RESUMO
BACKGROUND: The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer. METHODS: sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes. RESULTS: 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively. CONCLUSIONS: Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica , Combinação de Medicamentos , Oxaliplatina , Ácido Oxônico , Receptor ErbB-2 , Neoplasias Gástricas , Tegafur , Trastuzumab , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/sangue , Feminino , Receptor ErbB-2/sangue , Trastuzumab/uso terapêutico , Trastuzumab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Ácido Oxônico/administração & dosagem , Ácido Oxônico/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Oxaliplatina/uso terapêutico , Oxaliplatina/administração & dosagem , Tegafur/administração & dosagem , Tegafur/uso terapêutico , Adulto , Estudos Prospectivos , Biomarcadores Tumorais/sangue , Intervalo Livre de ProgressãoRESUMO
OBJECTIVES: There are several types of colorectal cancer (CRC) according to the detection methods and intervals, including interval CRC (iCRC) and postcolonoscopy CRC (PCCRC). We aimed to examine their proportions and characteristics. METHODS: We conducted a multicenter prospective study using questionnaires in Japan ("C-DETECT study"), in which differences in CRC characteristics according to detection methods and intervals were examined from consecutive adult patients. Because the annual fecal immunochemical test (FIT) was used in population-based screening, the annual FIT-iCRC was assessed. RESULTS: In total, 1241 CRC patients (1064 with invasive CRC) were included. Annual FIT-iCRC (a), 3-year PCCRC (b), and CRC detected within 1 year after a positive FIT with noncompliance to colonoscopy (c) accounted for 4.5%, 7.0%, and 3.9% of all CRCs, respectively, and for 3.9%, 5.4%, and 4.3% of invasive CRCs, respectively. The comparison among these (a, b, c) and other CRCs (d) demonstrated differences in the proportions of ≥T2 invasion ([a] 58.9%, [b] 44.8%, [c] 87.5%, [d] 73.0%), metastasis ([a] 33.9%, [b] 21.8%, [c] 54.2%, [d] 43.9%), right-sided CRC ([a] 42.9%, [b] 40.2%, [c] 18.8%, [d] 28.6%), and female sex ([a] 53.6%, [b] 49.4%, [c] 27.1%, [d] 41.6%). In metastatic CRC, (a) and (b) showed a higher proportions of BRAF mutations ([a] [b] 12.0%, [c] [d] 3.1%). CONCLUSIONS: Annual FIT-iCRC and 3-year PCCRC existed in nonnegligible proportions. They were characterized by higher proportions of right-sided tumors, female sex, and BRAF mutations. These findings suggest that annual FIT-iCRC and 3-year PCCRC may have biological features different from those of other CRCs.
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BACKGROUND: Chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel is the standard perioperative treatment for resectable esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma (EGJ-AC) in Western countries. Meanwhile, preoperative chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there are few reports on the safety and efficacy of preoperative DCF for resectable EGJ-AC in the Japanese population. METHODS: Patients with histologically confirmed resectable EGJ-AC who received preoperative DCF (docetaxel 70 mg/m2 and cisplatin 70 mg/m2 on day 1 and continuous infusion of 5-fluorouracil 750 mg/m2/day on days 1-5 every 3 weeks with a maximum of three cycles) between January 2015 and April 2020 were retrospectively evaluated. We assessed the rates of completion of ≥ 2 courses of DCF and R0 resection, histopathological response, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Thirty-two patients were included. Median follow-up was 28.7 (range, 5.2-70.8) months and median age was 63 (range, 42-80) years. Twenty-one patients (66%) had a performance status of 0. The proportions of clinical stage IIA/IIB/III/IVA/IVB disease were 3%/0%/44%/44%/9%, respectively. The treatment completion rate was 84%. A histopathological response of grade 1a/1b/2/3 was obtained in 58%/26%/13%/3% of cases. Median PFS was 40.7 months (95% confidence interval 11.8-NA). Median OS was not reached (80.8% at 3 years). Grade ≥ 3 adverse events were observed in 63% of cases (neutropenia, 44%; febrile neutropenia, 13%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative DCF for resectable EGJ-AC was well tolerated and has promising efficacy.
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Adenocarcinoma , Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Docetaxel , Neoplasias Esofágicas , Junção Esofagogástrica , Fluoruracila , Humanos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Masculino , Junção Esofagogástrica/patologia , Pessoa de Meia-Idade , Idoso , Fluoruracila/administração & dosagem , Fluoruracila/uso terapêutico , Feminino , Docetaxel/administração & dosagem , Docetaxel/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Estudos Retrospectivos , Adulto , Idoso de 80 Anos ou mais , Japão/epidemiologia , Esofagectomia/métodos , Resultado do Tratamento , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia , Terapia Neoadjuvante/métodosRESUMO
Immunotherapy, especially immune checkpoint inhibitors, has revolutionized the standard-of-care of multiple types of tumors. For colorectal cancer, the clinical development of immune checkpoint inhibitors is mainly separated according to the status of microsatellite instability or mismatch repair in a tumor. High-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer generally has a tumor microenvironment with infiltration of T cells, associated with a favorable response to immune checkpoint inhibitors. Immune checkpoint inhibitors, including pembrolizumab (anti-PD-1 inhibitor) and nivolumab (anti-PD-1 inhibitor) with or without ipilimumab (anti-CTLA-4 inhibitor), have been integrated into the standard-of-care for high-level microsatellite instability/deficient mismatch repair metastatic colorectal cancer. Conversely, limited T-cell infiltration in the tumor microenvironment of microsatellite stable/proficient mismatch repair metastatic colorectal cancer, which constitutes the majority of metastatic colorectal cancer, is assumed to be a major resistant mechanism to immune checkpoint inhibitors. Currently, clinical trials to improve the clinical activity of immune checkpoint inhibitors by immunomodulation are ongoing for metastatic colorectal cancer. Furthermore, immune checkpoint inhibitors are under development in neoadjuvant and/or adjuvant setting. Here, we review the existing clinical data with ongoing trials and discuss the future perspectives with a focus on the immunotherapy of colorectal cancer.
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Neoplasias Colorretais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA , Humanos , Instabilidade de Microssatélites , Microambiente TumoralRESUMO
Background Ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard second-line chemotherapy for advanced gastric cancer (AGC). The subset analysis of the ABSOLUTE trial, which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis. We retrospectively evaluated the efficacy and safety of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC. Methods AGC patients who received RAM plus sb-PTX or nab-PTX as second-line chemotherapy from June 2015 to February 2019 were included in the study. Overall survival (OS), progression-free survival (PFS), response rate, and safety were assessed. Results A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group). PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95%CI 0.58-1.41, p = 0.643). OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95%CI 0.56-1.62, p = 0.847). A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively. RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 vs 3.5 months, HR 0.66; 95% CI 0.40-1.10, p = 0.109). Conclusion This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.
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Albuminas/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Albuminas/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/secundário , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Análise de Sobrevida , Resultado do Tratamento , RamucirumabRESUMO
PURPOSE: Gastrointestinal cancer is frequently associated with malignant ascites, resulting in poor prognosis. While cell-free and concentrated ascites reinfusion therapy (CART) improves ascites-related symptoms, its clinical impact in combination with systemic chemotherapy is unclear. The purpose of this study was to evaluate the safety and efficacy of CART in gastrointestinal cancer patients with massive ascites treated with chemotherapy. METHODS: We retrospectively reviewed the medical records of gastrointestinal cancer patients with massive ascites who received CART and chemotherapy at our hospital between July 2015 and September 2017. RESULTS: A total of 30 patients received CART and chemotherapy: gastric cancer (n = 21) and colorectal cancer (n = 9). The initial CART improved performance status in 20% of the patients, and the mean serum albumin and creatinine was significantly improved. Median time to treatment failure and overall survival of chemotherapy following CART were 2.1 and 3.5 months in gastric cancer patients and 5.8 and 5.8 months in colorectal cancer patients, respectively. The frequency of paracentesis was decreased after introduction of CART followed by chemotherapy in 83% of gastric cancer and in all colorectal cancer patients who had received paracentesis before the initial CART. There were no grade 3/4 adverse events during the CART procedure. Grade 3/4 hematotoxic and non-hematotoxic adverse events of chemotherapy following CART were 30% and less than 10%, respectively. CONCLUSIONS: The combination of CART followed by chemotherapy is safe and could be a treatment option for gastrointestinal cancer patients with massive ascites.
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Ascite/patologia , Líquido Ascítico/química , Remoção de Componentes Sanguíneos/métodos , Neoplasias Colorretais/terapia , Neoplasias Peritoneais/terapia , Neoplasias Gástricas/terapia , Adulto , Idoso , Líquido Ascítico/patologia , Creatinina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paracentese/métodos , Estudos Retrospectivos , Albumina Sérica/análiseRESUMO
BACKGROUND: Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). METHODS: The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). RESULTS: The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). CONCLUSIONS: The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Neoplasias Gástricas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , RamucirumabRESUMO
Neuroendocrine tumors (NET) are rare tumors for which somatostatin analogs (SSA) are used not only for symptom control due to a functioning tumor, but also for the disease control of unresectable NET. The efficacy of SSA for midgut NET has been verified by previous studies, but insufficient evidence exists for SSA treatment of NET in the foregut and hindgut (F/H-NET). The aim of this retrospective study was to evaluate the efficacy of SSA for unresectable F/H-NET. Patients with unresectable F/H-NET treated with SSA between February 2011 and August 2017 at our hospital were retrospectively reviewed. Parameters of efficacy were progression-free survival (PFS), overall survival, objective response rate (ORR), and adverse events. Twelve cases with unresectable F/H-NET were extracted from our database. With a median follow-up time of 25.9 months, the median PFS was 13.6 months. Two- and 3-year survival rates were 87.5 and 62.5%, respectively. The ORR was 8.3%, and the disease control rate was 75%. Serious adverse events were not observed. Subgroup analysis, including G1/G2, and hepatic tumor load, which is the volume of NET liver metastases, did not reveal a difference in PFS. The efficacy and safety of SSA for F/H-NET seemed similar to that found in the PROMID study, highlighting its relevance for the treatment of this disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Gastrointestinais/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Tumores Neuroendócrinos/mortalidade , Idoso , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Feminino , Seguimentos , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/patologia , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Masculino , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Octreotida/administração & dosagem , Peptídeos Cíclicos/administração & dosagem , Prognóstico , Estudos Retrospectivos , Somatostatina/administração & dosagem , Somatostatina/análogos & derivados , Taxa de SobrevidaRESUMO
BACKGROUND: Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with clinical benefit in patients with melanoma or lung cancer. In advanced gastric cancer (AGC) patients, there have been few reports about the correlation between irAEs and efficacy of immune checkpoint inhibitors. In this study, we retrospectively investigated the correlation between irAEs and efficacy in AGC patients treated with nivolumab. METHODS: The subjects of this study were AGC patients received nivolumab monotherapy between January 2015 and August 2018. IrAEs were defined as those AEs having a potential immunological basis that required close follow-up, or immunosuppressive therapy and/or endocrine therapy. We divided the patients who received nivolumab into two groups based on occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group). We assessed the efficacy in both groups. RESULTS: Of the 65 AGC patients that received nivolumab monotherapy, 14 developed irAEs. The median time to onset of irAEs was 30.5 days (range 3-407 days). Median follow-up period for survivors was 32 months (95% CI, 10.8 to 34.5). The median progression-free survival was 7.5 months (95% CI, 3.6 to 11.5) in the irAE group and 1.4 months (95% CI, 1.2 to 1.6) in the non-irAE group (HR = 0.11, p < 0.001). The median overall survival was 16.8 months (95% CI, 4.4 to not reached) in the irAE group and 3.2 months (95% CI, 2.2 to 4.1) in the non-irAE group (HR = 0.17, p < 0.001). Multivariate analysis demonstrated that number of metastatic sites ≥2 (HR = 2.15; 95% CI, 1.02 to 4.54), high ALP level (HR = 2.50; 95% CI, 1.27 to 4.54), and absence of irAEs (HR = 9.54, 95% CI, 3.34 to 27.30 for yes vs. no) were associated with a poor prognosis. The most frequent irAEs was diarrhea/colitis (n = 5). Grade 3 adverse events were observed in 6 patients; hyperglycemia (n = 2), diarrhea/colitis (n = 1), adrenal insufficiency (n = 1), aspartate aminotransferase increased (n = 1), peripheral motor neuropathy (n = 1). There were no grade 4 or 5 adverse events related to nivolumab. CONCLUSIONS: Development of irAEs was associated with clinical benefit for AGC patients receiving nivolumab monotherapy.
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Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Imunoterapia/efeitos adversos , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Insuficiência Adrenal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/farmacologia , Diarreia/etiologia , Feminino , Seguimentos , Humanos , Hiperglicemia/etiologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/farmacologia , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Taxa de SobrevidaRESUMO
Systemic treatment of advanced esophageal squamous cell carcinoma (ESCC) mainly consists of cytotoxic agents, aiming to palliate symptoms and prolong survival. Cisplatin and 5-fluorouracil have been considered standard treatment for several decades. Efforts to develop more effective treatment have led to clinical trials testing triplet, irinotecan-based, oxaliplatin-based and paclitaxel-based regimens. Molecular-targeting agents, mainly anti-EGFR inhibitors including gefitinib, panitumumab and nimotuzumab, have been investigated; however, no molecular-targeting agents demonstrate the clinical utility in Phase 3 trials so far. Negative results from Phase 3 trials testing gefitinib and panitumumab suggest the importance of identifying predictive biomarkers of responses to molecular-targeting agents. On the basis of results from Phase 3 trials testing PD-1 inhibitors, nivolumab and pembrolizumab, are anticipated to be the standard treatment for patients with ESCC. Dual immune checkpoint inhibition and immunotherapy in combination with cytotoxic agents are under study. Recent advances in next-generation sequencing technologies provide comprehensive catalogues of genetic alterations in ESCC which may lead to therapeutic breakthroughs in a personalized manner. Here, we review the existing clinical data and discuss future perspectives with a focus on the systemic treatment of advanced ESCC.
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Carcinoma de Células Escamosas do Esôfago/terapia , Imunoterapia , Terapia de Alvo Molecular , Ensaios Clínicos como Assunto , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/patologia , Humanos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: A combination of S-1 and cisplatin is recognized as one of the standard first-line chemotherapy regimens for patients with advanced gastric cancer. However, demographic analyses of pivotal phase III studies have showed that only a minority of treated patients were aged 76 years or older. The purpose of this phase II study was to evaluate the safety and efficacy of combination therapy with S-1 and cisplatin in elderly patients with chemotherapy-naive advanced gastric cancer. METHODS: Patients aged 76 years or older received S-1 40 mg/m2 orally twice daily for 21 days and cisplatin 60 mg/m2 intravenously infused at day 8 of each 35-day cycle. Dose modification was performed according to creatinine clearance. The primary endpoint was overall survival (OS). Secondary endpoints included response rate, progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 40 patients were enrolled. Median OS was 12.3 months, PFS was 7.8 months, and TTF was 4.3 months. The response rate was 54%. The most common grade 3-4 adverse events were anorexia (25%), neutropenia (23%), hyponatremia (20%), anemia (18%), and febrile neutropenia (8%). No treatment-related death occurred. CONCLUSIONS: Combination chemotherapy with S-1 and cisplatin is an effective and well-tolerated regimen for elderly patients with advanced gastric cancer when the dose is adjusted according to renal function.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/mortalidade , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Ácido Oxônico/administração & dosagem , Ácido Oxônico/efeitos adversos , Neoplasias Gástricas/mortalidade , Tegafur/administração & dosagem , Tegafur/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world clinical setting. METHODS: This single-institutional retrospective study included patients with advanced gastric or esophagogastric junction adenocarcinoma and a history of first-line chemotherapy with platinum-based doublet or triplet regimens between 2010 and 2020. To assess the impact of nivolumab on survival, the patients were divided based on the year of nivolumab approval into a pre-2017 (2010-2016) group and a post-2017 (2017-2020) group. RESULTS: From a total of 1918 patients, 1093 were excluded. There were 533 patients in the pre-2017 group and 292 in the post-2017 group. Immune checkpoint inhibitors were used significantly more often in the post-2017 group than in the pre-2017 group (8.6% vs. 47.9%). Median overall survival was significantly longer in the post-2017 group (16.9 vs. 13.9 months; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.63-0.90; p < 0.01). The proportion of patients transitioning to third-line treatment was higher in the post-2017 group than in the pre-2017 group (56.3% vs. 43.8%, p < 0.01). Median survival outcomes following progression on second-line treatment were significantly longer in the post-2017 group (4.3 vs. 3.2 months; HR 0.70, 95% CI 0.57-0.86; p < 0.01). CONCLUSION: The proportion of patients transitioning to third-line treatment and survival outcomes following progression on second-line treatment have improved since the approval of nivolumab. This drug might help to prolong overall survival in real-world practice.
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Inibidores de Checkpoint Imunológico , Nivolumabe , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Idoso , Japão , Estudos Retrospectivos , Pessoa de Meia-Idade , Nivolumabe/uso terapêutico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/mortalidade , Idoso de 80 Anos ou mais , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/patologia , Resultado do TratamentoRESUMO
Peritoneal tumor dissemination and subsequent malignant tumor ascites (MTA) occur unexpectedly and repeatedly in patients with gastrointestinal (GI) cancers, and worsen quality of life and prognosis of the patients. Various treatments have been clinically developed for these patients, while most of the MTA cases are refractory to the treatments. Thus, effective treatments are urgently needed to improve the clinical outcomes. In this study, we identified α-synuclein (SNCA) as an immunological determinant of MTA progression in GI cancer through translational research using mouse tumor models and clinical specimens collected from gastric cancer patients. We found that the SNCA+ subsets were significantly increased in CD3+ T cells, CD56+ NK cells, and CD11b+ myeloid cells within MTA and peripheral blood cells (PBCs) of MTA cases, albeit almost absent in PBCs of healthy donors, and spleen of naive mice. Of note, the SNCA+ T-cell subset was rarely seen in patients that intraperitoneal lavage fluid without tumor cells was collected before surgery as a tumor-free control, suggesting a possible cancer-induced product, especially within the peritoneal cavity. In vivo treatment with anti-SNCA blocking mAb significantly induced anti-tumor effects in mouse MTA models, and synergistically improved anti-PD1 therapeutic efficacy, providing a significantly better prognosis. These suggest that SNCA is involved in severe immunosuppression in the MTA cases, and that blocking SNCA is effective in dramatically improving the immune status in the hosts. Targeting SNCA will be a promising strategy to improve clinical outcomes in the treatment of GI cancer patients, especially with MTA.
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Targeting immune inhibitory checkpoint (IC) pathways have attracted great attention as a promising strategy for treating gastrointestinal (GI) cancer. However, the therapeutic efficacy is low in most cases, and little progress has been made in establishing biomarkers that predict the possible responses, and combination regimens that enhance the therapeutic efficacy. As a predictive biomarker, soluble forms of IC molecules have been recently highlighted. However, little is known about which IC molecules is most critically associated with the treatment resistance, and also about the biological and immunological roles of the IC molecules in GI cancer. In this study, we analyzed sera obtained from advanced gastric cancer patients before and one month after treatment with anti-PD1 nivolumab for soluble IC molecules by ELISA. We found that decrease of soluble CTLA4 (sCTLA4) at posttreatment were significantly associated with a better prognosis, and combination with low level of CRP at posttreatment more clearly defined anti-PD1 responders with long-term survival. Indeed, in the in vitro setting, CRP stimulation upregulated CTLA4 expression in tumor cells followed by generation of sCTLA4 that suppressed CTL induction, and simultaneously conferred high self-renewal and invasive abilities on the tumor cells accompanied by increase of EMT-related gene expressions. In the in vivo setting, CRP injection elevated sCTLA4 level in sera of mouse tumor metastasis models, leading to failure of anti-PD1 therapy. However, treatment with anti-CTLA4 mAb or a PPARγ agonist that can reduce in vivo CRP successfully elicited anti-tumor efficacy in the anti-PD1 resistant models. These suggest that targeting CRP and sCTLA4 may be a promising strategy for improving clinical outcomes in the treatments, including anti-PD1 therapy, of GI cancer.
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This report describes a case of BRAF V600E-mutated colorectal cancer with CNS metastases in which treatment with encorafenib, binimetinib and cetuximab was effective. There is limited information on the ability of encorafenib, binimetinib and cetuximab to enter the CNS.The patient was a 53-year-old man was diagnosed with ascending colon cancer (cT3N3M1c stage IVc). BRAF V600E mutation was confirmed. FOLFOX was started, but CNS metastases soon appeared. Encorafenib, binimetinib and cetuximab were administered and had a favorable effect on the CNS lesions. The patient initially responded well, but his disease progressed 2 months later. Further research is needed to improve management strategies for BRAF V600E-mutated colorectal cancer with CNS metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzimidazóis , Carbamatos , Cetuximab , Neoplasias Colorretais , Mutação , Proteínas Proto-Oncogênicas B-raf , Sulfonamidas , Humanos , Cetuximab/uso terapêutico , Cetuximab/administração & dosagem , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Carbamatos/uso terapêutico , Sulfonamidas/uso terapêutico , Benzimidazóis/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/secundário , Neoplasias do Sistema Nervoso Central/patologiaRESUMO
BACKGROUND/AIM: Definitive chemoradiotherapy with cisplatin (CDDP) plus 5-fluorouracil is the standard treatment for locally advanced esophageal squamous cell carcinoma (LA-ESCC); however, CDDP is unsuitable for patients with cardiac and/or renal dysfunction. Based on the results of the PRODIGE5/ACCORD17 trial, 5-fluorouracil and leucovorin with oxaliplatin plus radiotherapy (FOLFOX-RT) has been recognized as a treatment option. However, the efficacy and safety of FOLFOX-RT is still unclear in Japan. PATIENTS AND METHODS: Medical records were reviewed for patients with LA-ESCC who received FOLFOX-RT between April 2019 and July 2021 at our institution. We evaluated complete response rate, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Fifteen patients were analyzed and median age was 72.5 years (range=51-83 years). All patients completed three courses of FOLFOX and the planned radiotherapy. The complete response rate was 40.0%. With a median follow-up of 10.6 months, the 6-month PFS rate was 63.0% (95%CI=32.3-82.8%), and the 6-month OS rate was 85.7% (95%CI=53.9-96.2%). Common adverse events were esophagitis (80.0%), leukopenia (53.3%), fatigue (53.3%), and neutropenia (46.7%). Only one patient had grade 4 esophageal perforation. CONCLUSION: FOLFOX-RT for LA-ESCC was well tolerated and could be a treatment option for CDDP-intolerant patients.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Humanos , Idoso , Cisplatino , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Estudos Retrospectivos , Fluoruracila/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
PURPOSE: To investigate circulating tumor DNA (ctDNA) RAS mutant (MT) incidence before salvage-line treatment and the clinicopathological features and molecular biological factors associated with the efficacy of anti-epithelial growth factor receptor (EGFR) monoclonal antibody (mAb) rechallenge for tissue RAS/BRAF wild type (WT) metastatic colorectal cancer (mCRC). METHODS: This multi-institutional retrospective observational study included 74 patients with mCRC with tissue RAS/BRAF WT refractory to first-line chemotherapy containing anti-EGFR mAb. ctDNA RAS status was assessed using the OncoBEAM™ RAS CRC Kit. We explored the clinicopathological features associated with ctDNA RAS status and the factors related to anti-EGFR mAb rechallenge efficacy in multivariate Cox proportional hazard regression. RESULTS: The incidence of RAS MT in ctDNA was 40.5% (30/74), which was associated with primary tumor resection (P = 0.016), liver metastasis (P < 0.001), and high tumor marker levels (P < 0.001). Among the 39 patients treated with anti-EGFR mAb rechallenge, those with ctDNA RAS WT showed significantly longer progression-free survival (PFS) than those with ctDNA RAS MT (median 4.1 vs. 2.7 months, hazard ratio [HR] = 0.39, P = 0.045). Patients who responded to first-line anti-EGFR mAb showed significantly longer PFS (HR = 0.21, P = 0.0026) and overall survival (OS) (HR = 0.23, P = 0.026) than those with stable disease. CONCLUSIONS: The incidence of ctDNA RAS MT mCRC was 40.5%, which was associated with liver metastases and high tumor volumes. Anti-EGFR mAb rechallenge may be effective for patients with mCRC who responded to first-line chemotherapy containing anti-EGFR mAb. No patients with RAS MT in ctDNA responded to anti-EGFR mAb rechallenge.
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Neoplasias Colorretais , Receptores ErbB , Proteínas Proto-Oncogênicas B-raf , Humanos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/genética , Masculino , Feminino , Proteínas Proto-Oncogênicas B-raf/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Adulto , Idoso de 80 Anos ou mais , Mutação , DNA Tumoral Circulante/genética , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagemRESUMO
Although phase III randomized controlled trials (RCTs) represent the most robust statistical approach for answering clinical questions, they require massive expenditures in terms of time, labor, and funding. Ancillary and supplementary analyses using RCTs are sometimes conducted as alternative approaches to answering clinical questions, but the available integrated databases of RCTs are limited. In this background, the Colorectal Cancer Study Group (CCSG) of the Japan Clinical Oncology Group (JCOG) established a database of ancillary studies integrating four phase III RCTs (JCOG0212, JCOG0404, JCOG0910 and JCOG1006) conducted by the CCSG to investigate specific clinicopathological factors in pStage II/III colorectal cancer (JCOG2310A). This database will be updated by adding another clinical trial data and accelerating several analyses that are clinically relevant in the management of localized colorectal cancer. This study describes the details of this database and planned and ongoing analyses as an initiative of JCOG cOlorectal Young investigators (JOY).
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Ensaios Clínicos Fase III como Assunto , Neoplasias Colorretais , Bases de Dados Factuais , Humanos , Neoplasias Colorretais/terapia , Neoplasias Colorretais/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Japão , Estadiamento de NeoplasiasRESUMO
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
BACKGROUND: Radical surgery is the standard treatment for rectal cancer, but can impact quality of life. Recently, the concept of total neoadjuvant therapy with a watch-and-wait strategy has been proposed in which patients with a cCR after total neoadjuvant therapy do not proceed to surgery. However, most investigations of a watch-and-wait strategy have reported cases where cCR was achieved coincidentally via total neoadjuvant therapy. The aim is to assess whether total neoadjuvant therapy is effective in early-stage rectal cancer in patients that achieve cCR and are offered a watch-and-wait strategy. METHODS: JCOG2010 (TOWARd) is a multi-institutional, single-arm phase II/III confirmatory investigation of the safety and efficacy of total neoadjuvant therapy followed by a watch-and-wait strategy for rectal cancer. Key eligibility criteria include cT2-3 N0 M0 rectal adenocarcinoma, tumour diameter less than or equal to 5â cm, age 18-75 years, performance status 0-1, and no history of pelvic irradiation or rectal surgery. Total neoadjuvant therapy involves neoadjuvant chemoradiotherapy (capecitabine and radiotherapy: 45â Gy/25 fractions to the whole pelvis plus boost of 5.4â Gy/3 fractions to the primary tumour) followed by consolidation chemotherapy (four cycles of capecitabine/oxaliplatin). Patients will be re-staged every 8 weeks after total neoadjuvant therapy, and those who achieve cCR will undergo a watch-and-wait strategy, those with near complete response will undergo a watch-and-wait strategy or local resection, and those with an incomplete response will undergo radical surgery. The primary endpoint is the cCR rate in phase II and 5-year overall survival in phase III. Secondary endpoints include postoperative anal, urinary, and sexual function. A total of 105 patients (phase II, 40 patients; phase III, 65 patients) will be enrolled over 3.5 years. CONCLUSION: This trial will determine whether total neoadjuvant therapy and a watch-and-wait strategy is an effective alternative to radical surgery for early-stage rectal cancer in patients with cT2-3 N0 M0 and tumour size less than or equal to 5â cm. REGISTRATION NUMBER: jRCTs031220288 (https://jrct.niph.go.jp/en-latest-detail/jRCTs031220288).