazard ratio was 0.92 (95% CI, 0.55-1.55; P = .76) for FOLFOX4 with bevacizumab vs FOLFOX4 and 0.85 (95% CI, 0.50-1.44; P = .55) for XELOX with bevacizumab vs FOLFOX4. Conclusions and Relevance: In this secondary analysis of data from the AVANT trial, adding bevacizumab to oxaliplatin-based chemotherapy was not associated with longer DFS or OS in patients with high-risk stage II CC. The findings suggest that the definition of high-risk stage II CC needs to be revisited. Trial Registration: ClinicalTrial.gov Identifiers: AVANT (NCT00112918); S-AVANT (NCT02228668).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Capecitabina/uso terapêutico , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/mortalidade , Oxaloacetatos/uso terapêutico , Idoso , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Modelos de Riscos Proporcionais , Resultado do TratamentoRESUMO
BACKGROUND: The phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided. RESULTS: Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.
Assuntos
Adenocarcinoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Transferência Ressonante de Energia de Fluorescência , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/terapia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Teorema de Bayes , Capecitabina/uso terapêutico , Estudos de Coortes , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/terapia , Feminino , Humanos , Análise de Classes Latentes , Masculino , Microscopia/métodos , Pessoa de Meia-Idade , Oxaloacetatos/uso terapêutico , Prognóstico , Multimerização Proteica , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Receptor ErbB-2/análise , Receptor ErbB-3/análise , Análise Serial de Tecidos , Resultado do TratamentoRESUMO
INTRODUCTION: We evaluated the feasibility and efficacy of chemoradiotherapy with concurrent regional arterial chemotherapy (CRT/RAC) for locally bulky unresectable rectal cancer (LBURC). CASE PRESENTATION: We retrospectively reviewed 9 patients with LBURC who received CRT/RAC between January 2012 and December 2018. The regimen consisted of chemoradiotherapy and 3 cycles of regional arterial chemotherapy. Surgery was performed 6 weeks after completion of radiotherapy. The median longest tumor diameter was 10 cm (range 8.2-13.6). Grade 3 toxicity and postoperative complications occurred in 3 and 4 patients, respectively. All patients showed partial response according to the Response Evaluation Criteria in Solid Tumors (RECIST). One patient refused the operation after completion of the scheduled regimen but then had a bowel obstruction and had to undergo urgent surgery. Of the 8 patients who underwent scheduled surgery, all had R0 resection without multivisceral resection; 3 achieved pathological complete response and 5 exhibited good tumor regression. The median follow-up period was 35 months (range 9-63). Recurrences occurred in 3 of 9 patients (pelvic relapses in 2 and lung in 1). CONCLUSION: CRT/RAC appeared to be beneficial to LBURC, as it achieves remarkable rates of R0 resection, good tumor regression, and pathologic complete response. These preliminary results have to be confirmed in larger cohorts of patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Capecitabina/uso terapêutico , Quimiorradioterapia/métodos , Quimioterapia do Câncer por Perfusão Regional/métodos , Oxaloacetatos/uso terapêutico , Neoplasias Retais/terapia , Terapia Combinada , Procedimentos Cirúrgicos do Sistema Digestório , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Retrospectivos , Análise de Sobrevida , Resultado do TratamentoRESUMO
PURPOSE: Recent sequencing studies revealed that a subset of colorectal cancer harbors a significantly higher number of somatic mutations. These hypermutated tumors show distinct clinicopathologic features. However, the prognostic impact of the hypermutated tumors is not clearly established. EXPERIMENTAL DESIGN: We analyzed tumor mutation burden (TMB) from targeted next-generation sequencing data of 40 major genes in 516 patients with colorectal cancer. TMB was defined as total number of nonsynonymous mutations per tumor. Cutoff value for TMB-high was chosen by which best discriminated relapse-free survival (RFS) using the Contal and O'Quigley method. RESULTS: In the TCGA data, mutation count of the selected 40 genes reflected the whole exome mutation burden (Pearson correlation = 0.873, P < 0.001). In our patient cohort, 8 or more mutations in the 40 genes was defined as TMB-high, which best discriminated RFS. A total of 55 patients (10.7%) had TMB-high. TMB-high tumors were more frequently found in a proximal location (63.6%) and had a higher proportion of N0 disease (30.9%) and MSI-H (49.1%) compared with TMB-low. Most importantly, TMB-high was associated with better 5-year RFS compared with TMB-low (96.3% vs. 79.8%, P = 0.005). Although there was significant overlap between TMB-high and MSI-H, MSI-H status was not significantly associated with RFS. Multivariate analysis revealed TMB-high as an independent positive prognostic factor for RFS [adjusted HR, 0.16 (95% confidence interval, 0.04-0.66), P = 0.011]. CONCLUSIONS: TMB-high is associated with better prognosis in patients with colorectal cancer treated with curative surgery followed by adjuvant fluoropyrimidine and oxaliplatin chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Capecitabina/uso terapêutico , Neoplasias Colorretais/genética , Recidiva Local de Neoplasia/epidemiologia , Oxaloacetatos/uso terapêutico , Idoso , Quimioterapia Adjuvante/métodos , Colo/patologia , Colo/cirurgia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/terapia , Análise Mutacional de DNA , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucovorina/uso terapêutico , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Prognóstico , Reto/patologia , Reto/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: Hepatic resection is regarded to as a potentially curative option for colorectal cancer liver metastases (CRLM), but it is associated with a high rate of recurrence. The present study intended to establish an effective nomogram to predict disease free survival (DFS) and select candidates of hepatic resection. METHODS: The nomogram was based on a retrospective study on 447 CRLM patients treated with preoperative chemotherapy followed by hepatic resection using a multicentric database between January 1st, 2010 and December 31st, 2017. Results were validated using bootstrap resampling on 117 patients. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve. Overall survival, disease free survival, and local recurrence rate for patients with colorectal cancer were measured. RESULTS: Based on multivariate analysis of the primary cohort, independent factors for DFS included tumor size larger than 5â¯cm, multiple liver metastases(>1), RAS mutation, primary lymph node metastasis and tumor size increase after preoperative chemotherapy. These five factors were all considered in the nomogram. The C-index of the nomogram for predicting survival was 0.675. With external validation, the C-index of the nomogram for the prediction of the DFS was 0.77, which demonstrated that this model has a good level of discriminative ability. For the 382 patients (66.7%) who developed recurrence, the optimal cutoff point for early recurrence was determined to be 12 months after hepatic resection. CONCLUSIONS: The proposed nomogram demonstrated accurate prognostic prediction of DFS for CRLM patients with preoperative chemotherapy followed by hepatic resection.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma/terapia , Neoplasias Colorretais/patologia , Hepatectomia , Neoplasias Hepáticas/terapia , Metastasectomia , Terapia Neoadjuvante , Nomogramas , Adulto , Idoso , Bevacizumab/administração & dosagem , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Capecitabina/uso terapêutico , Carcinoma/secundário , Cetuximab/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/uso terapêutico , Humanos , Leucovorina/uso terapêutico , Neoplasias Hepáticas/secundário , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/uso terapêutico , Oxaloacetatos/uso terapêutico , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Carga TumoralRESUMO
There are numerous reports dealing with the significantly reduced citrate secretion in (recurrent) tone formers. The critical values of the Ca/citrate ratio in the nocturnal urine of (oxalate) stone formers has also been reported, emphasizing the need of medicaments being capable to increase the citrate secretion and to raise the basal citrate level of the nocturnal urine in these patients. In our in vitro experiments, we tested quantitatively the inhibitory activity of some new substances on crystal growth. In Wistar rats we measured the Ca2+-binding capacity as well as the citrate and oxalate excretion before and after oral application of a great number of new compounds. Some of them were highly efficacious in the reduction of the Ca-oxalate activity product, as can be derived from the increased Ca2+-binding capacity and/or the decreased oxalate secretion in urine.