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1.
Colorectal Dis ; 23(6): 1357-1369, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33580623

RESUMO

AIM: Neoadjuvant chemotherapy has proven valuable in locally advanced resectable colon cancer (CC) but its effect on oncological outcomes is uncertain. The aim of the present paper was to report 3-year oncological outcomes, representing the secondary endpoints of the PRODIGE 22 trial. METHOD: PRODIGE 22 was a randomized multicentre phase II trial in high-risk T3, T4 and/or N2 CC patients on CT scan. Patients were randomized between 6 months of adjuvant FOLFOX (upfront surgery) or perioperative FOLFOX (four cycles before surgery and eight cycles after; FOLFOX perioperative). In wild-type RAS patients, a third arm testing perioperative FOLFOX-cetuximab was added. The primary endpoint was the tumour regression grade. Secondary endpoints were 3-year overall survival (OS), disease-free survival (DFS), recurrence-free survival (RFS) and time to recurrence (TTR). RESULTS: Overall, 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped for futility. The remaining 104 patients represented our intention-to-treat population. In the perioperative group, 96% received the scheduled four neoadjuvant cycles and all but one had adjuvant FOLFOX for eight cycles. In the control arm, 38 (73%) patients received adjuvant FOLFOX. The median follow-up was 54.3 months. Three-year OS was 90.4% in both arms [hazard ratio (HR) = 0.85], 3-year DFS, RFS and TTR were, respectively, 76.8% and 69.2% (HR=0.94), 73% and 69.2% (HR = 0.86) and 82% and 72% (HR = 0.67) in the perioperative and control arms, respectively. Forest plots did not show any subgroup with significant difference for survival outcomes. No benefit from adding cetuximab was observed. CONCLUSION: Perioperative FOLFOX has no detrimental effect on long-term oncological outcomes and may be an option for some patients with locally advanced CC.


Assuntos
Neoplasias do Colo , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Neoplasias do Colo/tratamento farmacológico , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Leucovorina/uso terapêutico , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Compostos Organoplatínicos/uso terapêutico , Prognóstico
2.
Gut ; 69(3): 531-539, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31101691

RESUMO

PURPOSE: The objective of this study was to build and validate a radiomic signature to predict early a poor outcome using baseline and 2-month evaluation CT and to compare it to the RECIST1·1 and morphological criteria defined by changes in homogeneity and borders. METHODS: This study is an ancillary study from the PRODIGE-9 multicentre prospective study for which 491 patients with metastatic colorectal cancer (mCRC) treated by 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) and bevacizumab had been analysed. In 230 patients, computed texture analysis was performed on the dominant liver lesion (DLL) at baseline and 2 months after chemotherapy. RECIST1·1 evaluation was performed at 6 months. A radiomic signature (Survival PrEdiction in patients treated by FOLFIRI and bevacizumab for mCRC using contrast-enhanced CT TextuRe Analysis (SPECTRA) Score) combining the significant predictive features was built using multivariable Cox analysis in 120 patients, then locked, and validated in 110 patients. Overall survival (OS) was estimated with the Kaplan-Meier method and compared between groups with the logrank test. An external validation was performed in another cohort of 40 patients from the PRODIGE 20 Trial. RESULTS: In the training cohort, the significant predictive features for OS were: decrease in sum of the target liver lesions (STL), (adjusted hasard-ratio(aHR)=13·7, p=1·93×10-7), decrease in kurtosis (ssf=4) (aHR=1·08, p=0·001) and high baseline density of DLL, (aHR=0·98, p<0·001). Patients with a SPECTRA Score >0·02 had a lower OS in the training cohort (p<0·0001), in the validation cohort (p<0·0008) and in the external validation cohort (p=0·0027). SPECTRA Score at 2 months had the same prognostic value as RECIST at 6 months, while non-response according to RECIST1·1 at 2 months was not associated with a lower OS in the validation cohort (p=0·238). Morphological response was not associated with OS (p=0·41). CONCLUSION: A radiomic signature (combining decrease in STL, density and computed texture analysis of the DLL) at baseline and 2-month CT was able to predict OS, and identify good responders better than RECIST1.1 criteria in patients with mCRC treated by FOLFIRI and bevacizumab as a first-line treatment. This tool should now be validated by further prospective studies. TRIAL REGISTRATION: Clinicaltrial.gov identifier of the PRODIGE 9 study: NCT00952029.Clinicaltrial.gov identifier of the PRODIGE 20 study: NCT01900717.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/patologia , Biologia Computacional , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Interpretação de Imagem Radiográfica Assistida por Computador , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida
3.
J Hepatol ; 71(3): 516-522, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31125576

RESUMO

BACKGROUND & AIMS: Sorafenib is the standard of care for advanced hepatocellular carcinoma (HCC). Combining sorafenib with another treatment, to improve overall survival (OS) within an acceptable safety profile, might be the next step forward in the management of patients with advanced HCC. We aimed to assess whether a combination of sorafenib and a statin improved survival in patients with HCC. METHODS: The objective of the PRODIGE-11 trial was to compare the respective clinical outcomes of the sorafenib-pravastatin combination (arm A) versus sorafenib alone (arm B) in patients with advanced HCC. Child-Pugh A patients with advanced HCC who were naive to systemic treatment (n = 323) were randomly assigned to sorafenib-pravastatin combination (n = 162) or sorafenib alone (n = 161). The primary endpoint was OS; secondary endpoints were progression-free survival, time to tumor progression, time to treatment failure, safety, and quality of life. RESULTS: After randomization, 312 patients received at least 1 dose of study treatment. After a median follow-up of 35 months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7 months vs. 10.5 months; hazard ratio = 1.00; p = 0.975); no difference was observed in secondary survival endpoints either. In the univariate analysis, the significant prognostic factors for OS were CLIP score, performance status, and quality of life scores. The multivariate analysis showed that the only prognostic factor for OS was the CLIP score. The main toxicity was diarrhea (which was severe in 11% of patients in arm A, and 8.9% in arm B), while severe nausea-vomiting was rare, and no toxicity-related deaths were reported. CONCLUSION: Adding pravastatin to sorafenib did not improve survival in patients with advanced HCC. LAY SUMMARY: Sorafenib has proven efficacy for the treatment of patients with advanced hepatocellular carcinoma. However, overall survival remains poor in these patients, so we were interested to see if the addition of a statin, pravastatin, improved outcomes in patients with advanced HCC. This randomized-controlled trial demonstrated that the sorafenib-pravastatin combination did not improve overall survival in this study population compared to sorafenib alone. Clinical trial number: NCT01075555.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Pravastatina/uso terapêutico , Sorafenibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Diarreia/induzido quimicamente , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Pravastatina/efeitos adversos , Prognóstico , Intervalo Livre de Progressão , Qualidade de Vida , Sorafenibe/efeitos adversos
4.
Radiology ; 291(3): 801-808, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31038408

RESUMO

Background A prior in vitro study showed that idarubicin was the most cytotoxic agent for hepatocellular carcinoma (HCC) cell lines. Idarubicin-loaded beads for transarterial chemoembolization (TACE) were previously evaluated for the appropriate dose in a phase I dose-escalation study. Purpose To evaluate objective response rate (ORR), safety, and survival after TACE by using idarubicin-loaded beads for unresectable HCC. Materials and Methods This prospective single-arm phase II study was conducted between January 2015 and January 2017. Participants with unresectable HCC were included in the trial and underwent TACE with idarubicin-eluting beads. The primary end point was 6-month ORR assessed with independent central review by using modified Response Evaluation Criteria in Solid Tumors. Secondary end points were best ORR during the first 6 months, overall survival, progression-free survival, time to progression, and safety. A two-stage Fleming statistical design was used. Results Forty-six study participants (mean age, 71.2 years ± 10.2; six women and 40 men) were included; 44 participants underwent at least one TACE session. The 6-month ORR was 52% (23 of 44). The best ORR achieved was 68% (30 of 44). Fourteen of 44 (32%) participants underwent a curative treatment after TACE. Median progression-free survival, time to progression, and overall survival were 6.6 months, 9.5 months, and 18.6 months, respectively. TACE was discontinued for toxicity in four of 44 (9%) participants. The most frequent grade 3-4 adverse events were elevated aspartate aminotransferase (14 of 44, 32%), elevated γ-glutamyl transpeptidase (eight of 44, 18%), hyperbilirubinemia (seven of 44, 16%), elevated alanine aminotransferase (seven of 44, 16%), and pain (seven of 44, 16%). Conclusion Idarubicin-eluting beads showed a good safety profile and promising objective response rate and time to progression when used as part of a transarterial chemoembolization regimen for unresectable hepatocellular carcinoma. © RSNA, 2019 See also the editorial by Padia in this issue.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Idarubicina/uso terapêutico , Neoplasias Hepáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Feminino , Humanos , Idarubicina/administração & dosagem , Idarubicina/efeitos adversos , Masculino , Pessoa de Meia-Idade
5.
JAMA Netw Open ; 7(8): e2425581, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-39093560

RESUMO

Importance: The prognosis of patients with adenocarcinoma of the esophagus and esophagogastric junction (AEG) is poor. From current evidence, it remains unclear to what extent preoperative chemoradiotherapy (CRT) or preoperative and/or perioperative chemotherapy achieve better outcomes than surgery alone. Objective: To assess the association of preoperative CRT and preoperative and/or perioperative chemotherapy in patients with AEG with overall survival and other outcomes. Data Sources: Literature search in PubMed, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, ClinicalTrials.gov, and International Clinical Trials Registry Platform was performed from inception to April 21, 2023. Study Selection: Two blinded reviewers screened for randomized clinical trials comparing preoperative CRT plus surgery with preoperative and/or perioperative chemotherapy plus surgery, 1 intervention with surgery alone, or all 3 treatments. Only data from participants with AEG were included from trials that encompassed mixed histology or gastric cancer. Among 2768 initially identified studies, 17 (0.6%) met the selection criteria. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines were followed for extracting data and assessing data quality by 2 independent extractors. A bayesian network meta-analysis was conducted using the 2-stage approach. Main Outcomes and Measures: Overall and disease-free survival, postoperative morbidity, and mortality. Results: The analyses included 2549 patients (2206 [86.5%] male; mean [SD] age, 61.0 [9.4] years) from 17 trials (conducted from 1989-2016). Both preoperative CRT plus surgery (hazard ratio [HR], 0.75 [95% credible interval (CrI), 0.62-0.90]; 3-year difference, 105 deaths per 1000 patients) and preoperative and/or perioperative chemotherapy plus surgery (HR, 0.78 [95% CrI, 0.64-0.91]; 3-year difference, 90 deaths per 1000 patients) showed longer overall survival than surgery alone. Comparing the 2 modalities yielded similar overall survival (HR, 1.04 [95% CrI], 0.83-1.28]; 3-year difference, 15 deaths per 1000 patients fewer for CRT). Similarly, disease-free survival was longer for both modalities compared with surgery alone. Postoperative morbidity was more frequent after CRT plus surgery (odds ratio [OR], 2.94 [95% CrI, 1.01-8.59]) than surgery alone. Postoperative mortality was not significantly more frequent after CRT plus surgery than surgery alone (OR, 2.50 [95% CrI, 0.66-10.56]) or after chemotherapy plus surgery than CRT plus surgery (OR, 0.44 [95% CrI, 0.08-2.00]). Conclusions and Relevance: In this meta-analysis of patients with AEG, both preoperative CRT and preoperative and/or perioperative chemotherapy were associated with longer survival without relevant differences between the 2 modalities. Thus, either of the 2 treatments may be recommended to patients.


Assuntos
Adenocarcinoma , Quimiorradioterapia , Neoplasias Esofágicas , Junção Esofagogástrica , Metanálise em Rede , Neoplasias Gástricas , Humanos , Adenocarcinoma/terapia , Adenocarcinoma/mortalidade , Junção Esofagogástrica/patologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/mortalidade , Quimiorradioterapia/métodos , Neoplasias Gástricas/terapia , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/tratamento farmacológico , Masculino , Cuidados Pré-Operatórios/métodos , Pessoa de Meia-Idade , Feminino , Idoso , Intervalo Livre de Doença
6.
Cancer Med ; 12(5): 5341-5351, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36394147

RESUMO

BACKGROUND: Around 50% of gastric cancers are diagnosed at an advanced stage. Several chemotherapy regimens are now internationally validated. Few data are available on the routine daily management of advanced gastric or gastroesophageal junction cancers. We aimed to describe chemotherapy practices, tolerance, and efficacy overall survival (OS) and Progression free survival (PFS) in a prospective French cohort. METHODS: Patients starting palliative chemotherapy were prospectively enrolled in 49 French centres. The primary objective was to report and describe patients' characteristics and treatment strategies. Secondary objectives were OS, PFS, objective response rate, adverse events rate, performance status deterioration during the chemotherapy. RESULTS: A total of 182 patients were included; 179 were analysed. Most patients received platinium-based chemotherapy as the first treatment and FOLFIRI as second; 62.0% of patients received a second line, and 32.4% a third line. More than two thirds of Her2-positive patients were first treated with trastuzumab. The FOLFIRI regimen was the most frequently used second-line therapy. Median OS was 13.3 months, similar whatever the chemotherapy or combinations used in the first line. One- and 2-year OS increased with the number of chemotherapy lines received, from respectively 24.7% and 5.7% (1 line), to 46.9% and 12.4% (2 lines) and 88.1% and 29.9% (3 or more lines) (p < 0.0001). CONCLUSION: Our study showed that treatment strategies in France are based on a succession of doublets, making it possible to offer a second and third line of treatment more often. This treatment strategy must be taken into account for future trials with immunotherapy combinations.


Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Estudos Prospectivos , Junção Esofagogástrica , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
7.
Dig Liver Dis ; 55(4): 541-548, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36115817

RESUMO

BACKGROUND: Colon adenocarcinoma mainly occurs in older patients. Oxaliplatin-based adjuvant chemotherapy improved disease-free survival after stage III colon cancer resection, but this improvement was not demonstrated in older patients. METHODS: The purpose of ADAGE-PRODIGE 34, randomized open phase III trial is to compare in patients over 70 years oxaliplatin plus fluoropyrimidine with fluoropyrimidine alone in fit patients (Group 1) and fluoropyrimidine with observation in frail patients (Group 2) after resection of stage III colon adenocarcinoma. We report a preliminary tolerance analysis on 50% of the first patients enrolled. RESULTS: The analysis was conducted on 491 patients (378 in Group 1 and 113 in Group 2). Patients in Group 2 were older and showed more frailty criteria than those in Group 1. Cumulative grade 3-5 toxicities were more frequent in patients treated with oxaliplatin in Group 1 or with fluoropyrimidine in Group 2 than in patients treated with fluoropyrimidine in Group 1. At least one course was deferred in more than half of the patients in all groups. Early treatment cessation was more frequent in Group 2. CONCLUSION: No safety concerns were raised for the continuation of accrual. The frailty criteria distribution suggests that the investigator's evaluation for group allocation was accurate.


Assuntos
Adenocarcinoma , Neoplasias do Colo , Fragilidade , Humanos , Idoso , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/cirurgia , Neoplasias do Colo/patologia , Oxaliplatina/uso terapêutico , Fluoruracila/uso terapêutico , Capecitabina/efeitos adversos , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Adenocarcinoma/etiologia , Intervalo Livre de Doença , Quimioterapia Adjuvante/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estadiamento de Neoplasias , Leucovorina/uso terapêutico
8.
J Clin Oncol ; 40(3): 262-271, 2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-34662180

RESUMO

PURPOSE: Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown. METHODS: In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected). RESULTS: A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one). CONCLUSION: mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Cisplatino/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , França , Humanos , Irinotecano/efeitos adversos , Irinotecano/uso terapêutico , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/efeitos adversos , Oxaliplatina/uso terapêutico , Intervalo Livre de Progressão , Fatores de Tempo , Gencitabina
9.
Dig Liver Dis ; 53(6): 776-784, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33867291

RESUMO

INTRODUCTION: for localized T1N0 squamous cell carcinoma of the anus (SCCA) standard radiotherapy (RT) may result in overtreatment and alternative strategies are debated. METHODS: T1N0M0 SCCA treated between 2015 and 2020 by local excision (LE) or RT were analyzed from the French prospective FFCD ANABASE cohort. Treatment strategies, recurrence-free and colostomy-free survivals (RFS, CFS) and prognostic factors were reported. RESULTS: among 1135 SCCA patients, 99 T1N0M0 were treated by LE(n = 17,17.2%), or RT (n = 82,82.8%) including RT alone (n = 65,79.2%) or chemo-RT (n = 17, 20.7%). Median follow-up was 27.2 months [0.03-54.44]. Median tumor size were 11.4 mm [0.9-20] and 15.3 mm [2-20] in the LE and RT groups respectively. Mean RT tumor dose was 59.4 Gy [18-69.4 Gy]. One patient in LE group and 9 in RT group had a pelvic recurrence, either local (60%), nodal (10%) or both (30%). RFS and CFS at 24 months were 92.2%[95%CI,83.4-96.4] and 94.6%[95%CI,86.1-98.0], at 36 months 88.1%[95%CI,77.1-94.2] and 88.5%[95%CI,77.0-94.5], in LE and RT group respectively, without any significative difference (HR = 0.57;[95%CI,0.07-4.45];p = 0.60). By univariate analysis, male gender was the only prognostic factor(HR = 5.57;95%CI, 1.76-17.63; p = 0.004). CONCLUSION: this cohort confirms the heterogeneity of T1N0M0 SCCA management, questioning the place of RT alone, reduced dose or RT volume, and the safety of LE.


Assuntos
Canal Anal/cirurgia , Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Radioterapia , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Ânus/patologia , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Dig Liver Dis ; 53(3): 318-323, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33359404

RESUMO

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Feminino , França , Humanos , Masculino , Instabilidade de Microssatélites , Estudos Multicêntricos como Assunto , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Cancers (Basel) ; 13(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430396

RESUMO

PURPOSE: Chemo-radiotherapy (CRT) is the standard treatment for non-metastatic anal squamous cell carcinomas (ASCC). Despite excellent results for T1-2 stages, relapses still occur in around 35% of locally advanced tumors. Recent strategies focus on treatment intensification, but could benefit from a better patient selection. Our goal was to assess the prognostic value of pre-therapeutic MRI radiomics on 2-year disease control (DC). METHODS: We retrospectively selected patients with non-metastatic ASCC treated at the CHU Bordeaux and in the French FFCD0904 multicentric trial. Radiomic features were extracted from T2-weighted pre-therapeutic MRI delineated sequences. After random division between training and testing sets on a 2:1 ratio, univariate and multivariate analysis were performed on the training cohort to select optimal features. The correlation with 2-year DC was assessed using logistic regression models, with AUC and accuracy as performance gauges, and the prediction of disease-free survival using Cox regression and Kaplan-Meier analysis. RESULTS: A total of 82 patients were randomized in the training (n = 54) and testing sets (n = 28). At 2 years, 24 patients (29%) presented relapse. In the training set, two clinical (tumor size and CRT length) and two radiomic features (FirstOrder_Entropy and GLCM_JointEnergy) were associated with disease control in univariate analysis and included in the model. The clinical model was outperformed by the mixed (clinical and radiomic) model in both the training (AUC 0.758 versus 0.825, accuracy of 75.9% versus 87%) and testing (AUC 0.714 versus 0.898, accuracy of 78.6% versus 85.7%) sets, which led to distinctive high and low risk of disease relapse groups (HR 8.60, p = 0.005). CONCLUSION: A mixed model with two clinical and two radiomic features was predictive of 2-year disease control after CRT and could contribute to identify high risk patients amenable to treatment intensification with view of personalized medicine.

12.
Dig Liver Dis ; 52(10): 1143-1147, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32747302

RESUMO

BACKGROUND: Maintenance treatments with fluoropyrimidine alone or combined with bevacizumab after induction chemotherapy are two standard options in first-line metastatic colorectal cancer (mCRC). However, no trial has compared these two maintenance regimens. METHODS: BEVAMAINT is a multicenter, open-label, randomized phase III trial comparing fluoropyrimidine alone or plus bevacizumab as maintenance treatment after induction polychemotherapy in mCRC. The primary endpoint is the time-to-treatment failure (TTF), calculated from date of randomization to first radiological progression, death, start of a new chemotherapy regimen (different from induction or maintenance chemotherapy) or end of maintenance treatment without introduction of further chemotherapy. We expect a 2-month TTF improvement from 6 months in the monotherapy arm to 8 months in the combination arm (hazard ratio [HR], 0.75). Based on a two-sided α risk of 5% and a power of 80%, using Schoenfeld method, 379 events are required (planned enrolment, 400 patients). Patients with mCRC, whose disease is measurable according to RECIST 1.1 criteria and controlled (objective response or stable disease) - but remains unresectable - after 4 to 6 months of induction polychemotherapy (doublet or triplet chemotherapy with or without anti-EGFR or bevacizumab), and who have recovered from limiting adverse events of induction polychemotherapy are eligible for randomization. Randomization is stratified according to center, response to induction chemotherapy (objective response vs stable disease), ECOG performance status (0-1 vs 2), maintenance fluoropyrimidine (5-fluorouracil vs capecitabine) and primary tumor status (resected vs not). Capecitabine or bolus and infusional 5-fluorouracil plus folinic acid (simplified LV5FU2 regimen) are both accepted for maintenance chemotherapy, at investigator's discretion. Clinical evaluation, tumor imaging, carcinoembryonic antigen and circulating tumor DNA dosages are planned at enrolment and every 9 weeks. The maintenance treatment will be discontinued in the event of unbearable toxicity, progression or patient refusal. After maintenance discontinuation, reintroduction of induction polychemotherapy is recommended; otherwise a second-line treatment is started. The enrolment has begun in January 2020.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Bevacizumab/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Quimioterapia de Indução/métodos , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Ensaios Clínicos Controlados Aleatórios como Assunto
13.
Dig Liver Dis ; 52(3): 347-350, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31899122

RESUMO

Half of patients newly diagnosed with esophageal squamous cell cancer (ESCC) have metastatic disease (mESCC) and therefore a poor prognosis. Furthermore, half of patients with initial loco-regional disease present disease recurrence after surgery and/or chemoradiation. In mESCC, the recommended first-line treatment combines 5-fluorouracil and cisplatin, although this has not been validated by a phase III trial. Patients with disease progression or recurrence after platinum-based chemotherapy and good performance status probably benefit from second-line chemotherapy. Several molecules have been evaluated in phase I/II trials or retrospective studies (docetaxel, paclitaxel and irinotecan) but no randomised studies are available. OESIRI is a multicentre, randomised, open-label phase II trial designed to evaluate efficacy and safety of liposomal irinotecan (nal-IRI) plus 5-FU versus paclitaxel as second-line therapy in patients with mESCC. The main inclusion criteria are histologically proven mESCC in progression after first-line platinum-based chemotherapy. Patients with initial resectable disease can be included if recurrence occurred within 6 months. The primary objective is to evaluate the percentage of patients alive 9 months after randomisation. Secondary endpoints are progression-free survival, overall survival, response rate, safety and quality of life. In addition, circulating tumour DNA will be monitored to assess its prognostic value.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Fluoruracila/administração & dosagem , França , Humanos , Irinotecano/administração & dosagem , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia , Paclitaxel/administração & dosagem , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida
14.
Radiother Oncol ; 140: 84-89, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31185328

RESUMO

BACKGROUND AND PURPOSE: Standard treatment of epidermoid anal cancer is 5-fluorouracil (5FU) and mitomycin C (MMC) based chemoradiotherapy (CRT). This phase I study aims to evaluate the addition of panitumumab (Pmab) to CRT and to determine the maximum tolerated dose (MTD) of Pmab and 5-FU in combination with CRT. MATERIALS AND METHODS: Immunocompetent patients with locally advanced tumour without metastases (Stage T2, T3 or T4, whatever N stage; Stage N1-N3 whatever T stage) followed two RT periods (45 Gy in 5 weeks and 20 Gy in 2 weeks, separated by a 2-week break) with concomitant CT sessions of 5FU/MMC at RT weeks 1, 5 and 8. Pmab was administered on RT weeks 1, 3, 5, 8 and 10 according to a predefined dose escalation schedule. RESULTS: Ten patients were enroled. One was excluded due to unmet dose constraints respect. Three patients received dose level (DL) 0 (Pmab 3 mg/kg + 5FU 600 mg/m2/day) and six received DL-1 (Pmab 3 mg/kg + 5FU 400 mg/m2/day). Dose-limiting toxicities occurred in all patients at DL 0 and 2 at DL-1. Most common grade 3-4 toxicities observed at DL 0 were haematologic (100%), dermatitis (67%), and anaemia (67%). No death occurred. Four months after ending CRT, five and two patients had a local complete response and a partial response, respectively. One patient had a colostomy with abdomino-perineal amputation due to a tumour recurrence. CONCLUSIONS: The MTD is 5FU at 400 mg/m2/day, MMC at 10 mg/m2 and Pmab at 3 mg/kg. The effect of the MTD on tumour response is evaluated in the phase 2 study.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/terapia , Quimiorradioterapia , Receptores ErbB/antagonistas & inibidores , Panitumumabe/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Mitomicina/administração & dosagem , Estudos Prospectivos
15.
Dig Liver Dis ; 51(2): 318-320, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30581069

RESUMO

INTRODUCTION: Combination of cisplatine and Gemcitabine (CisGem) is the reference 1st line Chemotherapy in patients with advanced biliary cancer. FOLFIRINOX demonstrated an overall survival superiority when compared to gemcitabine in 1st line for patients with metastatic pancreatic adenocarcinoma. Because of similarities between pancreatic and biliary cancers, we proposed a randomized trial comparing mFOLFIRINOX and CisGEm. AIM: PRODIGE38-AMEBICA is a phase II/III trial evaluating efficacy of modifed FOLFIRINOX (D1 bolus removed) or CisGEm on patients with locally advanced non resectable or metastatic biliary tract cancer. PATIENTS AND METHODS: Main inclusion criteria are histologically or cytologically proven biliary tract tumor (intra or extra hepatic or hilar or gallbladder carcinoma), measurable disease (metastases and/or primary tumor), Bilirubin <1,5 N and transaminases <5 N. The randomization (ratio 1:1) will be stratified on center, stage of the disease, tumor localization and previous adjuvant treatment. The Phase II trial has an objective of 73% patients alive and without progression at 6 months for Folfirinox (versus 59% for Gemcis). 128 additional patients should be added in the phase III trial with an objective of overall survival improvement of 4 months in favor of mFOLFIRINOX. CONCLUSION: The study is opened in France (EudraCT no.: 2015-002282-35). All the patients (188) of the phase II part are currently randomized.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias dos Ductos Biliares , Carcinoma , Cisplatino/administração & dosagem , Desoxicitidina/análogos & derivados , Antineoplásicos/administração & dosagem , Neoplasias dos Ductos Biliares/tratamento farmacológico , Neoplasias dos Ductos Biliares/patologia , Carcinoma/tratamento farmacológico , Carcinoma/patologia , Desoxicitidina/administração & dosagem , Monitoramento de Medicamentos , Feminino , Fluoruracila/administração & dosagem , França , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Masculino , Invasividade Neoplásica , Estadiamento de Neoplasias , Oxaliplatina/administração & dosagem , Gencitabina
16.
Eur J Cancer ; 123: 92-100, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31678771

RESUMO

BACKGROUND: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity. METHODS: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%. RESULTS: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%). CONCLUSIONS: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease. TRIAL REGISTRATION: NCT01678664 (clinicaltrials.gov).


Assuntos
Antineoplásicos/uso terapêutico , Embolização Terapêutica , Everolimo/uso terapêutico , Neoplasias Gastrointestinais/patologia , Artéria Hepática , Neoplasias Hepáticas/terapia , Tumores Neuroendócrinos/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Quimioembolização Terapêutica , Doxorrubicina/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/secundário , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/secundário , Intervalo Livre de Progressão , Estreptozocina/administração & dosagem
17.
Eur J Cancer ; 98: 1-9, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29807237

RESUMO

BACKGROUND: Previous studies showed that high and low body mass index (BMI) was associated with worse prognosis in early-stage colorectal cancer (CRC), and low BMI was associated with worse prognosis in metastatic CRC (mCRC). We aimed to assess efficacy outcomes according to BMI. PATIENTS AND METHODS: A pooled analysis of individual data from 2085 patients enrolled in eight FFCD first-line mCRC trials from 1991 to 2013 was performed. Comparisons were made according to the BMI cut-off: Obese (BMI ≥30), overweight patients (BMI ≥ 25), normal BMI patients (BMI: 18.5-24) and thin patients (BMI <18.5). Interaction tests were performed between BMI effect and sex, age and the addition of antiangiogenics to chemotherapy. RESULTS: The rate of BMI ≥25 patients was 41.5%, ranging from 37.6% (1991-1999 period) to 41.5% (2000-2006 period) and 44.8% (2007-2013 period). Comparison of overweight patients versus normal BMI range patients revealed a significant improvement of median overall survival (OS) (18.5 versus 16.3 months, HR = 0.88 [0.80-0.98] p = 0.02) and objective response rate (ORR) (42% versus 36% OR = 1.23 [1.01-1.50] p = 0.04) but a comparable median progression-free survival (PFS) (7.8 versus 7.2 months, HR = 0.96 [0.87-1.05] p = 0.35). Subgroup analyses revealed that overweight was significantly associated with better OS in men. OS and PFS were significantly shorter in thin patients. CONCLUSION: Overweight patients had a prolonged OS compared with normal weight patients with mCRC. The association of overweight with better OS was only observed in men. The pejorative prognosis of BMI <18.5 was confirmed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Índice de Massa Corporal , Neoplasias Colorretais/tratamento farmacológico , Sobrepeso/fisiopatologia , Idoso , Inibidores da Angiogênese/administração & dosagem , Ensaios Clínicos como Assunto , Neoplasias Colorretais/patologia , Neoplasias Colorretais/fisiopatologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Metástase Neoplásica , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Prognóstico
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