RESUMEN
BACKGROUND: Mismatch repair-deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited. METHODS: We conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses. RESULTS: Of 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease. CONCLUSIONS: In patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.).
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Antineoplásicos Inmunológicos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias del Colon , Reparación de la Incompatibilidad de ADN , Ipilimumab , Terapia Neoadyuvante , Nivolumab , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/genética , Neoplasias del Colon/patología , Neoplasias del Colon/cirugía , Supervivencia sin Enfermedad , Ipilimumab/administración & dosificación , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Nivolumab/administración & dosificación , Nivolumab/efectos adversos , Nivolumab/uso terapéutico , Tiempo de Tratamiento , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Países Bajos , Adulto JovenRESUMEN
BACKGROUND: No adjuvant treatment has been established for patients who remain at high risk for recurrence after neoadjuvant chemoradiotherapy and surgery for esophageal or gastroesophageal junction cancer. METHODS: We conducted CheckMate 577, a global, randomized, double-blind, placebo-controlled phase 3 trial to evaluate a checkpoint inhibitor as adjuvant therapy in patients with esophageal or gastroesophageal junction cancer. Adults with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy and had residual pathological disease were randomly assigned in a 2:1 ratio to receive nivolumab (at a dose of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at a dose of 480 mg every 4 weeks) or matching placebo. The maximum duration of the trial intervention period was 1 year. The primary end point was disease-free survival. RESULTS: The median follow-up was 24.4 months. Among the 532 patients who received nivolumab, the median disease-free survival was 22.4 months (95% confidence interval [CI], 16.6 to 34.0), as compared with 11.0 months (95% CI, 8.3 to 14.3) among the 262 patients who received placebo (hazard ratio for disease recurrence or death, 0.69; 96.4% CI, 0.56 to 0.86; P<0.001). Disease-free survival favored nivolumab across multiple prespecified subgroups. Grade 3 or 4 adverse events that were considered by the investigators to be related to the active drug or placebo occurred in 71 of 532 patients (13%) in the nivolumab group and 15 of 260 patients (6%) in the placebo group. The trial regimen was discontinued because of adverse events related to the active drug or placebo in 9% of the patients in the nivolumab group and 3% of those in the placebo group. CONCLUSIONS: Among patients with resected esophageal or gastroesophageal junction cancer who had received neoadjuvant chemoradiotherapy, disease-free survival was significantly longer among those who received nivolumab adjuvant therapy than among those who received placebo. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 577 ClinicalTrials.gov number, NCT02743494.).
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Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias Esofágicas/terapia , Unión Esofagogástrica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Nivolumab/uso terapéutico , Adenocarcinoma/inmunología , Adenocarcinoma/cirugía , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Quimioradioterapia Adyuvante , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Método Doble Ciego , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/cirugía , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Análisis de Intención de Tratar , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Nivolumab/efectos adversos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/terapiaRESUMEN
INTRODUCTION: This study investigates the incidence of extrahepatic perfusion and incomplete hepatic perfusion at intraoperative methylene blue testing and on postoperative nuclear imaging in patients undergoing hepatic arterial infusion pump (HAIP) chemotherapy. METHODS: The first 150 consecutive patients who underwent pump implantation in the Netherlands were included. All patients underwent surgical pump implantation with the catheter in the gastroduodenal artery. All patients underwent intraoperative methylene blue testing and postoperative nuclear imaging (99mTc-Macroaggregated albumin SPECT/CT) to determine perfusion via the pump. RESULTS: Patients were included between January-2018 and December-2021 across eight centers. During methylene blue testing, 29.3% had extrahepatic perfusion, all successfully managed intraoperatively. On nuclear imaging, no clinically relevant extrahepatic perfusion was detected (0%, 95%CI: 0.0-2.5%). During methylene blue testing, 2.0% had unresolved incomplete hepatic perfusion. On postoperative nuclear imaging, 8.1% had incomplete hepatic perfusion, leading to embolization in only 1.3%. CONCLUSION: Methylene blue testing during pump placement for intra-arterial chemotherapy identified extrahepatic perfusion in 29.3% of patients, but could be resolved intraoperatively in all patients. Postoperative nuclear imaging found no clinically relevant extrahepatic perfusion and led to embolization in only 1.3% of patients. The role of routine nuclear imaging after HAIP implantation should be studied in a larger cohort.
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Arteria Hepática , Infusiones Intraarteriales , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Antineoplásicos/administración & dosificación , Arteria Hepática/diagnóstico por imagen , Incidencia , Bombas de Infusión Implantables , Circulación Hepática , Neoplasias Hepáticas/cirugía , Azul de Metileno/administración & dosificación , Países Bajos/epidemiología , Estudios Retrospectivos , Tomografía Computarizada por Tomografía Computarizada de Emisión de Fotón Único , Agregado de Albúmina Marcado con Tecnecio Tc 99m/administración & dosificaciónRESUMEN
BACKGROUND AND AIMS: In gastric cancer (GC), HER2 was the first biomarker for guided therapy registered for clinical use. Considering the recent approvals of immune check-point blockade (ICB) in gastro-oesophageal cancers, testing for mismatch repair deficiency (dMMR), Epstein-Barr virus (EBV) and PD-L1 combined positive score (CPS) is becoming increasingly important. Here we describe a real-world cohort on biomarker assessment in GC patients. METHODS: Patients diagnosed with GC between 2017 and 2021 were included. Biomarker results were retrieved from electronic patient files. PD-L1 CPS was determined retrospectively on dMMR and EBV-positive (EBV+) tumours. Data on genomic sequencing were analysed separately. RESULTS: Of 363 patients identified, 45% had metastatic disease. In 335 patients (92%) at least one biomarker was tested. The prevalence of HER2+, dMMR and EBV+ tumours was 10% (32 of 319), 7% (20 of 294) and 1% (three of 235), respectively. Of the dMMR and EBV+ tumours, 95% had a PD-L1 CPS ≥ 5. Therapeutic strategy was adjusted in 31 of 55 patients and consisted of anti-HER2 therapies as well as ICB in clinical trials. Genomic alterations were found in 44 of 60 tested patients. TP53 (73%) and PIK3CA (20%) mutations were most common, followed by KRAS mutations (11%) and amplifications (11%). CONCLUSIONS: In this real-world cohort, testing for HER2, dMMR and EBV status affected treatment decisions in 56% of the patients. Although most dMMR and EBV+ tumours had a PD-L1 CPS ≥ 5, not all patients with a high probability of treatment response are identified. Based on these results, a stepwise diagnostic strategy is proposed.
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Infecciones por Virus de Epstein-Barr , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/genética , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Antígeno B7-H1/genéticaRESUMEN
PURPOSE: Respiratory-induced motion of oesophageal tumours and lymph nodes can influence positron-emission tomography/computed tomography (PET/CT). The aim was to compare standard three-dimensional (3D) and motion-compensated PET/CT regarding standardized uptake value (SUV), metabolic tumour volume (MTV) and detection of lymph node metastases. METHODS: This prospective observational study (NCT02424864) included 37 newly diagnosed oesophageal cancer patients. Diagnostic PET/CT was reconstructed in 3D and motion-compensated PET/CT. MTVs of the primary tumour were calculated using an automated region-growing algorithm with SUV thresholds of 2.5 (MTV2.5) and ≥â¯50% of SUVmax (MTV50%). Blinded for reconstruction method, a nuclear medicine physician assessed all lymph nodes showing 18Ffluorodeoxyglucose uptake for their degree of suspicion. RESULTS: The mean (95% CI) SUVmax of the primary tumour was 13.1 (10.6-15.5) versus 13.0 (10.4-15.6) for 3D and motion-compensated PET/CT, respectively. MTVs were also similar between the two techniques. Bland-Altman analysis showed mean differences between both measurements (95% limits of agreement) of 0.08 (-3.60-3.75), -0.26 (-2.34-1.82), 4.66 (-29.61-38.92) cm3 and -0.95 (-19.9-18.0) cm3 for tumour SUVmax, lymph node SUVmax, MTV2.5 and MTV50%, respectively. Lymph nodes were classified as highly suspicious (30/34 nodes), suspicious (20/22) and dubious (66/59) for metastases on 3D/motion-compensated PET/CT. No additional lymph node metastases were found on motion-compensated PET/CT. SUVmax of the most intense lymph nodes was similar for both scans: mean (95% CI) 6.6 (4.3-8.8) and 6.8 (4.5-9.1) for 3D and motion-compensated, respectively. CONCLUSION: SUVmax of the primary oesophageal tumour and lymph nodes was comparable on 3D and motion-compensated PET/CT. The use of motion-compensated PET/CT did not improve lymph node detection.
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Neoplasias Esofágicas , Fluorodesoxiglucosa F18 , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Humanos , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Metástasis Linfática/diagnóstico por imagen , Metástasis Linfática/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/métodos , RadiofármacosRESUMEN
INTRODUCTION: The PERISCOPE I (Treatment of PERItoneal dissemination in Stomach Cancer patients with cytOreductive surgery and hyPErthermic intraperitoneal chemotherapy) study was conducted to investigate the safety and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) in gastric cancer patients with limited peritoneal dissemination. In this study, tumor characteristics and clinical outcome of the patients treated in the PERISCOPE I trial were investigated. METHODS: Patients who had undergone the full study protocol were selected; that is, preoperative systemic chemotherapy, followed by a surgical procedure consisting of a (sub)total gastrectomy, cytoreductive surgery, and HIPEC with oxaliplatin (460 mg/m2 ) and docetaxel (in escalating doses). RESULTS: Twenty-five PERISCOPE I patients underwent the full study protocol. Most patients had an ypT3-4 tumor (96%) and the diffuse-type histology was predominant (64%). Seven patients (28%) had a microscopically irradical (R1) resection. In all patients, a complete cytoreduction was achieved. Median follow-up was 37 (95% confidence interval [CI]: 34-39) months. Disease recurrence was detected in 17 patients (68%). Median disease-free and overall survival were 12 and 15 months, respectively. CONCLUSION: In this series of gastric cancer patients with limited peritoneal dissemination who underwent HIPEC surgery, unfavorable tumor characteristics were common. Survival might be encouraging but disease recurrence was frequent. The efficacy of an HIPEC procedure in improving prognosis is currently being investigated in the PERISCOPE II trial.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Procedimientos Quirúrgicos de Citorreducción/mortalidad , Hipertermia Inducida/mortalidad , Quimioterapia Intraperitoneal Hipertérmica/mortalidad , Neoplasias Peritoneales/secundario , Neoplasias Gástricas/patología , Adulto , Anciano , Terapia Combinada , Docetaxel/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/administración & dosificación , Neoplasias Peritoneales/terapia , Pronóstico , Neoplasias Gástricas/terapia , Tasa de SupervivenciaRESUMEN
INTRODUCTION: The peritoneum is a predilection site for gastric cancer metastases. Current standard treatment for gastric cancer patients with synchronous peritoneal metastases is palliative systemic therapy. However, its efficacy is largely unknown. The aim of this study was to investigate the incidence, treatment and survival patterns of gastric cancer patients with synchronous peritoneal metastases in the Netherlands. METHODS: All newly diagnosed gastric adenocarcinoma patients with synchronous peritoneal metastases between 1999 and 2017 were selected from the Netherlands Cancer Registry (NCR). Incidence, treatment and survival patterns were analyzed. RESULTS: In total, 3,773 patients were identified from the NCR. The incidence of synchronous peritoneal metastases in gastric cancer patients increased from 18% in 2008 to 27% in 2017. The use of systemic therapy increased from 15% in 1999-2002 to 43% in 2013-2017 (p < 0.001). The median survival of the entire cohort did not significantly increase over time. Median survival of patients treated with systemic therapy increased from 7.4 months in 1999-2002 to 9.4 months in 2013-2017 (p = 0.005). In contrast, median survival of patients not treated with systemic therapy decreased from 3.3 months in 1999-2002 to 2.1 months in 2013-2017 (p < 0.001). Some clinical and pathological data such as the extent of the peritoneal metastases were not available. CONCLUSION: Synchronous peritoneal metastases are increasingly diagnosed in gastric cancer patients. In recent years, more patients were treated with systemic treatment and survival of these patients increased. However, as survival of the entire group did not improve over time, the effect of systemic therapy remains unknown.
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Adenocarcinoma/mortalidad , Neoplasias Peritoneales/mortalidad , Neoplasias Gástricas/mortalidad , Adenocarcinoma/secundario , Anciano , Femenino , Humanos , Incidencia , Masculino , Países Bajos/epidemiología , Cuidados Paliativos/métodos , Neoplasias Peritoneales/secundario , Neoplasias Peritoneales/terapia , Peritoneo/patología , Sistema de Registros , Estudios Retrospectivos , Neoplasias Gástricas/patología , Neoplasias Gástricas/terapia , Tasa de SupervivenciaRESUMEN
BACKGROUND: This pilot trial explores the feasibility of measuring muscle contractile properties in patients with cancer, effects of exercise during chemotherapy on muscle contractile properties and the association between changes in contractile muscle properties and perceived fatigue. METHOD: Patients who received (neo)adjuvant chemotherapy for breast or colon cancer were randomized to a 9-12 week exercise intervention or a waitlist-control group. At baseline and follow-up, we measured knee extensor strength using maximal voluntary contraction (MVC), contractile muscle properties of the quadriceps muscle using electrical stimulation, and perceived fatigue using the Multidimensional Fatigue Inventory. Feasibility was assessed by the proportion of patients who successfully completed measurements of contractile muscle properties. Exercise effects on muscle contractile properties were explored using linear regression analyses. Between-group differences >10% were considered potentially relevant. Pearson correlation (rp ) of changes in contractile muscle properties and changes in perceived fatigue was calculated. RESULTS: Twenty two of 30 patients completed baseline and follow-up assessments. Measurements of contractile properties were feasible except for muscle fatigability. We found a potentially relevant between-group difference in the rate of force development favoring the intervention group (1192 N/s, 95% CI = -335; 2739). Change in rate of force development was negatively correlated with change in perceived general (rp = -0.54, P = .04) and physical (rp = -0.59, P = .02) fatigue. CONCLUSION: Chemotherapy induces a decrease in the rate of force development, which may reflect a larger loss in type II muscle fibers. This may be attenuated with (resistance) exercise. The increase in the rate of force development was related to a decrease in perceived fatigue.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Ejercicio Físico/fisiología , Contracción Muscular/fisiología , Músculo Cuádriceps/fisiopatología , Neoplasias de la Mama/fisiopatología , Quimioterapia Adyuvante , Neoplasias del Colon/fisiopatología , Estudios de Factibilidad , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Contracción Muscular/efectos de los fármacos , Fatiga Muscular/fisiología , Terapia Neoadyuvante , Países Bajos , Proyectos Piloto , Músculo Cuádriceps/efectos de los fármacos , Listas de EsperaRESUMEN
BACKGROUND: The 10-year overall survival with adjuvant hepatic arterial infusion pump (HAIP) chemotherapy after resection of colorectal liver metastases (CRLMs) was 61% in clinical trials from Memorial Sloan Kettering Cancer Center. A pilot study was performed to evaluate the safety and feasibility of adjuvant HAIP chemotherapy in patients with resectable CRLMs. STUDY DESIGN: A phase II study was performed in two centers in The Netherlands. Patients with resectable CRLM without extrahepatic disease were eligible. All patients underwent complete resection and/or ablation of CRLMs and pump implantation. Safety was determined by the 90-day HAIP-related postoperative complications from the day of pump placement (Clavien-Dindo classification, grade III or higher) and feasibility by the successful administration of the first cycle of HAIP chemotherapy. RESULTS: A total of 20 patients, with a median age of 57 years (interquartile range [IQR] 51-64) were included. Grade III or higher HAIP-related postoperative complications were found in two patients (10%), both of whom had a reoperation (without laparotomy) to replace a pump with a slow flow rate or to reposition a flipped pump. No arterial bleeding, arterial dissection, arterial thrombosis, extrahepatic perfusion, pump pocket hematoma, or pump pocket infections were found within 90 days after surgery. After a median of 43 days (IQR 29-52) following surgery, all patients received the first dose of HAIP chemotherapy, which was completed uneventfully in all patients. CONCLUSION: Pump implantation is safe, and administration of HAIP chemotherapy is feasible, in patients with resectable CRLMs, after training of a dedicated multidisciplinary team.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/mortalidad , Neoplasias Colorrectales/tratamiento farmacológico , Hepatectomía/mortalidad , Arteria Hepática , Bombas de Infusión Implantables , Neoplasias Hepáticas/tratamiento farmacológico , Adulto , Anciano , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Terapia Combinada , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Infusiones Intraarteriales , Neoplasias Hepáticas/secundario , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Países Bajos , Proyectos Piloto , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: For esophageal cancer patients treated with neoadjuvant chemoradiotherapy (nCRT), restaging using F18-fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET-CT) following nCRT can detect interval metastases, including liver metastases, in almost 10% of patients. However, in clinical practice, focal FDG liver uptake, unrelated to liver metastases, is observed after chemoradiotherapy. This radiation-induced liver injury (RILI) can potentially lead to overstaging. METHODS: A systematic search for potential cases of RILI after (chemo)radiotherapy for esophageal cancer was performed in the electronic reports from all PET-CT scans made between 2006 and 2015 in our hospital. Additional data about potential cases were obtained from the electronic medical records. A literature review of RILI was also performed. RESULTS: Of 205 patients undergoing nCRT, 6 cases with localized increased FDG uptake in the caudate or left liver lobe following nCRT for esophageal cancer were identified. None of these patients had signs of liver metastases with additional imaging, during surgery, on biopsy, or during follow-up (range 11-46 months). At our institute, the incidence of RILI after neoadjuvant chemoradiotherapy for esophageal cancer was 3%. In the literature, RILI is described in about 8% of patients at the time of restaging. FDG-avid lesions occur in the high radiation dose area, usually corresponding to the caudate or left liver lobe. CONCLUSIONS: FDG accumulation in the caudate or left liver lobe after CRT in the area that received a high radiation dose may be caused by metastases or RILI. Awareness of the pitfall of high FDG uptake in RILI is crucial to avoid misinterpretation and overstaging.
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Fluorodesoxiglucosa F18 , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Hígado/diagnóstico por imagen , Hígado/efectos de la radiación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Traumatismos por Radiación/diagnóstico por imagen , Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/patología , Adenocarcinoma/terapia , Adulto , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Quimioradioterapia Adyuvante , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/terapia , Reacciones Falso Positivas , Femenino , Humanos , Hígado/patología , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Estudios RetrospectivosRESUMEN
BACKGROUND: The assessment of colorectal liver metastases (CRLM) after treatment with chemotherapy is challenging due to morphological and/or functional change without changes in size. The aim of this review was to assess the value of FDG-PET, FDG-PET-CT, CT and MRI in predicting response to chemotherapy in CRLM. METHODS: A systematic review was undertaken based on PRISMA statement. PubMed and Embase were searched up to October 2016 for studies on the accuracy of PET, PET-CT, CT and MRI in predicting RECIST or metabolic response to chemotherapy and/or survival in patients with CRLM. Articles evaluating the assessment of response after chemotherapy were excluded. RESULTS: Sixteen studies met the inclusion criteria and were included for further analysis. Study results were available for 6 studies for FDG-PET(-CT), 6 studies for CT and 9 studies for MRI. Generally, features predicting RECIST or metabolic response often predicted shorter survival. The ADC (apparent diffusion coefficient, on MRI) seems to be the most promising predictor of response and survival. In CT-related studies, few attenuation-related parameters and texture features show promising results. In FDG-PET(-CT), findings were ambiguous. CONCLUSION: Radiological data on the prediction of response to chemotherapy for CRLM is relatively sparse and heterogeneous. Despite that, a promising parameter might be ADC. Second, there seems to be a seemingly counterintuitive correlation between parameters that predict a good response and also predict poor survival.
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Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/tratamiento farmacológico , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Toma de Decisiones Clínicas , Neoplasias Colorrectales/mortalidad , Humanos , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/secundario , Tomografía Computarizada por Tomografía de Emisión de Positrones , Valor Predictivo de las Pruebas , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND: The current study was a multicenter, single-arm, phase 2 study performed to investigate the feasibility and efficacy of bevacizumab combined with docetaxel, oxaliplatin, and capecitabine (B-DOC) in patients with advanced human epidermal growth factor receptor 2 (HER2)-negative, previously untreated, gastric or gastroesophageal adenocarcinoma. METHODS: Tumor HER2 status was determined centrally. Patients received 6 cycles of bevacizumab at a dose of 7.5 mg/kg, docetaxel at a dose of 50 mg/m(2) , and oxaliplatin at a dose of 100 mg/m(2) (all on day 1) combined with capecitabine at a dose of 850 mg/m(2) twice daily (days 1-14) every 3 weeks followed by maintenance with capecitabine and bevacizumab in patients with disease control. The primary objective was to demonstrate a progression-free survival (PFS) of >6.5 months, according to the 95% confidence interval (95% CI). Secondary endpoints included safety, objective response rate, overall survival (OS), analyses of circulating tumor cells (CTCs), and pharmacogenetic analyses. RESULTS: Sixty eligible patients were enrolled. The median PFS was 8.3 months (95% CI, 7.2-10.9 months). The objective response rate was 70% (95% CI, 55%-83%) and the disease control rate was 96% (95% CI, 85%-99%). The median OS was 12.0 months (95% CI, 10.2-16.1 months). According to CTC-AE v4.0, the most common treatment-related grade ≥3 adverse events were neutropenia (20%), leukocytopenia (18%), diarrhea (15%), and nausea/vomiting (15%). The presence of CTCs at baseline was strongly predictive of PFS (hazard ratio [HR], 3.8; P =.007) and OS (HR, 3.4; P =.014). The methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype was strongly associated with PFS (HR, 4.7 for TT vs CC or CT; P =.0007) and OS (HR, 5.9; P =.0001). CONCLUSIONS: The B-DOC regimen plus maintenance was feasible and active. CTCs were found to be prognostic in patients treated with B-DOC. Docetaxel-based triplet chemotherapy as a backbone for targeted therapies is feasible and deserves further study. Cancer 2016;122:1434-1443. © 2016 American Cancer Society.
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Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Capecitabina/administración & dosificación , Docetaxel , Esquema de Medicación , Femenino , Humanos , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Persona de Mediana Edad , Células Neoplásicas Circulantes , Compuestos Organoplatinos/administración & dosificación , Oxaliplatino , Estudios Prospectivos , Receptor ErbB-2 , Neoplasias Gástricas/patología , Taxoides/administración & dosificaciónAsunto(s)
Actitud Frente a la Muerte , Objetivos , Neoplasias/psicología , Cuidados Paliativos/psicología , Satisfacción del Paciente , Calidad de Vida/psicología , Terapias Espirituales/psicología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Gastric and gastroesophageal junction (G/GEJ) cancers carry a poor prognosis, and despite recent advancements, most patients die of their disease. Although immune checkpoint blockade became part of the standard-of-care for patients with metastatic G/GEJ cancers, its efficacy and impact on the tumor microenvironment (TME) in early disease remain largely unknown. We hypothesized higher efficacy of neoadjuvant immunotherapy plus chemotherapy in patients with nonmetastatic G/GEJ cancer. In the phase 2 PANDA trial, patients with previously untreated resectable G/GEJ tumors (n = 21) received neoadjuvant treatment with one cycle of atezolizumab monotherapy followed by four cycles of atezolizumab plus docetaxel, oxaliplatin and capecitabine. Treatment was well tolerated. There were grade 3 immune-related adverse events in two of 20 patients (10%) but no grade 4 or 5 immune-related adverse events, and all patients underwent resection without treatment-related delays, meeting the primary endpoint of safety and feasibility. Tissue was obtained at multiple time points, allowing analysis of the effects of single-agent anti-programmed cell death ligand 1 (PD-L1) and the subsequent combination with chemotherapy on the TME. Twenty of 21 patients underwent surgery and were evaluable for secondary pathologic response and survival endpoints, and 19 were evaluable for exploratory translational analyses. A major pathologic response (≤10% residual viable tumor) was observed in 14 of 20 (70%, 95% confidence interval 46-88%) patients, including 9 (45%, 95% confidence interval 23-68%) pathologic complete responses. At a median follow-up of 47 months, 13 of 14 responders were alive and disease-free, and five of six nonresponders had died as a result of recurrence. Notably, baseline anti-programmed cell death protein 1 (PD-1)+CD8+ T cell infiltration was significantly higher in responders versus nonresponders, and comparison of TME alterations following anti-PD-L1 monotherapy versus the subsequent combination with chemotherapy showed an increased immune activation on single-agent PD-1/L1 axis blockade. On the basis of these data, monotherapy anti-PD-L1 before its combination with chemotherapy warrants further exploration and validation in a larger cohort of patients with nonmetastatic G/GEJ cancer. ClinicalTrials.gov registration: NCT03448835 .
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Adenocarcinoma , Anticuerpos Monoclonales Humanizados , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Terapia Neoadyuvante , Receptor de Muerte Celular Programada 1 , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patología , Unión Esofagogástrica/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Microambiente TumoralRESUMEN
BACKGROUND: Floxuridine's high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine. METHODS: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed. RESULTS: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472-0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470-0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463-0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257-0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation. The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %-37.8 %) over a period of 15 days (n = 18). CONCLUSION: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.
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Neoplasias Colorrectales , Neoplasias Hepáticas , Humanos , Floxuridina/uso terapéutico , Neoplasias Colorrectales/patología , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Hepáticas/tratamiento farmacológico , Bombas de InfusiónRESUMEN
OBJECTIVES: The objectives of this study are to analyse the long-term follow-up of a randomised controlled trial of induction treatment with azathioprine/methylprednisolone (AZA/MP) versus high-dose intravenous cyclophosphamide (ivCY) in patients with proliferative lupus nephritis (LN) and to evaluate the predictive value of clinical, laboratory and renal biopsy parameters regarding renal outcome. METHODS: 87 patients with biopsy-proven proliferative LN were treated with either AZA/MP (n=37) or ivCY (n=50), both with oral prednisone. After 2 years, renal biopsy was repeated, and all patients continued with AZA/oral prednisone. The primary study end point was sustained doubling of serum creatinine. Secondary end points included renal relapse, end-stage renal disease and mortality. RESULTS: After a median follow-up of 9.6 years, no significant differences between AZA/MP versus ivCY groups were found in the proportion of patients with sustained doubling of serum creatinine (n=6 (16%) vs n=4 (8%); p=0.313), end-stage renal disease (n=2 (5%) vs n=2 (4%); p=1.000) or mortality (n=6 (16%) vs n=5 (10%); p=0.388). Renal relapses occurred more often in the AZA/MP group (n=14 (38%) vs n=5 (10%); p=0.002, HR: 4.5). Serum creatinine, proteinuria and immunosuppressive treatment regimens at the last follow-up were comparable. Clinical and laboratory parameters at baseline and after 2 years, and renal biopsy parameters (only) at baseline predicted renal outcome. CONCLUSION: Induction treatment with ivCY was superior to AZA/MP in preventing renal relapses, but other parameters for renal function did not differ. AZA/MP can therefore serve as an alternative in patients with proliferative LN who wish to avoid gonadal toxicity of CY. Several prognostic factors of long-term renal outcome were identified.
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Azatioprina/administración & dosificación , Ciclofosfamida/administración & dosificación , Inmunosupresores/administración & dosificación , Nefritis Lúpica/tratamiento farmacológico , Metilprednisolona/administración & dosificación , Adolescente , Adulto , Antiinflamatorios/administración & dosificación , Creatinina/sangre , Femenino , Estudios de Seguimiento , Humanos , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/prevención & control , Nefritis Lúpica/sangre , Nefritis Lúpica/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Proteinuria/sangre , Proteinuria/tratamiento farmacológico , Proteinuria/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
(1) Background: Perioperative chemotherapy is the current standard treatment for patients with resectable gastric cancer. Based on studies in patients with metastatic gastric cancer, oxaliplatin has replaced cisplatin in the curative setting as well. However, evidence to prefer oxaliplatin over cisplatin in the curative setting is limited. (2) Methods: We compared patient-related and tumor-related outcomes for cisplatin versus oxaliplatin in patients with resectable gastric cancer treated with perioperative chemotherapy in the CRITICS trial. (3) Results: Preoperatively, 632 patients received cisplatin and 149 patients received oxaliplatin. Preoperative severe toxicity was encountered in 422 (67%) patients who received cisplatin versus 89 (60%) patients who received oxaliplatin (p = 0.105). Severe neuropathy was observed in 5 (1%) versus 6 (4%; p = 0.009) patients, respectively. Postoperative severe toxicity occurred in 109 (60%) versus 26 (51%) (p = 0.266) patients; severe neuropathy in 2 (1%) versus 2 (4%; p = 0.209) for patients who received cisplatin or oxaliplatin, respectively. Diarrhea impacted the quality of life more frequently in patients who received oxaliplatin compared to cisplatin. Complete or near-complete pathological response was achieved in 94 (21%) versus 16 (15%; p = 0.126) patients who received cisplatin or oxaliplatin, respectively. Overall survival was not significantly different in both groups (p = 0.300). (4) Conclusions: Both cisplatin and oxaliplatin are legitimate options as part of systemic treatment in patients with resectable gastric cancer.
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We assessed the feasibility of adjuvant S-1 and oxaliplatin following neoadjuvant chemoradiotherapy (nCRT) and esophagectomy. Patients treated with nCRT (paclitaxel, carboplatin) and esophagectomy received six 21-day cycles with oxaliplatin (130 mg/m2) on day 1 and S-1 (25 mg/m2 twice daily) on days 1-14. The primary endpoint was feasibility, defined as ≥50% completing treatment. We performed exploratory propensity-score matching to compare survival, ERCC1 and Thymidylate Synthase (TS) immunohistochemistry analyses, proteomics biomarker discovery and 5-FU pharmacokinetic analyses. Forty patients were enrolled and 48% completed all adjuvant cycles. Median dose intensity was 98% for S-1 and 62% for oxaliplatin. The main reason for early discontinuation was toxicity (67%). The median recurrence-free and overall survival were 28.3 months and 40.8 months, respectively (median follow-up 29.1 months). Survival was not significantly prolonged compared to a matched cohort (p = 0.09). Patients with ERCC1 negative tumor expression had significantly better survival compared to ERCC1 positivity (p = 0.01). Our protein signature model was predictive of survival [p = 0.04; Area under the curve (AUC) 0.80]. Moreover, 5-FU pharmacokinetics significantly correlated with treatment-related toxicity. To conclude, six cycles adjuvant S-1 and oxaliplatin were not feasible in pretreated esophageal adenocarcinoma. Although the question remains whether additional treatment with chemotherapy should be provided in the adjuvant setting, subgroups such as patients with ERCC1 negativity could potentially benefit from adjuvant SOX based on our exploratory biomarker research.
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BACKGROUND: The occurrence of a venous thromboembolism (VTE) is common in patients with cancer. Gastric cancer has been associated with one of the highest risks for VTE. Chemotherapy, especially cisplatin has been associated with a high VTE risk. In this study, risk factors for VTE occurrence and their potential impact on subsequent therapeutic interventions were investigated in patients who underwent preoperative chemotherapy, in the CRITICS gastric cancer trial. PATIENTS AND METHODS: Patients with resectable gastric cancer were preoperatively treated with three cycles of 3-weekly epirubicin, cisplatin or oxaliplatin, and capecitabine (ECC/EOC). VTE was defined as any thrombus in the venous system, excluding superficial and/or device related VTEs. Potential risk factors were analyzed in a multivariable regression model with age, gender, Body Mass Index (BMI), tumor localization, Lauren classification, type of chemotherapy (ECC/EOC), (cardiovascular) comorbidity, and previous VTE as independent risk factors. The impact of VTE on completion rate of preoperative chemotherapy, surgical resection rate, postoperative complications, and start of postoperative therapy were investigated. RESULTS: Of 781 patients, 78 (10%) of 781 patients developed a VTE during preoperative chemotherapy. On multivariable analysis, BMI ≥ 30 kg/m2 and previous VTE were associated with VTE occurrence (reference BMI < 25 kg/m2 ; OR 2.190; 95% CI 1.152-4.164; P = .017/previous VTE; OR 3.617; 95% CI 1.201-10.890; P = .022). Treatment with cisplatin was, compared to oxaliplatin, not significantly associated with VTE occurrence (OR 1.535; 95% CI 0.761-3.094; P = .231). VTE occurrence did not affect completion of preoperative chemotherapy, surgical resection rate, postoperative complications, or start of postoperative therapy. CONCLUSION: High BMI and previous VTE were independent risk factors for VTE occurrence during preoperative chemotherapy in patients with resectable gastric cancer. VTE occurrence in the preoperative setting did not affect receipt of further treatment.
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Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Terapia Neoadyuvante/efectos adversos , Neoplasias Gástricas/tratamiento farmacológico , Tromboembolia Venosa/inducido químicamente , Adenocarcinoma/patología , Adenocarcinoma/cirugía , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Quimioterapia Adyuvante/efectos adversos , Femenino , Gastrectomía , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Factores de Tiempo , Resultado del Tratamiento , Tromboembolia Venosa/diagnósticoRESUMEN
PD-1 plus CTLA-4 blockade is highly effective in advanced-stage, mismatch repair (MMR)-deficient (dMMR) colorectal cancers, yet not in MMR-proficient (pMMR) tumors. We postulated a higher efficacy of neoadjuvant immunotherapy in early-stage colon cancers. In the exploratory NICHE study (ClinicalTrials.gov: NCT03026140), patients with dMMR or pMMR tumors received a single dose of ipilimumab and two doses of nivolumab before surgery, the pMMR group with or without celecoxib. The primary objective was safety and feasibility; 40 patients with 21 dMMR and 20 pMMR tumors were treated, and 3 patients received nivolumab monotherapy in the safety run-in. Treatment was well tolerated and all patients underwent radical resections without delays, meeting the primary endpoint. Of the patients who received ipilimumab + nivolumab (20 dMMR and 15 pMMR tumors), 35 were evaluable for efficacy and translational endpoints. Pathological response was observed in 20/20 (100%; 95% exact confidence interval (CI): 86-100%) dMMR tumors, with 19 major pathological responses (MPRs, ≤10% residual viable tumor) and 12 pathological complete responses. In pMMR tumors, 4/15 (27%; 95% exact CI: 8-55%) showed pathological responses, with 3 MPRs and 1 partial response. CD8+PD-1+ T cell infiltration was predictive of response in pMMR tumors. These data indicate that neoadjuvant immunotherapy may have the potential to become the standard of care for a defined group of colon cancer patients when validated in larger studies with at least 3 years of disease-free survival data.