RESUMEN
BACKGROUND: The development of triplet regimens for advanced gastric cancer is challenging. The aim of this phase I dose-escalation study was to determine the maximum tolerated dose and recommended dose of the combination of irinotecan, cisplatin, and S-1 in chemotherapy-naïve patients with HER2-negative advanced gastric cancer. METHODS: The 3 + 3 design was adopted. Every 4 weeks, patients received an escalating dose of intravenous irinotecan (100-150 mg/m2) on day 1 and fixed doses of intravenous cisplatin (60 mg/m2) on day 1 and oral S-1 (80 mg/m2) on days 1 to 14. RESULTS: Twelve patients were enrolled in two dose level cohorts. In the level 1 cohort (irinotecan 100 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicity including grade 4 neutropenia and febrile neutropenia occurred in one of six patients, whereas in the level 2 cohort (irinotecan 125 mg/m2, cisplatin 60 mg/m2, and S-1 80 mg/m2), dose-limiting toxicities including grade 4 neutropenia developed in two of six patients. Thus, the level 1 and 2 doses were determined to be the recommended and maximum tolerated doses, respectively. Common grade 3 or higher adverse events were neutropenia (75%; n = 9), anemia (25%; n = 3), anorexia (8%; n = 1), and febrile neutropenia (17%; n = 2). Irinotecan, cisplatin, and S-1 combination therapy achieved an overall response rate of 67% with a median progression-free survival and overall survival of 19.3 and 22.4 months, respectively. CONCLUSIONS: The potential treatment efficacy of this triplet regimen in HER2-negative advanced gastric cancer warrants further evaluation, especially in patients requiring intensive chemotherapy.
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Neutropenia Febril , Neoplasias Gástricas , Humanos , Irinotecán/uso terapéutico , Cisplatino , Neoplasias Gástricas/tratamiento farmacológico , Camptotecina , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neutropenia Febril/inducido químicamente , Dosis Máxima ToleradaRESUMEN
Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II-IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49-24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT.
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Neoplasias Colorrectales , Recurrencia Local de Neoplasia , Humanos , Recurrencia Local de Neoplasia/patología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Quimioterapia Adyuvante , Modelos de Riesgos Proporcionales , Japón , Biomarcadores de Tumor/genética , Neoplasia Residual/tratamiento farmacológicoRESUMEN
BACKGROUND: Primary tumor location is considered a predictor of overall survival (OS) in RAS wild-type (WT) metastatic colorectal cancer (mCRC) treated with bevacizumab (BEV) or an anti-epidermal growth factor antibody (cetuximab or panitumumab [CET/PAN]) as first-line molecularly targeted therapy. BEV is recommended for right-sided mCRC and CET/PAN for left-sided mCRC based on post-hoc analyses of clinical trial data, but real-world evidence is lacking. METHODS: We retrospectively collected data of patients who started BEV or CET/PAN plus 5-fluorouracil-based doublet chemotherapy between January 2013 and December 2016 as first-line treatment for RAS WT mCRC at any of 24 Japanese institutions. OS was compared between the BEV and CET/PAN groups according to primary tumor location by Cox multivariate regression analysis in the full cohort and in a propensity score-matched cohort. RESULTS: In total, 935 patients were enrolled. Median OS was 24.6 months with BEV and 20.9 months with CET/PAN in right-sided mCRC (n = 213; adjusted hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06) and 35.7 months and 30.0 months, respectively, in left-sided mCRC (n = 722; adjusted HR 0.92, 95% CI 0.74-1.13). In the propensity score-matched cohort, OS was significantly better in the BEV group than in the CET/PAN group in right-sided mCRC (HR 0.52, 95% CI 0.28-0.96) but was not significantly different in left-sided mCRC (HR 0.78, 95% CI 0.53-1.07). CONCLUSION: Real-world data showed that OS was better with BEV than with CET/PAN in right-sided mCRC. However, there was no significant difference in OS in left-sided mCRC.
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Neoplasias del Colon , Neoplasias Colorrectales , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Cetuximab/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Fluorouracilo , Humanos , Japón , Panitumumab/uso terapéutico , Recto/patología , Estudios RetrospectivosRESUMEN
BACKGROUND: Recently, the JCOG0502 has shown a comparable efficacy of chemoradiotherapy and esophagectomy in patients with clinical T1N0M0 esophageal squamous cell carcinoma. However, few studies have compared the clinical outcomes of these treatments in esophageal squamous cell carcinoma patients (including elderly patients) based on real-world data. METHODS: This retrospective study determined real-world outcomes in patients who underwent chemoradiotherapy or esophagectomy, including those with clinical T1N0M0 esophageal squamous cell carcinoma, between 2009 and 2017 at the National Cancer Center Hospital East. RESULTS: Among a total of 156 patients, 120 and 36 patients underwent esophagectomy and chemoradiotherapy, respectively; 138, 12 and 6 patients had Eastern Cooperative Oncology Group performance status 0, 1, and 2, respectively; and 33 and 123 patients had clinical tumor depth MM-SM1 and SM2-SM3, respectively. In a median follow-up of 72 months, 5-year progression-free survival and overall survival were respectively 77.0% and 81.5% in the esophagectomy group and 74.4% and 82.6% in the chemoradiotherapy group (P = 0.48 and, P = 0.89). Moreover, no treatment-related death was detected in both groups. In elderly patients (75 years or older), 5-year progression-free survival and overall survival were not significantly different between esophagectomy and chemoradiotherapy groups (5-year progression-free survival: 72.3% vs. 81.8%, P = 0.38; 5-year overall survival: 76.9% vs. 81.8%, P = 0.59). CONCLUSIONS: This real-world study confirms the results of a previous clinical trial, and the present findings support chemoradiotherapy as one of the standard treatment options in patients of all ages with clinical T1N0M0 esophageal squamous cell carcinoma.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Anciano , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/cirugía , Quimioradioterapia/métodos , Terapia Combinada , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/tratamiento farmacológico , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía/métodos , Humanos , Estudios Retrospectivos , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: We previously reported preliminary activity of regorafenib plus nivolumab (REGONIVO) or lenvatinib plus pembrolizumab (LENPEM) in advanced gastric cancer (AGC). Meanwhile, several studies demonstrated liver metastases are less responsive to immunotherapy. PATIENTS AND METHODS: Combined efficacy outcomes with a longer follow-up in a phase Ib trial of REGONIVO and a phase II trial of LENPEM were examined in AGC with or without liver metastases (REGONIVO plus LENPEM cohort). We also investigated the efficacy of anti-PD-1 monotherapies (anti-PD-1 monotherapy cohort). A comparison of the immune microenvironment between gastric primary tumors and liver metastases was also conducted by multiplex IHC. RESULTS: In the REGONIVO plus LENPEM cohort, with a median follow-up of 14.0 months, objective response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) were 46%, 7.8 months, and 15.6 months in patients with liver metastases, while 69%, 6.9 months, and 15.5 months in those without. In the anti-PD-1 monotherapy cohort, with a median follow-up of 27.6 months, ORR, mPFS, and mOS were 9%, 1.4 months, and 6.4 months in patients with liver metastases, while 22%, 2.3 months, and 9.0 months in those without. Multiplex IHC revealed liver metastases were associated with an abundance of immune-suppressive cells, such as tumor-associated macrophages and regulatory T cells, with fewer CD8+ T cells compared with gastric primary tumors. CONCLUSIONS: Anti-PD-1 antibodies plus regorafenib or lenvatinib for AGC showed promising antitumor activity with a longer follow-up, irrespective of liver metastases status, despite a more immune-suppressive tumor microenvironment in liver metastases.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas , Neoplasias Gástricas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos como Asunto , Humanos , Inmunoterapia , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/secundario , Nivolumab/uso terapéutico , Supervivencia sin Progresión , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Resultado del Tratamiento , Microambiente TumoralRESUMEN
The balance of programmed death-1 (PD-1)-expressing CD8+ T cells and regulatory T (Treg) cells in the tumor microenvironment (TME) determines the clinical efficacy of PD-1 blockade therapy through the competition of their reactivation. However, factors that determine this balance remain unknown. Here, we show that Treg cells gain higher PD-1 expression than effector T cells in highly glycolytic tumors, including MYC-amplified tumors and liver tumors. Under low-glucose environments via glucose consumption by tumor cells, Treg cells actively absorbed lactic acid (LA) through monocarboxylate transporter 1 (MCT1), promoting NFAT1 translocation into the nucleus, thereby enhancing the expression of PD-1, whereas PD-1 expression by effector T cells was dampened. PD-1 blockade invigorated the PD-1-expressing Treg cells, resulting in treatment failure. We propose that LA in the highly glycolytic TME is an active checkpoint for the function of Treg cells in the TME via upregulation of PD-1 expression.
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Regulación Neoplásica de la Expresión Génica , Ácido Láctico/metabolismo , Receptor de Muerte Celular Programada 1/genética , Linfocitos T Reguladores/metabolismo , Microambiente Tumoral/genética , Animales , Biomarcadores de Tumor , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glucólisis , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Proteínas de Punto de Control Inmunitario/metabolismo , Inmunofenotipificación , Ácido Láctico/farmacología , Activación de Linfocitos , Recuento de Linfocitos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Terapia Molecular Dirigida , Pronóstico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacosRESUMEN
According to the current international guidelines, high-risk patients diagnosed with pathological T1 (pT1) colorectal cancer (CRC) who underwent complete local resection but may have risk of developing lymph node metastasis (LNM) are recommended additional intestinal resection with lymph node dissection. However, around 90% of the patients without LNM are exposed to the risk of being overtreated due to the insufficient pathological criteria for risk stratification of LNM. Circulating tumor DNA (ctDNA) is a noninvasive biomarker for molecular residual disease and relapse detection after treatments including surgical and endoscopic resection of solid tumors. The CIRCULATE-Japan project includes a large-scale patient-screening registry of the GALAXY study to track ctDNA status of patients with stage II to IV or recurrent CRC that can be completely resected. Based on the CIRCULATE-Japan platform, we launched DENEB, a new prospective study, within the GALAXY study for patients with pT1 CRC who underwent complete local resection and were scheduled for additional intestinal resection with lymph node dissection based on the standard pathologic risk stratification criteria for LNM. The aim of this study is to explore the ability of predicting LNM using ctDNA analysis compared with the standard pathological criteria. The ctDNA assay will build new evidence to establish a noninvasive personalized diagnosis in patients, which will facilitate tailored/optimal treatment strategies for CRC patients.
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ADN Tumoral Circulante , Neoplasias Colorrectales , ADN Tumoral Circulante/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Humanos , Biopsia Líquida , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Metástasis Linfática/patología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Estudios Prospectivos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
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Neoplasias , Animales , Ratones , Estudios de Cohortes , Neoplasias/genética , Inmunoterapia/métodos , Linfocitos T , Linfocitos Infiltrantes de TumorRESUMEN
BACKGROUND: Endoscopic resection (ER) is performed for early esophageal squamous cell carcinoma (ESCC) cases. Additional esophagectomy or chemoradiotherapy is recommended for non-curative resection (NCR) even with pathologically negative vertical margins (pVM0); however, their clinical outcomes remain unknown. We examined the long-term clinical outcomes of NCR for ESCCs according to additional treatments. METHODS: We retrospectively analyzed the data of patients who underwent ER for cT1N0M0 ESCC between 2009 and 2017 judged to have NCR, which defined when pathologically diagnosed as invading the submucosa (SM) or muscularis mucosae (MM) involving lymphovascular invasion (LVI), pVM0, and endoscopically judged as negative horizontal margin. Additional esophagectomy (involving three-field lymphadenectomy), chemoradiotherapy [mainly cisplatin and 5-fluorouracil with concurrent radiotherapy (41.4 Gy)], or observation was undertaken. Thereafter, computed tomography was performed every 6-12 months. The cumulative recurrence (CRR) and recurrence-free survival (RFS) rates were evaluated. RESULTS: Eighty-nine patients were included. Among them, 14 had pathologically diagnosed pMM with LVI; 9 and 6, and 32 and 28 patients had pSM1 and pSM2 without and with LVI. Twenty-one patients underwent observation, whereas 18 and 50 underwent esophagectomy and chemoradiotherapy. During the 60.6-month median follow-up period, nine patients had recurrence; among them, six patients had occurrence at > 4 years after ER. The 5-year CRR/RFS rates were 35.7%/48.1%, 13.4%/80.4%, and 0.0%/98.0% in the observation, esophagectomy, and chemoradiotherapy groups, respectively (observation vs. chemoradiotherapy; P < 0.001). CONCLUSIONS: Additional treatments showed better long-term outcomes than observation for patients with NCR. As recurrence may occur at > 4 years after ER, careful long-term follow-up examinations are needed.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Humanos , Membrana Mucosa/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Adjuvant chemotherapy has reduced the risk of tumor recurrence and improved survival in patients with resected colorectal cancer. Potential utility of circulating tumor DNA (ctDNA) prior to and post surgery has been reported across various solid tumors. We initiated a new type of adaptive platform trials to evaluate the clinical benefits of ctDNA analysis and refine precision adjuvant therapy for resectable colorectal cancer, named CIRCULATE-Japan including three clinical trials. The GALAXY study is a prospectively conducted large-scale registry designed to monitor ctDNA for patients with clinical stage II to IV or recurrent colorectal cancer who can undergo complete surgical resection. The VEGA trial is a randomized phase III study designed to test whether postoperative surgery alone is noninferior to the standard therapy with capecitabine plus oxaliplatin for 3 months in patients with high-risk stage II or low-risk stage III colon cancer if ctDNA status is negative at week 4 after curative surgery in the GALAXY study. The ALTAIR trial is a double-blind, phase III study designed to establish the superiority of trifluridine/tipiracil as compared with placebo in patients with resected colorectal cancer who show circulating tumor-positive status in the GALAXY study. Therefore, CIRCULATE-Japan encompasses both "de-escalation" and "escalation" trials for ctDNA-negative and -positive patients, respectively, and helps to answer whether measuring ctDNA postoperatively has prognostic and/or predictive value. Our ctDNA-guided adaptive platform trials will accelerate clinical development toward further precision oncology in the field of adjuvant therapy. Analysis of ctDNA status could be utilized as a predictor of risk stratification for recurrence and to monitor the effectiveness of adjuvant chemotherapy. ctDNA is a promising, noninvasive tumor biomarker that can aid in tumor monitoring throughout disease management.
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ADN Tumoral Circulante/sangre , Neoplasias Colorrectales/sangre , Recurrencia Local de Neoplasia/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Capecitabina/administración & dosificación , Quimioterapia Adyuvante , Neoplasias del Colon/sangre , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/terapia , Método Doble Ciego , Humanos , Japón , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Oxaliplatino/administración & dosificación , Estudios Prospectivos , Pirrolidinas/administración & dosificación , Timina/administración & dosificación , Trifluridina/administración & dosificaciónRESUMEN
BACKGROUND/AIM: Neoadjuvant chemotherapy without radiation (NAC) shows favorable outcomes for locally advanced rectal cancer (LARC), however, the optimal regimen has not been determined yet. This study aimed to compare the efficacy and safety of oxaliplatin, irinotecan, folinic acid, and 5-fluorouracil (mFOLFOXIRI) with capecitabine/S-1 and oxaliplatin (XELOX/SOX) in rectal cancer patients. PATIENTS AND METHODS: We retrospectively examined patients with LARC who received mFOLFOXIRI or XELOX/SOX as NAC. RESULTS: Between January 2015 and July 2019, 49 patients received mFOLFOXIRI and 37 patients received XELOX/SOX. The pathological response rates (over two-thirds affected tumor area) were 36.7% and 40.5% in the mFOLFOXIRI and XELOX/SOX groups, respectively. Grade 3/4 neutropenia was experienced by 45.0% of the patients in the mFOLFOXIRI group and 8.0% in the XEOX/SOX group. CONCLUSION: Although pathological responses were comparable between two groups, mFOLFOXIRI tended to be more toxic compared to XELOX/SOX as NAC for LARC.
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Terapia Neoadyuvante , Neoplasias del Recto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Capecitabina , Quimioterapia Adyuvante , Fluorouracilo/efectos adversos , Humanos , Terapia Neoadyuvante/efectos adversos , Oxaloacetatos , Neoplasias del Recto/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
AIM: Gastric cancer patients are normally treated with oral fluoropyrimidine and cisplatin or oxaliplatin; however, treating patients who also have a gastrointestinal obstruction is often difficult because of their poor oral intake. Instead, a modified (m)FOLFOX-6 regimen is administered, even to patients with gastrointestinal obstructions. The aim of this study was to assess the efficacy of mFOLFOX-6 for gastric cancer patients with a gastrointestinal obstruction. METHODS: Patients with a poor oral intake because of a gastrointestinal obstruction who received mFOLFOX-6 as systemic chemotherapy were retrospectively analyzed. Poor oral intake was defined as receiving a daily intravenous drip infusion due to a gastrointestinal obstruction. RESULTS: Eighteen patients received mFOLFOX-6; the median progression-free survival was 6.8 months (95% confidence interval [CI], 1.9-9.7), the median overall survival was 8.0 months (95% CI, 2.8-20.8) and the median time to treatment failure was 2.2 months (95% CI, 1.2-5.7). An improved oral intake was observed in 13 of the 18 treated patients, with 12 of these continuing treatment as outpatients. CONCLUSIONS: A mFOLFOX-6 treatment regimen seems promising for gastric cancer patients who have a gastrointestinal obstruction.