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OBJECTIVE: To evaluate the efficacy and safety of tislelizumab added to chemotherapy as first line (primary) treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma compared with placebo plus chemotherapy. DESIGN: Randomised, double blind, placebo controlled, phase 3 study. SETTING: 146 medical centres across Asia, Europe, and North America, between 13 December 2018 and 28 February 2023. PARTICIPANTS: 1657 patients aged ≥18 years with human epidermal growth factor receptor 2 negative locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma, regardless of programmed death-ligand 1 (PD-L1) expression status, who had not received systemic anticancer therapy for advanced disease. INTERVENTIONS: Patients were randomly (1:1) assigned to receive either tislelizumab 200 mg or placebo intravenously every three weeks in combination with chemotherapy (investigator's choice of oxaliplatin and capecitabine, or cisplatin and 5-fluorouracil) and stratified by region, PD-L1 expression, presence or absence of peritoneal metastases, and investigator's choice of chemotherapy. Treatment continued until disease progression or unacceptable toxicity. MAIN OUTCOME MEASURES: The primary endpoint was overall survival, both in patients with a PD-L1 tumour area positivity (TAP) score of ≥5% and in all randomised patients. Safety was assessed in all those who received at least one dose of study treatment. RESULTS: Of 1657 patients screened between 13 December 2018 and 9 February 2021, 660 were ineligible due to not meeting the eligibility criteria, withdrawal of consent, adverse events, or other reasons. Overall, 997 were randomly assigned to receive tislelizumab plus chemotherapy (n=501) or placebo plus chemotherapy (n=496). Tislelizumab plus chemotherapy showed statistically significant improvements in overall survival versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5% (median 17.2 months v 12.6 months; hazard ratio 0.74 (95% confidence interval 0.59 to 0.94); P=0.006 (interim analysis)) and in all randomised patients (median 15.0 months v 12.9 months; hazard ratio 0.80 (0.70 to 0.92); P=0.001 (final analysis)). Grade 3 or worse treatment related adverse events were observed in 54% (268/498) of patients in the tislelizumab plus chemotherapy arm versus 50% (246/494) in the placebo plus chemotherapy arm. CONCLUSIONS: Tislelizumab added to chemotherapy as primary treatment for advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma provided superior overall survival with a manageable safety profile versus placebo plus chemotherapy in patients with a PD-L1 TAP score of ≥5%, and in all randomised patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03777657.
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Adenocarcinoma , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Esofágicas , Junção Esofagogástrica , Neoplasias Gástricas , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Masculino , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/mortalidade , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/mortalidade , Junção Esofagogástrica/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Adulto , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Capecitabina/administração & dosagem , Capecitabina/uso terapêutico , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêuticoRESUMO
Introduction: Intratumoral administration of pexa-vec (pexastimogene devacirepvec), an oncolytic and immunotherapeutic vaccinia virus, given to patients with hepatocellular carcinoma (HCC), is associated with both local and distant tumor responses. We hypothesized subsequent treatment with sorafenib could demonstrate superior efficacy. Methods: This random phase III open-label study evaluated the sequential treatment with pexa-vec followed by sorafenib compared to sorafenib in patients with advanced HCC and no prior systemic treatment. The primary endpoint is overall survival (OS). Key secondary endpoints included time to progression (TTP), progression-free survival, overall response rate (ORR), and disease control rate (DCR). Safety was assessed in all patients who received ≥1 dose of study treatment. Results: The study was conducted at 142 sites in 16 countries. From December 30, 2015, to the interim analysis on August 2, 2019, 459 patients were randomly assigned (pexa-vec plus sorafenib: 234, sorafenib: 225). At the interim analysis, the median OS was 12.7 months (95% CI: 9.89, 14.95) in the pexa-vec plus sorafenib arm and 14.0 months (95% CI: 11.01, 18.00) in the sorafenib arm. This led to the early termination of the study. The median TTP was 2.0 months (95% CI: 1.77, 2.96) and 4.2 months (95% CI: 2.92, 4.63); ORR was 19.2% (45 patients) and 20.9% (47 patients); and DCR was 50.0% (117 patients) and 57.3% (129 patients) in the pexa-vec plus sorafenib and sorafenib arms, respectively. Serious adverse events were reported in 117 (53.7%) patients in the pexa-vec plus sorafenib and 77 (35.5%) patients in the sorafenib arm. Liver failure was the most frequently reported in both groups. Conclusion: Sequential pexa-vec plus sorafenib treatment did not demonstrate increased clinical benefit in advanced HCC and fared worse compared to sorafenib alone. The advent of the added value of checkpoint inhibitors should direct any further development of oncolytic virus therapy strategies.
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BACKGROUND AND AIM: The REgistry of Selective Internal radiation therapy in AsiaNs (RESIN) was a multicenter, single-arm, prospective, observational study of 90Y resin microspheres in patients with hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) from Taiwan. RESIN is the first real-life clinical study of this therapy in an Asian cohort. Study objectives were to evaluate the safety and efficacy of 90Y resin microspheres. METHODS: Adults with HCC or mCRC scheduled to receive SIRT with 90Y resin microspheres were included. Primary endpoints were best overall response rate (ORR), adverse events, and changes from baseline in liver function. Secondary efficacy endpoints included overall survival (OS). RESULTS: Of 107 enrolled patients, 83 had HCC, and 24 had mCRC. ORR was 55.41% (HCC) and 33.33% (mCRC). Of 58 HCC patients with 6-month post-SIRT data, 13.79% (n = 8) had resection, transplantation, transarterial chemoembolization, or radiofrequency ablation as the result of down-staging or down-sizing of their lesions. One hundred and ten treatment emergent adverse events (TEAEs) were reported in 51 patients, and five serious adverse events (SAEs) were reported in five patients. The most frequent TEAEs were abdominal pain, nausea and decreased appetite (HCC), and abdominal pain, decreased appetite, fatigue, and vomiting (mCRC). Two deaths due to SAEs (probably related to SIRT) were reported, both in patients with extensive HCC, active hepatitis infection, and other comorbidities. Median OS was 24.07 (HCC) and 12.66 (mCRC) months. CONCLUSIONS: Safety and efficacy outcomes with the routine use of SIRT with 90Y resin microspheres in Taiwan are consistent with published data.
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Carcinoma Hepatocelular , Neoplasias Colorretais , Neoplasias Hepáticas , Microesferas , Sistema de Registros , Radioisótopos de Ítrio , Humanos , Neoplasias Hepáticas/radioterapia , Radioisótopos de Ítrio/efeitos adversos , Radioisótopos de Ítrio/administração & dosagem , Radioisótopos de Ítrio/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Carcinoma Hepatocelular/radioterapia , Idoso , Neoplasias Colorretais/radioterapia , Resultado do Tratamento , Taiwan , Estudos Prospectivos , Adulto , Braquiterapia/métodos , Braquiterapia/efeitos adversos , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Automatic segmentation of hepatocellular carcinoma (HCC) on computed tomography (CT) scans is in urgent need to assist diagnosis and radiomics analysis. The aim of this study is to develop a deep learning based network to detect HCC from dynamic CT images. METHODS: Dynamic CT images of 595 patients with HCC were used. Tumors in dynamic CT images were labeled by radiologists. Patients were randomly divided into training, validation and test sets in a ratio of 5:2:3, respectively. We developed a hierarchical fusion strategy of deep learning networks (HFS-Net). Global dice, sensitivity, precision and F1-score were used to measure performance of the HFS-Net model. RESULTS: The 2D DenseU-Net using dynamic CT images was more effective for segmenting small tumors, whereas the 2D U-Net using portal venous phase images was more effective for segmenting large tumors. The HFS-Net model performed better, compared with the single-strategy deep learning models in segmenting small and large tumors. In the test set, the HFS-Net model achieved good performance in identifying HCC on dynamic CT images with global dice of 82.8%. The overall sensitivity, precision and F1-score were 84.3%, 75.5% and 79.6% per slice, respectively, and 92.2%, 93.2% and 92.7% per patient, respectively. The sensitivity in tumors < 2 cm, 2-3, 3-5 cm and > 5 cm were 72.7%, 92.9%, 94.2% and 100% per patient, respectively. CONCLUSIONS: The HFS-Net model achieved good performance in the detection and segmentation of HCC from dynamic CT images, which may support radiologic diagnosis and facilitate automatic radiomics analysis.
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Carcinoma Hepatocelular , Aprendizado Profundo , Neoplasias Hepáticas , Humanos , Processamento de Imagem Assistida por Computador , Veia Porta , Tomografia Computadorizada por Raios XRESUMO
Introduction: Outcomes of transarterial chemoembolization (TACE) for intermediate-stage hepatocellular carcinoma (HCC) are diverse because of the heterogeneity of tumor burden. Radiologic pattern is one criterion for determining whether TACE is unsuitable. However, additional evidence is required. This study determined the influence of radiologic morphology on the outcomes of initial and subsequent TACE. Methods: From January 2007 to September 2021, 633 treatment-naive patients with HCC with intermediate-stage HCC undergoing TACE were retrospectively enrolled. Of these patients, 386 patients received repeated TACE. The radiological features of HCC were evaluated by two radiologists and classified into encapsulated nodular type, simple nodular type with extranodular growth, confluent multinodular type, and infiltrative type. The objective response rate (ORR) and survival rate after initial and subsequent TACE among various radiologic morphologies were compared. Results: After initial TACE, encapsulated nodular type HCC had the highest ORR (58%), followed by extranodular type (45.8%), confluent multinodular type (29%), and infiltrative type (19.5%). Notably, radiologic pattern was highly associated with tumor burden. Tumor burden and radiologic morphology were significantly associated with ORR and overall survival (OS) in the multivariate analysis. In 386 patients with subsequent TACE, encapsulated nodular type HCC had the highest ORR (48.7%), followed by extranodular type (37.3%), confluent multinodular type (26.2%), and infiltrative type (10%). In the multivariate analysis, radiologic features were significant independent predictors of ORR and OS after receiving subsequent TACE. Conclusion: Radiologic patterns determine the outcomes of initial and subsequent TACE. Systemic therapy should be considered for patients with intermediate-stage HCC with unfavorable radiologic patterns.
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BACKGROUND: Despite the utilization of immune checkpoint inhibitors (ICIs) in treating numerous types of cancers being approved, their efficacy in tumor control in the clinic is not satisfactory. Since adoptive cell therapy (ACT) can alter the tumor microenvironment, we hypothesized that ACT potentially synergized with ICI in tumor control and examined this hypothesis via a murine allograft model. METHODS: Female C57BL/6 mice were stimulated with interleukin 15 and granulocyte monocyte-colony stimulating factor, followed by collecting their bone marrow cells for murine NKDC cultivation. Then, female C57BL/6 mice, inoculated with lymphoma cancer cell line E.G7-OVA, were administrated with murine NKDC cells, murine anti-program cell death ligand-1 antibody (α-mPD-L1), or both for 28 days. After 28 days of treatment, mice were sacrificed whose inoculated tumors, spleen, sentinel lymph nodes, and peripheral blood were collected to measure tumor size, lymphocyte infiltration, and change of immune cell profile. RESULTS: Combined treatment of NKDCs with α-mPD-L1 exhibited significantly stronger tumor control efficacy than treatment of NKDCs or α-mPD-L1 alone. NKDCs/α-mPD-L1 combination increased migration of dendritic cells, CD4, CD8 T cells, and activated CD8 T cells to the tumor-bedding site, and promoted endogenous tumor-specific cytotoxic T-cell response. CONCLUSION: The current study confirmed our hypothesis that combining NKDC ACT with ICI therapy can potentiate tumor control efficacy by manipulating the tumor microenvironment. This study provided a novel circumstance on tumor immunotherapy.
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Antígeno B7-H1 , Neoplasias , Feminino , Camundongos , Animais , Antígeno B7-H1/metabolismo , Camundongos Endogâmicos C57BL , Células Matadoras Naturais , Células Dendríticas , Aloenxertos/metabolismo , Microambiente Tumoral , Linhagem Celular TumoralRESUMO
BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.
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Piridinas , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/patologia , Método Duplo-CegoRESUMO
Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7-48.8) months for pembrolizumab and 39.8 (31.7-47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4-22.5%) for pembrolizumab and 11.7% (6.8-17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3-13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0-23.4%) for pembrolizumab and 4.4% (1.6-9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.
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BACKGROUND: Gastrectomy remains the curative option in gastric cancer. However, the growing concern that preoperative waiting jeopardizes survival has not been fully addressed. The present population-based cohort study aimed to clarify the impact of preoperative waiting time (PreWT). METHODS: We included patients with clinical Stage II-III gastric cancer who received curative surgery from 2008 to 2017 of Taiwan Cancer Registry. PreWT was defined as the time from endoscopic diagnosis to surgery. The prognostic impact on overall survival (OS) was evaluated with Cox and restricted cubic spline regressions. RESULTS: A total of 3059 patients with a median age of 68 years were evaluated. The median PreWT was 16 days (interquartile range, 11-24 days), and patients with a shorter PreWT were younger, had a more advanced disease and received adjuvant therapies. Despite a shorter OS occurring with prolonged PreWT (median OS by PreWT [days]: 7-13, 2.7 years; 14-20, 3.1 years; 21-27, 3.0 years; 28-34, 4.7 years; 35-31, 3.7 years; 42-48, 3.4 years; 49-118, 2.8 years; p = 0.029), the differences were not significant after adjustment. The Cox and restricted cubic spline regressions showed that prolonged PreWT was not a significant prognostic factor for OS (p = 0.719). CONCLUSIONS: The population-based study suggests that a PreWT of 49-118 days does not independently correlate with a poor prognosis in Stage II-III gastric cancer. The study provides rationale for a window period for preoperative therapies and patient optimization.
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Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Idoso , Neoplasias Gástricas/patologia , Estudos de Coortes , Listas de Espera , Prognóstico , Junção Esofagogástrica/cirurgia , Junção Esofagogástrica/patologia , Gastrectomia , Neoplasias Esofágicas/patologia , Estudos Retrospectivos , Estadiamento de NeoplasiasRESUMO
BACKGROUND: Colorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM. METHODS: A total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non-anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal. RESULTS: Patients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis. CONCLUSIONS: Anti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.
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Neoplasias Encefálicas , Neoplasias Colorretais , Humanos , Estudos Retrospectivos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Intervalo Livre de Progressão , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundárioRESUMO
PURPOSE: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents. METHODS: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284). RESULTS: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response. CONCLUSIONS: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.
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Adenocarcinoma , DNA Tumoral Circulante , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Receptor ErbB-2/genética , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Gastric adenosquamous carcinoma (GASC) is a rare subtype of gastric cancer. Research on GASC treatment is limited, and its outcome is usually poor. We investigated the clinical features, immunoprofile of GASC, and determined the optimal treatment modality for these patients. METHODS: Patients with GASC from Taipei Veterans General Hospital were retrospectively reviewed. Clinical features and treatment outcomes were evaluated. Adequate samples were examined for surrogate biomarkers for immunotherapy by IHC staining. RESULTS: Total 14 (0.35%) GASC patients were found among 4034 gastric cancer patients. The median tumor size was 6.8 cm in 10 patients with stage III GASC, and all these patients underwent radical gastrectomy followed by adjuvant therapy. The median progression-free survival (PFS) and overall survival (OS) were 6.0 and 11.5 months, respectively. Two patients with stage IV GASC received frontline immunotherapy. Their median PFS and OS were 9.0 and 12.5 months. In immunoprofiling, 25.0% (n = 3), 75.0% (n = 9), and 33.3% (n = 4) of the samples had deficient mismatch repair (dMMR) protein, combined positive score (CPS) of ≥1, and CPS of ≥10, respectively. The univariate analysis revealed that programmed death-ligand 1 ≥5% (HR: 0.12; 95% CI: 0.01-0.97; p = 0.047) was significant associated with superior OS. One stage IV patient with CPS ≥10 and dMMR proteins received nivolumab monotherapy as frontline treatment that resulted 14-month PFS. CONCLUSION: Patients with GASC are more likely to yield positive results for CPS and dMMR. Biomarkers should be examined, and immunotherapy can be considered as frontline systemic treatment.
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Carcinoma Adenoescamoso , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patologia , Carcinoma Adenoescamoso/terapia , Estudos Retrospectivos , Resultado do Tratamento , Terapia CombinadaRESUMO
Immunotherapy in combination with chemotherapy is the current treatment of choice for frontline programmed cell death ligand 1 (PD-L1)-positive gastric cancer. However, the best treatment strategy remains an unmet medical need for elderly or fragile patients with gastric cancer. Previous studies have revealed that PD-L1 expression, Epstein-Barr virus association, and microsatellite instability-high (MSI-H) are the potential predictive biomarkers for immunotherapy use in gastric cancer. In this study, we showed that PD-L1 expression, tumor mutation burden, and the proportion of MSI-H were significantly elevated in elderly patients with gastric cancer who were older than 70 years compared with patients younger than 70 years from analysis of The Cancer Genome Atlas gastric adenocarcinoma cohort [≥70/<70: MSI-H: 26.8%/15.0%, P =0.003; tumor mutation burden: 6.7/5.1 Mut/Mb, P =0.0004; PD-L1 mRNA: 5.6/3.9 counts per million mapped reads, P =0.005]. In our real-world study, 416 gastric cancer patients were analyzed and showed similar results (≥70/<70: MSI-H: 12.5%/6.6%, P =0.041; combined positive score ≥1: 38.1%/21.5%, P <0.001). We also evaluated 16 elderly patients with gastric cancer treated with immunotherapy and revealed an objective response of 43.8%, a median overall survival of 14.8 months, and a median progression-free survival of 7.0 months. Our research showed that a durable clinical response could be expected when treating elderly patients with gastric cancer with immunotherapy, and this approach is worth further study.
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Infecções por Vírus Epstein-Barr , Neoplasias Gástricas , Humanos , Idoso , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Herpesvirus Humano 4 , Neoplasias Gástricas/genética , Neoplasias Gástricas/terapia , Instabilidade de Microssatélites , Biomarcadores Tumorais/genéticaRESUMO
Compared to stage I-III gastric cancer (GC), the level of cell-free DNA (cfDNA) was significantly higher in stage IV GC. The mutation patterns of different metastatic patterns between cfDNA and tumor DNA in stage IV GC have not yet been reported. We used next-generation sequencing (NGS) to analyze cfDNA and tumor DNA in 56 stage IV GC patients. Tumor DNA and cfDNA were analyzed using a 29-gene NGS panel. In tumor samples, the most commonly mutated gene was TP53 (64%), followed by ARID1A (62%), KMT2C (60%) and KMT2D (58%). In cfDNA samples, the most commonly mutated genes were FAT4 (19%) and MACF1 (19%), followed by KMT2D (18%), ARID1A (14%) and LRP1B (14%). The concordance of mutation patterns in these 29 genes was 42.0% between cfDNA and tumor DNA. A specificity of 100% was found when using the mutation status of cfDNA to predict mutations in tumor samples. The sensitivity of the mutation status of cfDNA to predict mutation in tumor samples was highest in FAT4 (88.9%), followed by MACF1 (80%), CDH1 (75%) and PLB1 (75%). For cfDNA with PLB1 mutations, patients were more likely to develop distant lymphatic metastasis than peritoneal metastasis. Patients with multiple-site metastases had significantly more mutated spots than patients with single-site metastasis. Due to the high sensitivity and specificity of some genes in the prediction of mutation in tumor samples, monitoring the mutation pattern of cfDNA may be useful in the stage IV GC treatment.
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Ácidos Nucleicos Livres , Neoplasias Gástricas , Humanos , Ácidos Nucleicos Livres/genética , Neoplasias Gástricas/genética , DNA de Neoplasias/genética , Mutação , Sequenciamento de Nucleotídeos em Larga Escala , Biomarcadores Tumorais/genéticaRESUMO
OBJECTIVE: First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia. METHODS: Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary). RESULTS: A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively. CONCLUSIONS: This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Padrão de Cuidado , Neoplasias Gástricas , Humanos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asiático , Cisplatino/uso terapêutico , Junção Esofagogástrica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologiaRESUMO
BACKGROUND: The prognosis of unfavorable cancer of unknown primary is extremely poor. This is the first report to compared the treatment results between generations of CUP and examined prognostic factors. METHODS: This retrospective single-center cohort study enrolled 68 patients with newly diagnosed unfavorable cancer of unknown primary at Taipei Veteran General Hospital from 2017 to 2020 as study cohort and 167 patients from 2000 to 2009 as historical cohort. RESULTS: The median overall survival was 4.3 months in the study cohort (95% CI, 2.7-6.2 months) and 4.5 months in the historical cohort (95% CI, 3.0-5.5 months; p = 0.858). Eleven patients in the study cohort received immunotherapy. The disease control rates were 45%. Multivariate analysis showed that an Eastern Cooperative Oncology Group score > 1 and a C-reactive protein level > 1 correlated with poor survival. A new prognostic stratification model was constructed by using Eastern Cooperative Oncology Group score and C-reactive protein values. The good-, intermediate-, and poor-risk groups had distinct median overall survival of 18.3, 7.0 and 1.2 months, respectively (area under the curve, 0.817; p < 0.001). CONCLUSION: The outcome of unfavorable cancer of unknown primary has not changed much over the last 20 years. The application of a new prognostic stratification model can further stratify unfavorable cancer of unknown primary.
Assuntos
Neoplasias Primárias Desconhecidas , Humanos , Estudos de Coortes , Neoplasias Primárias Desconhecidas/terapia , Estudos Retrospectivos , Proteína C-Reativa , PrognósticoRESUMO
BACKGROUND: To evaluate the clinical relative biological effectiveness (RBE) of carbon-ion radiotherapy (C-ion RT) for prostate cancer. METHODS: The records of 262 patients with low-risk prostate cancer (median age, 65 [47-80] years) treated with C-ion RT at QST Hospital, National Institutes for Quantum Science and Technology in Japan during 2000-2018 were reviewed retrospectively. Four different protocol outcomes and prostate-specific antigen (PSA) responses were evaluated. The median follow-up was 8.4 years. The Kaplan-Meier method was used to estimate the biochemical or clinical failure-free rate (BCFFR). Clinical RBE was calculated using the tumor control probability model. RESULTS: The 5-, 7-, and 10-year BCFFRs were 91.7%, 83.8%, and 73.2%, respectively. The 10-year BCFFRs of patients who received C-ion RT at 66 Gy (RBE) in 20 fractions, 63 Gy (RBE) in 20 fractions, and 57.6 Gy (RBE) in 16 fractions were 81.4%, 70.9%, and 68.9%, respectively. The PSA level and density during follow-up were better in the patients treated with the lower fraction size. A higher PSA nadir and shorter time to PSA nadir were risk factors for biochemical or clinical failure by multivariate Cox regression. The tumor control probability analysis showed that the estimated clinical RBE values to achieve an 80% BCFFR at 10 years for 20, 16, and 12 fractions were 2.19 (2.18-2.24), 2.16 (2.14-2.23), and 2.12 (2.09-2.21), respectively. CONCLUSIONS: Using clinical data from low-risk prostate cancer patients, we showed the clinical RBE of C-ion RT decreased with increasing dose per fraction.
Assuntos
Antígeno Prostático Específico , Neoplasias da Próstata , Masculino , Humanos , Idoso , Estudos Retrospectivos , Eficiência Biológica Relativa , Neoplasias da Próstata/radioterapia , Neoplasias da Próstata/patologia , CarbonoRESUMO
BACKGROUND: To date, few reports have investigated the genetic alterations and clinicopathological features among gastric cancer (GC) patients with no tumor recurrence, early recurrence, and late recurrence following curative surgery. METHODS: A total of 473 GC patients undergoing curative surgery were included. The clinicopathological characteristics, patient prognosis, recurrence patterns, and genetic alterations were compared between GC patients with early recurrence and late recurrence. RESULTS: Among the 473 GC patients, 119 had early recurrence (<2 years) and 45 had late recurrence (≥2 years). Patients with early recurrence had tumor size larger than 5 cm, fewer superficial-type tumors, more lymphovascular invasion, more advanced pathological T and N categories and Tumor, Node, Metastasis (TNM) stages, and worse 5-year overall survival than patients with late recurrence and no recurrence. For intestinal-type GC, patients with no tumor recurrence had more Helicobacter pylori infection than patients with early recurrence and late recurrence; for diffuse-type GC patients, the frequency of PIK3CA amplification was the highest in early recurrence, followed by late recurrence and no recurrence. GC patients with single-site recurrence had more ARID1A mutations than those with multiple-site recurrence. Multivariate analysis demonstrated that age, tumor recurrence, and pathological N categories were independent prognostic factors. CONCLUSION: PIK3CA amplifications were more common in diffuse-type GC with early recurrence, whereas ARID1A mutations were more common in patients with single-site recurrence. Targeted therapy and immunotherapy might be helpful for these patients.