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1.
Ann Oncol ; 2024 Jun 19.
Artículo en Inglés | MEDLINE | ID: mdl-38906254

RESUMEN

BACKGROUND: After surgical resection of pancreatic ductal adenocarcinoma (PDAC), patients are predominantly treated with adjuvant chemotherapy, commonly consisting of gemcitabine (GEM)-based regimens or the modified FOLFIRINOX (mFFX) regimen. While mFFX regimen has been shown to be more effective than GEM-based regimens, it is also associated with higher toxicity. Current treatment decisions are based on patient performance status rather than on the molecular characteristics of the tumor. To address this gap, the goal of this study was to develop drug-specific transcriptomic signatures for personalized chemotherapy treatment. PATIENTS AND METHODS: We used PDAC datasets from preclinical models, encompassing chemotherapy response profiles for the mFFX regimen components. From them we identified specific gene transcripts associated with chemotherapy response. Three transcriptomic artificial intelligence signatures were obtained by combining independent component analysis and the least absolute shrinkage and selection operator-random forest approach. We integrated a previously developed GEM signature with three newly developed ones. The machine learning strategy employed to enhance these signatures incorporates transcriptomic features from the tumor microenvironment, leading to the development of the 'Pancreas-View' tool ultimately clinically validated in a cohort of 343 patients from the PRODIGE-24/CCTG PA6 trial. RESULTS: Patients who were predicted to be sensitive to the administered drugs (n = 164; 47.8%) had longer disease-free survival (DFS) than the other patients. The median DFS in the mFFX-sensitive group treated with mFFX was 50.0 months [stratified hazard ratio (HR) 0.31, 95% confidence interval (CI) 0.21-0.44, P < 0.001] and 33.7 months (stratified HR 0.40, 95% CI 0.17-0.59, P < 0.001) in the GEM-sensitive group when treated with GEM. Comparatively patients with signature predictions unmatched with the treatments (n = 86; 25.1%) or those resistant to all drugs (n = 93; 27.1%) had shorter DFS (10.6 and 10.8 months, respectively). CONCLUSIONS: This study presents a transcriptome-based tool that was developed using preclinical models and machine learning to accurately predict sensitivity to mFFX and GEM.

2.
Ann Oncol ; 32(5): 600-608, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33539945

RESUMEN

BACKGROUND: First-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC) includes nab-paclitaxel/gemcitabine. Ibrutinib, a Bruton's tyrosine kinase inhibitor, exhibits antitumor activity through tumor microenvironment modulation. The safety and efficacy of first-line ibrutinib plus nab-paclitaxel/gemcitabine treatment in patients with PDAC were evaluated. PATIENTS AND METHODS: RESOLVE (NCT02436668) was a phase III, randomized, double-blind, placebo-controlled study. Patients (histologically-confirmed PDAC; stage IV diagnosis ≥6 weeks of randomization; Karnofsky performance score ≥70) were randomized to once-daily oral ibrutinib (560 mg) or placebo plus nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2). Primary endpoints were overall survival (OS) and investigator-assessed progression-free survival (PFS); overall response rate and safety were assessed. RESULTS: In total, 424 patients were randomized (ibrutinib arm, n = 211; placebo arm, n = 213). Baseline characteristics were balanced across arms. After a median follow-up of 25 months, there was no significant difference in OS between ibrutinib plus nab-paclitaxel/gemcitabine versus placebo plus nab-paclitaxel/gemcitabine (median of 9.7 versus 10.8 months; P = 0.3225). PFS was shorter for ibrutinib plus nab-paclitaxel/gemcitabine compared with placebo plus nab-paclitaxel/gemcitabine (median 5.3 versus 6.0 months; P < 0.0001). Overall response rates were 29% and 42%, respectively (P = 0.0058). Patients in the ibrutinib arm had less time on treatment and received lower cumulative doses for all agents compared with the placebo arm. The most common grade ≥3 adverse events for ibrutinib versus placebo arms included neutropenia (24% versus 35%), peripheral sensory neuropathy (17% versus 8%), and anemia (16% versus 17%). Primary reasons for any treatment discontinuation were disease progression and adverse events. CONCLUSIONS: Ibrutinib plus nab-paclitaxel/gemcitabine did not improve OS or PFS for patients with PDAC. Safety was consistent with known profiles for these agents.


Asunto(s)
Adenocarcinoma , Neoplasias Pancreáticas , Adenina/análogos & derivados , Adenocarcinoma/tratamiento farmacológico , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/análogos & derivados , Humanos , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Piperidinas , Resultado del Tratamiento , Microambiente Tumoral , Gemcitabina
3.
Ann Oncol ; 32(2): 250-260, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33188873

RESUMEN

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/genética , Quimioterapia Adyuvante , Desoxicitidina/análogos & derivados , Humanos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/genética , Estudios Retrospectivos , Transcriptoma , Gemcitabina
4.
Br J Surg ; 106(9): 1237-1247, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31183866

RESUMEN

BACKGROUND: BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF-mutated CRLMs. METHODS: The study included patients who underwent resection for BRAF-mutated CRLMs in 24 centres between 2012 and 2016. A case-matched comparison was made with 183 patients who underwent resection of CRLMs with wild-type BRAF during the same interval. RESULTS: Sixty-six patients who underwent resection for BRAF-mutated CRLMs in 24 centres were compared with 183 patients with wild-type BRAF. The 1- and 3-year disease-free survival (DFS) rates were 46 and 19 per cent for the BRAF-mutated group, and 55·4 and 27·8 per cent for the group with wild-type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1- and 3-year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild-type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild-type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF-mutated group (48 versus 29·8 per cent; P = 0·034). CONCLUSION: These results support surgical treatment for resectable BRAF-mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non-metastatic colorectal cancer.


Asunto(s)
Neoplasias Colorrectales/genética , Neoplasias Hepáticas/secundario , Recurrencia Local de Neoplasia/genética , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Estudios de Casos y Controles , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/cirugía , Supervivencia sin Enfermedad , Femenino , Hepatectomía , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/mortalidad , Neoplasias Hepáticas/cirugía , Masculino , Persona de Mediana Edad , Mutación/genética , Análisis de Supervivencia
5.
Ann Oncol ; 29(5): 1211-1219, 2018 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-29438522

RESUMEN

Background: RAS mutations are currently sought for in tumor samples, which takes a median of almost 3 weeks in western European countries. This creates problems in clinical situations that require urgent treatment and for inclusion in therapeutic trials that need RAS status for randomization. Analysis of circulating tumor DNA might help to shorten the time required to determine RAS mutational status before anti-epidermal growth factor receptor antibody therapy for metastatic colorectal cancer. Here we compared plasma with tissue RAS analysis in a large prospective multicenter cohort. Patients and methods: Plasma samples were collected prospectively from chemotherapy-naive patients and analyzed centrally by next-generation sequencing (NGS) with the colon lung cancer V2 Ampliseq panel and by methylation digital PCR (WIF1 and NPY genes). Tumoral RAS status was determined locally, in parallel, according to routine practice. For a minimal κ coefficient of 0.7, reflecting acceptable concordance (precision ± 0.07), with an estimated 5% of non-exploitable data, 425 subjects were necessary. Results: From July 2015 to December 2016, 425 patients were enrolled. For the 412 patients with available paired plasma and tumor samples, the κ coefficient was 0.71 [95% confidence interval (CI), 0.64-0.77] and accuracy was 85.2% (95% CI, 81.4% to 88.5%). In the 329 patients with detectable ctDNA (at least one mutation or one methylated biomarker), the κ coefficient was 0.89 (95% CI, 0.84-0.94) and accuracy was 94.8% (95% CI, 91.9% to 97.0%). The absence of liver metastases was the main clinical factor associated with inconclusive circulating tumor DNA results [odds ratio = 0.11 (95% CI, 0.06-0.21)]. In patients with liver metastases, accuracy was 93.5% with NGS alone and 97% with NGS plus the methylated biomarkers. Conclusion: This prospective trial demonstrates excellent concordance between RAS status in plasma and tumor tissue from patients with colorectal cancer and liver metastases, thus validating plasma testing for routine RAS mutation analysis in these patients. Clinical Trial registration: Clinicaltrials.gov, NCT02502656.


Asunto(s)
Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/genética , Neoplasias Colorrectales/sangre , Neoplasias Hepáticas/sangre , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Análisis Mutacional de ADN/métodos , Femenino , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundario , Masculino , Persona de Mediana Edad , Selección de Paciente , Valor Predictivo de las Pruebas , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Adulto Joven
6.
Ann Oncol ; 29(4): 931-937, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29365058

RESUMEN

Background: [18F]2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (18FDG-PET/CT) has high sensitivity for detecting recurrences of colorectal cancer (CRC). Our objective was to determine whether adding routine 6-monthly 18FDG-PET/CT to our usual monitoring strategy improved patient outcomes and to assess the effect on costs. Patients and methods: In this open-label multicentre trial, patients in remission of CRC (stage II perforated, stage III, or stage IV) after curative surgery were randomly assigned (1 : 1) to usual monitoring alone (3-monthly physical and tumour marker assays, 6-monthly liver ultrasound and chest radiograph, and 6-monthly whole-body computed tomography) or with 6-monthly 18FDG-PET/CT, for 3 years. A multidisciplinary committee reviewed each patient's data every 3 months and classified the recurrence status as yes/no/doubtful. Recurrences were treated with curative surgery alone if feasible and with chemotherapy otherwise. The primary end point was treatment failure defined as unresectable recurrence or death. Relative risks were estimated, and survival was analysed using the Kaplan-Meier method, log-rank test, and Cox models. Direct costs were compared. Results: Of the 239 enrolled patients, 120 were in the intervention arm and 119 in the control arm. The failure rate was 29.2% (31 unresectable recurrences and 4 deaths) in the intervention group and 23.7% (27 unresectable recurrences and 1 death) in the control group (relative risk = 1.23; 95% confidence interval, 0.80-1.88; P = 0.34). The multivariate analysis also showed no significant difference (hazards ratio, 1.33; 95% confidence interval, 0.8-2.19; P = 0.27). Median time to diagnosis of unresectable recurrence (months) was significantly shorter in the intervention group [7 (3-20) versus 14.3 (7.3-27), P = 0.016]. Mean cost/patient was higher in the intervention group (18 192 ± 27 679 € versus 11 131 ± 13 €, P < 0.033). Conclusion: 18FDG-PET/CT, when added every 6 months, increased costs without decreasing treatment failure rates in patients in remission of CRC. The control group had very close follow-up, and any additional improvement (if present) would be small and hard to detect. ClinicalTrials.gov identifier: NCT00624260.


Asunto(s)
Neoplasias Colorrectales/diagnóstico por imagen , Fluorodesoxiglucosa F18/administración & dosificación , Monitoreo Fisiológico/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Anciano , Costos y Análisis de Costo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/economía
7.
Br J Cancer ; 115(10): 1245-1252, 2016 Nov 08.
Artículo en Inglés | MEDLINE | ID: mdl-27755532

RESUMEN

BACKGROUND: There is an increasing interest for Notch signalling pathway and particularly Delta-like ligand 4 (DLL4) as potential therapeutic target to improve outcome for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Using immunohistochemistry (IHC) and tissue microarray (TMA), we assessed the expression patterns of DLL4, Notch1 and Notch3 in 151 patients from two independent cohorts of resected PDAC. We investigated the prognostic and the predictive significance of these proteins. RESULTS: High IHC DLL4 expression in cancer cells was associated with worse overall survival (OS) and disease-free survival (DFS) than low DLL4 expression (median OS: 12.9 vs 30.4 months, P=0.004 and median DFS: 8.8 vs 17.4 months, P=0.02). High DLL4 expression remained a significant negative prognostic factor in multivariate analysis (HR for OS: 2.1, P=0.02 and HR for DFS: 2.0, P=0.02). Low DLL4 abundance was associated with a longer OS-only for patients who received an adjuvant gemcitabine-based chemotherapy (P<0.001) but not for patients who did not receive gemcitabine (P=0.72). Furthermore, the interaction test for adjuvant gemcitabine therapy was statistically significant (P<0.001). The validating cohort recapitulated the findings of the training cohort. CONCLUSIONS: Low DLL4 abundance in tumour cells may predict the benefit from adjuvant gemcitabine therapy after PDAC resection.


Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Desoxicitidina/análogos & derivados , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión al Calcio , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Quimioterapia Adyuvante/métodos , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Inmunohistoquímica/métodos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Pancreáticas/patología , Pronóstico , Receptor Notch1/metabolismo , Receptor Notch3/metabolismo , Gemcitabina
8.
Ann Surg Oncol ; 22(1): 295-301, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25037971

RESUMEN

BACKGROUND: First-line treatment with FOLFIRINOX significantly increases overall survival (OS) in patients with metastatic pancreatic adenocarcinoma (PA) compared with gemcitabine. The aim of this observational cohort was to evaluate the tolerability and efficacy of this regimen in unresectable locally advanced PA (LAPA). PATIENTS AND METHODS: From February 2010 to February 2012, all consecutive patients from 11 French centers treated by FOLFIRINOX for a histologically proven LAPA were prospectively enrolled. Unresectability was defined independently by each center's multidisciplinary staff at diagnosis. Absence of metastatic disease was confirmed by chest-abdomen-pelvis computed tomography scan. FOLFIRINOX was delivered every 2 weeks as previously reported until progressive disease, major toxicity, or consolidation treatment by radiotherapy and/or surgery. RESULTS: Seventy-seven patients were enrolled. They received a median number of five cycles (1-30). Grade 3-4 toxicities were neutropenia (11 %), nausea (9 %), diarrhea (6 %), fatigue (6 %), and anemia (1 %). Grade 2-3 sensory neuropathy occurred in 25 % of patients. No toxic death was reported and only 6 % of patients had to stop treatment because of toxicity. Disease control rate was 84 with 28 % of objective response (Response Evaluation Criteria in Solid Tumors). Seventy-five percent of patients received a consolidation therapy: 70 % had radiotherapy and 36 % underwent a surgical resection, with a curative intent. Within the whole cohort, 1-year OS rate was 77 % (95 % CI 65-86) and 1-year progression-free survival rate was 59 % (95 % CI 46-70). CONCLUSION: First-line FOLFIRINOX for LAPA seems to be effective and have a manageable toxicity profile. These promising results will have to be confirmed in a phase III randomized trial.


Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Adulto , Anciano , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Fluorouracilo/administración & dosificación , Estudios de Seguimiento , Humanos , Irinotecán , Leucovorina/administración & dosificación , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Invasividad Neoplásica , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Gemcitabina
9.
Dig Liver Dis ; 56(3): 514-521, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-37718226

RESUMEN

BACKGROUND: We sought to describe the reasons for intensive care unit (ICU) admission and outcomes of patients with pancreatic cancer requiring unplanned medical ICU admission. PATIENTS AND METHODS: Retrospective cohort study in five ICUs from 2009 to 2020. All patients with pancreatic cancer admitted to the ICU were included. Patients having undergone recent surgery were excluded (< 4 weeks). RESULTS: 269 patients were included. Tumors were mainly adenocarcinoma (90%). Main reason for admission was sepsis/septic shock (32%) with a biliary tract infection in 44 (51%) patients. Second reason for admission was gastrointestinal bleeding (28%). ICU and 3-month mortality rates were 26% and 59% respectively. Performance status 3-4 (odds ratio OR 3.58), disease status (responsive/stable -ref-, newly diagnosed OR 3.25, progressive OR 5.99), mechanical ventilation (OR 8.03), vasopressors (OR 4.19), SAPS 2 (OR 1.69) and pH (OR 0.02) were independently associated with ICU mortality. Performance status 3-4 (Hazard ratio HR 1.96) and disease status (responsive/stable -ref-, newly diagnosed HR 2.67, progressive HR 4.14) were associated with 3-month mortality. CONCLUSION: Reasons for ICU admissions of pancreatic cancer patients differ from those observed in other solid cancer. Short- and medium-term mortality are strongly influenced by performance status and disease status at ICU admission.


Asunto(s)
Neoplasias Pancreáticas , Choque Séptico , Humanos , Estudios Retrospectivos , Mortalidad Hospitalaria , Unidades de Cuidados Intensivos , Hospitalización , Neoplasias Pancreáticas/terapia
10.
Ann Oncol ; 24(2): 412-419, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23041588

RESUMEN

BACKGROUND: The purpose of this study was to evaluate the combination of panitumumab and irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to standard chemotherapy (oxaliplatin, fluoropyrimidines-irinotecan and bevacizumab). PATIENTS AND METHODS: KRAS status was first determined locally but subsequent validation of KRAS status and additional screenings (rare KRAS, NRAS, BRAF mutations and EGFR copy number) were centrally assessed. Patients received panitumumab (6 mg/kg) and irinotecan (180 mg/m²) every 2 weeks. RESULTS: Sixty-five eligible patients were analyzed. The objective response rate (ORR) was 29.2% [95% confidence interval (95% CI) 18.2-40.3]. Median progression-free and overall survivals were 5.5 and 9.7 months, respectively. Most frequent grade 3/4 toxic effects were skin 32.3%, diarrhea 15.4% and neutropenia 12.3%. Tissue samples were available for 60 patients. For the confirmed KRAS wild-type population codon 12 or 13 mutation (n = 54), ORR was 35.2% (95% CI 22.4.1-47.9). Thirteen patients had a NRAS, a BRAF or a rare KRAS mutation, and no tumor response was observed in this subgroup when compared with 46.3% (95% CI 31.1-61.6) ORR in the subgroup of 41 patients with no identified mutation. CONCLUSION: Panitumumab and irinotecan is an active third-line regimen in a well-defined population based on biomarkers. ClinicalTrials.gov Identifier NCT00655499.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/efectos adversos , Camptotecina/uso terapéutico , Neoplasias Colorrectales/patología , Resistencia a Antineoplásicos , Receptores ErbB/genética , Femenino , GTP Fosfohidrolasas/genética , Humanos , Irinotecán , Masculino , Proteínas de la Membrana/genética , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Panitumumab , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)
11.
Ann Oncol ; 24(8): 2057-61, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23676420

RESUMEN

BACKGROUND: Pancreatic carcinoma is one of the leading causes of cancer-related mortality. At the time of diagnosis, 30% of patients present with a locally advanced pancreatic carcinoma (LAPC). As circulating tumor cells (CTCs) count may be a surrogate of the cancer metastatic abilities, CTC detection rates and prognostic value were studied in a prospective cohort of LAPC patients. PATIENTS AND METHODS: An LAP07 international multicenter randomized study assesses in patients whose LAPC is controlled after 4 months of chemotherapy whether chemoradiotherapy could increase survival versus continuation of chemotherapy. A subgroup of patients included in the LAP07 trial was screened for CTCs (CellSearch®) before the start of the chemotherapy and after 2 months of treatment. Patient characteristics and survival were obtained prospectively and were correlated with CTC detection. RESULTS: Seventy-nine patients were included. One or more CTCs/7.5 ml were detected in 5% of patients before treatment and in 9% of patients after 2 months of treatment (overall detection rate: 11% of patients). CTC positivity was associated with poor tumor differentiation (P = 0.04), and with shorter overall survival (OS) in multivariable analysis (RR = 2.5, P = 0.01), together with anemia. CONCLUSIONS: The evaluation of micrometastatic disease using CTC detection appears as a promising prognostic tool in LAPC patients.


Asunto(s)
Adenocarcinoma/patología , Metástasis de la Neoplasia/diagnóstico , Células Neoplásicas Circulantes , Neoplasias Pancreáticas/patología , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/radioterapia , Adulto , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Quimioradioterapia , Estudios de Cohortes , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Estudios Prospectivos , Sobrevida , Adulto Joven , Gemcitabina
12.
J Eur Acad Dermatol Venereol ; 27(4): 419-29, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22211860

RESUMEN

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are part of the therapeutic arsenal available for advanced cancer. However, they are frequently associated with cutaneous side-effects, which can hamper compliance, lead to treatment refusal and impair quality of life. OBJECTIVE: To know the attitudes of French oncologists who deal with this skin toxicity. This work is one of the steps to build a therapeutic algorithm of side-effects induced by EGFR inhibitors taking both evidence-based medicine and standard practices into account. METHODS: Physicians completed a questionnaire as part of regional meetings, before any discussion. Questions concerned the management of 11 clinical situations in the context of EGFR inhibitor prescription. RESULTS: Sixty-seven questionnaires were analysed. The collaboration with dermatologists was especially planned for persisting or worsening lesions beyond 2 weeks, but never considered at the time of the introduction of targeted therapy. The results demonstrated the difficulties encountered in diagnosing and grading skin lesions. Attitudes of oncologists were uniform for preventive care and management of mild lesions for which moisturizing and cyclines were widely prescribed. Significant differences appeared in the treatment of less typical cases such as the involvement of skin appendages, secondary infections of folliculitis or cases associated with radiodermatitis. Discrepancies existed also for what to do in relation with maintenance or interruption of EGFR inhibitor mainly if they were responsible for severe lesions. CONCLUSION: This original survey emphasizes the interest of greater multidisciplinary collaboration and the necessity to harmonize practice.


Asunto(s)
Fármacos Dermatológicos/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Piel/efectos de los fármacos , Fármacos Dermatológicos/administración & dosificación , Francia , Humanos , Encuestas y Cuestionarios
13.
Clin Res Hepatol Gastroenterol ; 47(4): 102108, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36878461

RESUMEN

BACKGROUND: Trop-2 is overexpressed in tumor cells of various cancers, including pancreatic ductal adenocarcinoma (PDAC), and has emerged as a potent therapeutic target. We evaluated Trop-2 expression both at the transcriptomic and protein levels, and its correlation with tumor features and patients' outcomes in a large cohort of PDAC. METHODS: We included patients undergoing pancreatic resection for PDAC in 5 academic hospitals in France and Belgium. Transcriptomic profiles were obtained from FFPE tissue samples, with paired primary -25and metastatic lesions when available. Protein expression was evaluated by immunohistochemistry (IHC) using tissue micro-arrays. RESULTS: 495 patients (male 54%, median age 63 years) were included between 1996 and 2012. Trop-2 mRNA expression was significantly associated to tumor cellularity, but no association with survival nor with any clinical or pathological features was observed, with tumor cells showing an overall high expression among every subgroup. Trop-2 mRNA expression was maintained between primary and metastatic lesion in all 26 paired samples evaluated. In 50 tumors assessed by IHC, 30%, 68% and 2% harbored a high, medium, or low Trop-2 expression score, respectively. Trop-2 staining was significantly associated to mRNA expression, but not to survival or any pathological features. CONCLUSIONS: Our results suggest Trop-2 overexpression as a ubiquitous marker of PDAC tumor cells and thus a promising therapeutic target to evaluate in these patients.


Asunto(s)
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , ARN Mensajero/genética , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Pronóstico , Neoplasias Pancreáticas
14.
Ann Oncol ; 23(9): 2327-2335, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22377565

RESUMEN

BACKGROUND: Prognosis of patients with pancreatic adenocarcinoma is poor. Many prognostic biomarkers have been tested, but most studies included heterogeneous patients. We aimed to investigate the prognostic and/or predictive values of four relevant biomarkers in a multicentric cohort of patients. PATIENTS AND METHODS: A total of 471 patients who had resected pancreatic adenocarcinoma were included. Using tissue microarray, we assessed the relationship of biomarker expressions with the overall survival: Smad4, type II TGF-ß receptor, CXCR4, and LKB1. RESULTS: High CXCR4 expression was found to be the only independent negative prognostic biomarker [hazard ratio (HR) = 1.74; P < 0.0001]. In addition, it was significantly associated with a distant relapse pattern (HR = 2.19; P < 0.0001) and was the strongest prognostic factor compared with clinicopathological factors. In patients who did not received adjuvant treatment, there was a trend toward decrease in the overall survival for negative Smad4 expression. Loss of Smad4 expression was not correlated with recurrence pattern but was shown to be predictive for adjuvant chemotherapy (CT) benefit (HR = 0.59; P = 0.002). CONCLUSIONS: CXCR4 is a strong independent prognostic biomarker associated with distant metastatic recurrence and appears as an attractive target to be evaluated in pancreatic adenocarcinoma. Negative SMAD4 expression should be considered as a potential predictor of adjuvant CT benefit.


Asunto(s)
Adenocarcinoma/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pancreáticas/metabolismo , Receptores CXCR4/metabolismo , Proteína Smad4/metabolismo , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adenocarcinoma/terapia , Adulto , Anciano , Anciano de 80 o más Años , Quimioterapia Adyuvante , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Resultado del Tratamiento
15.
Ann Oncol ; 23(3): 570-576, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21810728

RESUMEN

Although the treatment of pancreatic ductal adenocarcinoma (PDAC) remains a huge challenge, it is entering a new era with the development of new strategies and trial designs. Because there is an increasing number of novel therapeutic agents and potential combinations available to test in patients with PDAC, the identification of robust prognostic and predictive markers and of new targets and relevant pathways is a top priority as well as the design of adequate trials incorporating molecular-driven hypothesis. We presently report a consensus strategy for research in pancreatic cancer that was developed by a multidisciplinary panel of experts from different European institutions and collaborative groups involved in pancreatic cancer. The expert panel embraces the concept of exploratory early proof of concept studies, based on the prediction of response to novel agents and combinations, and randomised phase II studies permitting the selection of the best therapeutic approach to go forward into phase III, where the recommended primary end point remains overall survival. Trials should contain as many translational components as possible, relying on standardised tissue and blood processing and robust biobanking, and including dynamic imaging. Attention should not only be paid to the pancreatic cancer cells but also to microenvironmental factors and stem/stellate cells.


Asunto(s)
Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Proyectos de Investigación , Antineoplásicos/farmacología , Europa (Continente) , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación/normas , Proyectos de Investigación/tendencias
16.
Colorectal Dis ; 14(1): 79-86, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22145739

RESUMEN

AIM: The total number of lymph nodes examined after salvage colectomy for endoscopically removed malignant polyps was evaluated and an attempt was made to determine whether there was an optimal number of lymph nodes that should be harvested. METHOD: From 2000 to 2009, 531 patients underwent segmental resection for non-metastatic colon cancer. Of these, 22 underwent a salvage colectomy for an endoscopically removed malignant polyp, the main indication for which was a resection margin of < 1 mm. The surgical procedure was identical to that used for all colon cancers. RESULTS: The mean number of lymph nodes examined was 11.6 ± 7.6 for the 22 patients with an endoscopically removed malignant polyp and 26.2 ± 13.9 for the remaining 509 patients (P = 0.0006). Fewer than 12 lymph nodes were examined in 62 (12%) of the 509 patients and in 13 (59%) of the 22 patients with an endoscopically removed malignant polyp (P < 0.0001). In the group of 22 patients who underwent a salvage colectomy, the total number of lymph nodes examined ranged from 2 to 33. At a mean follow up of 41 ± 15.6 months, no local or distant recurrence was observed in the 22 patients. CONCLUSION: The total number of lymph nodes examined after colectomy for endoscopically removed malignant polyps varies and is less than the recommended number of 12 in most cases: this does not appear to have long-term prognostic significance. There is no biological reason to explain this clinical observation.


Asunto(s)
Colectomía/métodos , Pólipos del Colon/patología , Pólipos del Colon/cirugía , Escisión del Ganglio Linfático/métodos , Terapia Recuperativa , Anciano , Distribución de Chi-Cuadrado , Colonoscopía , Femenino , Humanos , Metástasis Linfática/patología , Masculino , Estadificación de Neoplasias , Estudios Prospectivos , Estadísticas no Paramétricas , Resultado del Tratamiento
17.
Support Care Cancer ; 20(5): 909-21, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22361824

RESUMEN

PURPOSE: Advances in the understanding of the mechanisms involved in oncogenesis have led to the development of so-called targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors, which take on an increasingly important role in the management of cancer. These treatments have the advantage not to trigger the adverse effects traditionally encountered with chemotherapy, such as nausea, vomiting or haematological toxicity. However, they do cause new forms of toxicity: the most common one is skin toxicity. It is important to be aware of it because it can be debilitating, adversely impacting patients' quality of life and altering treatment compliance, although it appears to be correlated with treatment response in certain series. Non-specialists can have difficulty in recognising this unusual skin toxicity. METHODS: The dermatologic side effects most frequently triggered by EGFR inhibitors are discussed in this article. RESULTS: They are divided into three categories depending on their target: inflammation of the pilo-sebaceous follicle, represented by EGFR inhibitor-associated folliculitis, which occurs at an early stage and is frequent; alteration in the skin barrier, primarily responsible for xerosis, fissures and pruritus, which are frequent and delayed; and lesions of the skin appendages (paronychia, pyogenic granuloma, hair changes), which are delayed and less frequent. CONCLUSION: It is essential for all practitioners concerned to know about these dermatologic side effects in order to ensure better global management of patients, particularly in terms of quality of life.


Asunto(s)
Antineoplásicos/efectos adversos , Erupciones por Medicamentos/etiología , Receptores ErbB/antagonistas & inhibidores , Antineoplásicos/uso terapéutico , Sistemas de Liberación de Medicamentos , Erupciones por Medicamentos/fisiopatología , Humanos , Cumplimiento de la Medicación , Neoplasias/tratamiento farmacológico , Calidad de Vida , Factores de Tiempo
18.
Support Care Cancer ; 20(7): 1395-404, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22539049

RESUMEN

PURPOSE: Cutaneous adverse events induced by epidermal growth factor receptor (EGFR) inhibitors can hamper the patients' quality of life. The aim of our work was to draft an algorithm for the optimised management of this skin toxicity. METHODS: This algorithm was built in three steps under the responsibility of a steering committee. Step I: a systematic literature analysis (SLA) has been performed. Step II: the collection of information about practices was performed through a questionnaire.These questions were asked during regional meetings to which oncologists, gastro-enterologists, radiotherapists, and dermatologists were invited. Step III: a final meeting was organised involving the bibliography group and the steering committee and regional scientific committees for proposing a final algorithm. RESULTS: Step I: 14 publications were selected to evaluate the use of cyclines as curative or prophylactic treatment of the folliculitis induced by EGFR inhibitors. Nineteen publications were retained for the topical treatment of the folliculitis. Forty-six articles were selected for the management of the cutaneous lesions in link with appendages and 12 for xerosis and pruritus. Step II: 96 delegates attended the seven regional meetings and 67 questionnaires were analysed. Step III: a final algorithm was proposed on the basis of the conclusions of the first two steps and expert opinions present at this final meeting. The different propositions were unanimously approved by the 14 experts who voted. CONCLUSIONS: This multidisciplinary study summarising published data and current practices produced a therapeutic algorithm, which should facilitate the standardised, optimised management of skin toxicity associated with EGFR inhibitors in France.


Asunto(s)
Antineoplásicos/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Tetraciclinas/uso terapéutico , Algoritmos , Antineoplásicos/uso terapéutico , Erupciones por Medicamentos/etiología , Foliculitis/inducido químicamente , Foliculitis/tratamiento farmacológico , Francia , Humanos , Neoplasias/tratamiento farmacológico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Calidad de Vida , Encuestas y Cuestionarios
19.
Comput Methods Programs Biomed ; 214: 106537, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34879326

RESUMEN

BACKGROUND AND OBJECTIVE: Longitudinal analysis of patient-reported outcome (PRO) data remains challenging, as no standardization of statistical methods has been proposed, making comparison of PRO results between clinical trials difficult. In this context, the time to deterioration approach has recently been proposed and is regularly used as a modality of longitudinal PRO analysis in oncology. METHODS: Two new SAS macro programs were developed, %TTD and %TUDD, which implement longitudinal analysis of PRO data according to the time to deterioration approach. These programs implement the recommended deterioration definitions. We described the programs with their different functionalities. RESULTS: The %TTD macro calculates the time to first or transient deterioration, and the %TUDD macro calculates the time until definitive deterioration. These macros allow to obtain the survival variables from the time to deterioration approach. We illustrate our programs by presenting different applications on the randomized phase II AFUGEM GERCOR clinical trial. CONCLUSION: The implementation of the deterioration definitions in SAS software allows the dissemination of this approach, in order to move toward the goal of standardization of longitudinal PRO analysis in oncology clinical trials.


Asunto(s)
Neoplasias , Calidad de Vida , Humanos , Oncología Médica , Medición de Resultados Informados por el Paciente , Programas Informáticos
20.
Transl Oncol ; 16: 101315, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34906890

RESUMEN

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

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