RESUMO
BACKGROUND: Trans-arterial chemoembolization (TACE) is one first-line option therapy for patients with hepatocellular carcinoma (HCC) not suitable for surgical resection. AIMS: We evaluated the effects of sunitinib plus doxorubicin-TACE on bleeding or liver failure. METHODS: Seventy-eight patients with HCC were included in this randomized, double-blind study. They received one to three TACE plus either sunitinib or placebo four weeks out of six for one year. The occurrence of severe bleeding or liver failure was assessed during the week after the TACE. The safety and survival outcomes were evaluated. RESULTS: No bleeding complication was reported. One and two liver failures were respectively observed in sunitinib and placebo patients. Compliance to sunitinib treatment was acceptable. Sunitinib dose reduction occurred in 37% of patients due to acute toxicity. Main grade 3-4 toxicities were: thrombocytopenia, neutropenia, increased bilirubin, increased ALT and asthenia. In the sunitinib group, the median PFS and OS were 9.05 [5.81;11.63] and 25.0 [13.5;36.8] months, respectively. In the placebo group, the median PFS and OS were 5.51 [4.14;7.79] and 20.5 [15.1;30.6] months, respectively. CONCLUSIONS: TACE plus sunitinib in the first-line therapy for patients with HCC not suitable for surgical resection was feasible. CLINICALTRIALS. GOV NUMBER: NCT01164202.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Falência Hepática , Neoplasias Hepáticas , Carcinoma Hepatocelular/terapia , Humanos , Neoplasias Hepáticas/terapia , Sunitinibe , Resultado do TratamentoRESUMO
BACKGROUND: Disturbances in fatty acid (FA) metabolism have been reported in cirrhosis, but the role of FAs in the development of hepatocellular carcinoma (HCC) is still unclear. Biomarkers are a promising means to explore the associations between exogenous intake or endogenous production of FAs and cancer risk. AIM: To estimate the relationship between fatty acid content in erythrocyte membranes and HCC risk in cirrhotic patients METHODS: The "CiRCE" case-control study recruited cirrhotic patients from six French hospitals between 2008 and 2012. Cases were cirrhotic patients with HCC (n = 349); controls were cirrhotic patients without HCC at inclusion (n = 550). FA composition of phospholipids in erythrocyte membranes was determined by high performance gas chromatography. Odds ratios for HCC risk according to FA concentrations were estimated with multivariable logistic regression. RESULTS: HCC patients were older and more often men (P < 0.001). In both groups, saturated FAs represented more than 39% of all FAs in erythrocyte membranes, mono-unsaturated FAs around 14%, and polyunsaturated FAs around 46%. High levels of C15:0 + C17:0, C20:1 n-9, C18:2 n-6 and C20:2 n-6 were associated with higher risk of HCC. The levels of C18:0 and C20:4 n-6 were lower in HCC cases than in controls. CONCLUSIONS: The FA composition of erythrocyte membranes differed according to the presence of HCC with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids. These alterations may reflect particular dietary patterns and/or altered FA metabolism. Further investigations are warranted.
Assuntos
Carcinoma Hepatocelular/sangue , Membrana Eritrocítica/química , Ácidos Graxos/sangue , Cirrose Hepática/sangue , Neoplasias Hepáticas/sangue , Idoso , Biomarcadores/sangue , Carcinoma Hepatocelular/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Cirrose Hepática/epidemiologia , Neoplasias Hepáticas/epidemiologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fosfolipídeos/sangue , Fatores de RiscoRESUMO
BACKGROUND: Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection. METHODS: In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session. RESULTS: Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3). CONCLUSIONS: Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal. CLINICAL TRIAL REGISTRATION: NCT01839877.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioembolização Terapêutica/métodos , Neoplasias Colorretais/terapia , Irinotecano/administração & dosagem , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioembolização Terapêutica/efeitos adversos , Terapia Combinada , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Humanos , Irinotecano/efeitos adversos , Leucovorina/administração & dosagem , Leucovorina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/efeitos adversos , Análise de Sobrevida , Resultado do TratamentoRESUMO
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 SobrevidaRESUMO
BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care. PATIENTS AND METHODS: Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%. RESULTS: After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3-4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9-7.2) in the HAI group and 2.2 months (95% CI 1.2-4.3) with standard of care [HR 0.32 (95% CI 0.14-0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8-17.6) for the HAI group and 11.9 months (95% CI 2.8-14.3) for standard of care [HR 0.86 (95% CI 0.36-2.04), p = 0.73]. CONCLUSION: Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Oxaliplatina/administração & dosagem , Quinazolinas/administração & dosagem , Tiofenos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/efeitos adversos , Quimioterapia do Câncer por Perfusão Regional/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , França , Artéria Hepática , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Quinazolinas/efeitos adversos , Padrão de Cuidado , Tiofenos/efeitos adversos , Resultado do TratamentoRESUMO
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 (nâ¯=â¯323) were randomly assigned to sorafenib-pravastatin combination (nâ¯=â¯162) or sorafenib alone (nâ¯=â¯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 35â¯months, 269 patients died (arm A: 135; arm B: 134) with no difference in median OS between treatments arms (10.7â¯months vs. 10.5â¯months; hazard ratioâ¯=â¯1.00; pâ¯=â¯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 adversosRESUMO
BACKGROUND: Hypersensitivity reactions to platinum salts (PS) (cisplatin [CI], carboplatin [CA], and oxaliplatin [OX]) can be severe and their incidence is increasing due to their widespread use in cancer treatment. OBJECTIVE: To determine the rate of cross-reactivity between PS and whether CI can be administered without prior allergy testing in patients with a history of CA or OX hypersensitivity. METHODS: From September 2002 to April 2016, patients with suspected immediate PS hypersensitivity were tested and cross-reactivity between the 3 PS was evaluated. We then studied patients who were given CI without desensitization after immediate hypersensitivity to other PS. RESULTS: A total of 155 patients were included. Skin tests were positive in 97 patients (OX: 51, CA: 43, and CI: 3). Cross-reactivity to CA in OX-allergic patients was 45% (23 of 51) (95% confidence interval [CI]: 36% to 66%) and cross-reactivity to OX in CA-allergic patients was 37% (16 of 43) (95% CI: 23% to 53%). In contrast, cross-reactivity to CI was 0% (0 of 51) (95% CI: 0% to 7%) in OX-allergic patients and 7% (3 of 43) (95% CI: 2% to 17%) in CA-allergic patients. All these 3 patients had previously been exposed to CI in previous courses of chemotherapy. CI was initiated in 24 patients with proven hypersensitivity to CA or OX and had no hypersensitivity reactions. CONCLUSION: Initiating CI in patients with proven immediate hypersensitivity to CA or OX appeared to be safe in our study.
Assuntos
Antineoplásicos/efeitos adversos , Carboplatina/uso terapêutico , Hipersensibilidade a Drogas/epidemiologia , Neoplasias/tratamento farmacológico , Oxaliplatina/efeitos adversos , Compostos de Platina/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Reações Cruzadas , Hipersensibilidade a Drogas/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Sais , Testes CutâneosRESUMO
PURPOSE: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/cirurgia , Procedimentos Cirúrgicos do Sistema Biliar , Desoxicitidina/análogos & derivados , Oxaliplatina/administração & dosagem , Conduta Expectante , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Procedimentos Cirúrgicos do Sistema Biliar/mortalidade , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Feminino , França , Humanos , Masculino , Pessoa de Meia-Idade , Oxaliplatina/efeitos adversos , Intervalo Livre de Progressão , Qualidade de Vida , Fatores de Tempo , GencitabinaRESUMO
GOALS: The aims of this study were to evaluate whether cytomegalovirus (CMV) infection is associated with hepatocellular carcinoma (HCC) and liver-related mortality in cirrhotic patients. BACKGROUND: In cirrhotic patients, the determinants of HCC and liver-related death are imperfectly known. CMV infection, by its prooncogenic and proinflammatory properties, may favor both the development of HCC and deleterious systemic inflammation. STUDY: In the 1178 patients included between June 2008 and December 2012 in the CIrrhose et Risque de Carcinome Hépatocellulaire dans le grand-Est (CIRCE) study, a French multicenter case-control study designed to identify risk factors of HCC among cirrhotic patients, we identified 432 patients with interpretable CMV serological status at baseline. They included 159 cases with HCC and 273 controls. We measured factors associated with HCC at baseline and subsequent HCC in controls, and predictors of overall and liver-related death in the whole study population. RESULTS: During a median follow-up of 31 months, 25 cases of HCC developed in controls, and 209 deaths (163 liver-related) were recorded. There were 247 (57.2%) CMV-seropositive patients. CMV seropositivity was not associated with more frequent HCC at baseline or during follow-up, but among CMV-positive patients with HCC, the proportion of multinodular, infiltrative, or metastatic tumors at diagnosis was higher (73.8% vs. 57.3%; P=0.029), inducing higher mortality (74% vs. 52% at 3 years; P=0.004). By Cox-regression adjusted for age, gender, Model for End-stage Liver Disease (MELD) score, HCC at baseline, and diabetes, CMV seropositivity independently predicted all-cause (hazard ratio=1.45; 95% confidence interval, 1.08-1.94; P=0.013) and liver-related mortality (hazard ratio=1.56; 95% confidence interval, 1.04-2.30; P=0.031). CONCLUSIONS: In this preliminary study, CMV-seropositive cirrhotic patients were at higher risk of liver-related death caused by more aggressive HCCs or severe cirrhosis complications. These findings warrant confirmation.
Assuntos
Carcinoma Hepatocelular/epidemiologia , Infecções por Citomegalovirus , Cirrose Hepática , Neoplasias Hepáticas/epidemiologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/mortalidade , Estudos de Casos e Controles , Feminino , França/epidemiologia , Humanos , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/mortalidade , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10â¯mg, four patients at 15â¯mg, seven patients at 20â¯mg, and three patients at 25â¯mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25â¯mg, respectively. The calculated MTD of idarubicin was 20â¯mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4â¯months [95% confidence limit (CI) 3.0-14.6â¯months] and median overall survival was 20.6â¯months (95% CI 5.7-28.7â¯months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20â¯mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Idarubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Idoso , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/toxicidade , Carcinoma Hepatocelular/sangue , Emulsões , Óleo Etiodado/administração & dosagem , Feminino , Humanos , Idarubicina/sangue , Idarubicina/toxicidade , Injeções Intra-Arteriais , Neoplasias Hepáticas/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Qualidade de Vida , Segurança , Resultado do TratamentoRESUMO
The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10-4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 'AAA' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)-P=1.31×10-2]. In the Derivation#2 study, results were confirmed for the BRIP1 'GGG' haplotype [OR, 0.53 (0.36-0.79); FDR-P=3.90×10-3]. In both Validation#1 and #2 studies, BRIP1 'AAA' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR-P=7.30×10-2; and OR, 6.45 (4.17-9.99); FDR-P=2.33×10-19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.
RESUMO
AIM: Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis. METHOD: Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm3 and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL. CONCLUSION: The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Neoplasias Colorretais/mortalidade , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Avaliação Geriátrica , Humanos , Irinotecano , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Metástase Neoplásica , Estudos Prospectivos , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVES: The objective of this study was to explore the association between health-related quality of life (HRQoL) and the recommended phase 2 dose in a phase I clinical trial according to the Time to HRQoL deterioration approach (TTD). SETTING: This is a phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads performed in cirrhotic patients with hepatocellular carcinoma. Patients had to complete the EORTC QLQ-C30 HRQoL questionnaire at baseline and at days 15, 30 and 60 after TACE. PARTICIPANTS: Patients aged ≥18â years with HCC unsuitable for curative treatments were evaluated for the study (N=21). PRIMARY AND SECONDARY OUTCOME MEASUREMENTS: The primary objective was to determine the maximum tolerated dose (MTD) of idarubicin loaded after a single TACE session. MTD was defined as the dose level closest to that causing dose-limiting toxicity in 20% of patients. HRQoL was the secondary end point. RESULTS: Between March 2010 and March 2011, 9, 6 and 6 patients were included at idarubicin dose levels of 5, 10 and 15â mg, respectively. Calculated MTD of idarubicin was 10â mg. At the 10â mg idarubicin dose, patients presented a longer TTD than at 5â mg, for global health status (HR=0.91 (95% CI 0.18 to 4.72)), physical functioning (HR=0.38 (0.04 to 3.22)), fatigue (HR=0.67 (0.18 to 2.56)) and pain (HR=0.47 (0.05 to 4.24)). CONCLUSIONS: These HRQoL results were consistent with the estimated MTD, with a median TTD for global health status of 41â days (21 to NA) at 5â mg, 23â days (20 to NA) at 10â mg and 25â days (17 to NA) at 15â mg. These results show the importance of studying HRQoL in phase I trials. TRIAL REGISTRATION NUMBER: NCT01040559; Post-results.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Quimioembolização Terapêutica , Idarubicina/administração & dosagem , Neoplasias Hepáticas/tratamento farmacológico , Qualidade de Vida , Idoso , Antibióticos Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/mortalidade , Intervalo Livre de Doença , Fadiga/induzido quimicamente , Feminino , Humanos , Idarubicina/efeitos adversos , Neoplasias Hepáticas/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Dor/induzido quimicamenteRESUMO
BACKGROUND: Two randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended. METHODS: Eligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations. FINDINGS: Of the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p=0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p=0.58). Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR)=0.39 [0.25-0.61]; p<0.0001), and again was not different from that in responding, randomised patients (p=0.40). INTERPRETATION: In patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.
Assuntos
Adenocarcinoma/terapia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Esofagectomia , Terapia Neoadjuvante , Radioterapia Adjuvante , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/mortalidade , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/patologia , Neoplasias Esofágicas/cirurgia , Carcinoma de Células Escamosas do Esôfago , Esofagectomia/efeitos adversos , Esofagectomia/mortalidade , Feminino , França , Humanos , Estimativa de Kaplan-Meier , Masculino , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/mortalidade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Radioterapia Adjuvante/efeitos adversos , Radioterapia Adjuvante/mortalidade , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become a routine imaging modality for many malignancies and its use is currently increasing. In the present review article, we will summarize the evidence for FDG-PET/CT use in digestive cancers (excluding neuroendocrine tumours), and review the existing recommendations. While PET/CT is nowadays considered to be an important tool in the initial workup of oesophageal and anal cancers, new data are emerging regarding its use in assessing therapeutic efficacy, radiotherapy treatment planning, and detection of recurrence in case of isolated tumour marker elevation. Moreover, PET/CT may help decision making by detecting distant metastatic sites especially in potentially resectable metastatic colorectal cancer and, to a lesser extent, in localized gastric and pancreatic cancers. Finally, incidental focal colonic FDG uptakes require exploration by colonoscopy, as they are often associated with premalignant or malignant lesions.
Assuntos
Neoplasias do Sistema Digestório/diagnóstico , Fluordesoxiglucose F18 , Imagem Multimodal , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Humanos , Recidiva Local de Neoplasia/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Planejamento de Assistência ao Paciente , Guias de Prática Clínica como Assunto , PrognósticoRESUMO
BACKGROUND: Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH). PATIENTS AND METHODS: Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ⩽ 2, bilirubinemia ⩽ 50 µM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine+oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications. RESULTS: The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (± 2.8). Grade III-IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65-3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32-1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31-1.55]). CONCLUSIONS: Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Biliar/terapia , Quimiorradioterapia/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Sistema Biliar/mortalidade , Neoplasias do Sistema Biliar/patologia , Quimiorradioterapia/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Resultado do Tratamento , GencitabinaRESUMO
BACKGROUND: Transarterial chemoembolisation (TACE) is an effective treatment for unresectable hepatocellular carcinoma (HCC), but can cause severe toxicity. AIM: To identify predictive factors of severe TACE-related toxicity in patients with unresectable HCC. METHODS: All HCC patients who underwent TACE at the Dijon University Hospital between 2008 and 2011 were included in this retrospective study. Severe TACE-related toxicity was defined as the occurrence of any adverse event grade ≥ 4, or any adverse event that caused a prolongation of hospitalisation of >8 days, or any additional hospitalisation within 1 month after TACE. Factors predicting toxicity were identified using a logistic regression model. The robustness of the final model was confirmed using bootstrapping (500 replications). RESULTS: 124 patients were included, median age was 67 years and 90% were male; 22 patients (18%) experienced severe TACE-related toxicity. Factors that independently predicted severe TACE-related toxicity in multivariate analysis were total tumour size (OR, 1.15 cm(-1); 95%CI, 1.04-1.26; p=0.01), and high serum AST levels (OR, 1.10 per 10 IU/l; 95%CI, 1.01-1.21; p=0.04). The results were confirmed by bootstrapping. CONCLUSIONS: Total tumour size and high serum AST levels were predictive factors of severe TACE-related toxicity in this hospital-based series of patients with unresectable HCC.
Assuntos
Injúria Renal Aguda/etiologia , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/efeitos adversos , Encefalopatia Hepática/etiologia , Falência Hepática Aguda/etiologia , Neoplasias Hepáticas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Aspartato Aminotransferases/sangue , Carcinoma Hepatocelular/complicações , Carcinoma Hepatocelular/patologia , Doença Hepática Induzida por Substâncias e Drogas , Quimioembolização Terapêutica/mortalidade , Estudos de Coortes , Doxorrubicina/efeitos adversos , Feminino , Hepatite B Crônica/complicações , Hepatite C Crônica/complicações , Humanos , Idarubicina/efeitos adversos , Cirrose Hepática/complicações , Cirrose Hepática Alcoólica/complicações , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: For resectable gastric cancer, both postoperative chemoradiotherapy and perioperative chemotherapy demonstrate high-level evidence for improved survival in Western populations. To evaluate the feasibility of pre- or postoperative chemoradiotherapy, we proposed two multicentre phase II studies. PATIENTS AND METHODS: Patients with localised, histologically confirmed gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status <2 judged suitable for curative resection were eligible. Eligible patients were assigned to either preoperative chemoradiotherapy followed by surgical resection or surgical resection followed by chemoradiotherapy depending on each centre. Chemoradiotherapy regimen included four courses of FOLFIRI (5 Fluorouracil, Leucovorin, Irinotecan) regimen then Concurrent fluorouracil at 200 mg/m2/d by continuous infusion 5 days each week. A dose of 50 Gy in 25 fractions in the preoperative study, or 45 Gy in 25 fractions in the postoperative study, was delivered. The primary end-point for both studies was the proportion of patients, who completed the therapeutic sequence. RESULTS: Between September 2007 and January 2010, 63 patients were included in both studies. The postoperative study was stopped for futility at the first step. In the preoperative study, 31 patients (73.8%, confidence interval (CI) 95%: 65.8-90.1%) received complete therapeutic sequence. Serum albumin and dietary restriction evaluated by QLQ-STO22 (Quality of Life-Stomach module) score were significantly linked with chemoradiotherapy feasibility in univariate analysis with respectively Odds-ratio (OR) 1.16 [CI 95%: 1.01-1.33] and 0.17 [0.03-0.89], p=0.04. Median overall survival time was 26.4 months in the preoperative study. CONCLUSION: Feasibility of chemoradiotherapy was not achieved for these studies: 73.8% (CI 95%: 65.8-90.1) and 42.9% (CI 95%: 21.8-66%) in preoperative and postoperative settings respectively.
Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fracionamento da Dose de Radiação , Neoplasias Gástricas/terapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Quimiorradioterapia , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Período Pós-Operatório , Período Pré-Operatório , Estômago/efeitos dos fármacos , Estômago/efeitos da radiação , Estômago/cirurgia , Neoplasias Gástricas/cirurgia , Análise de Sobrevida , Resultado do TratamentoRESUMO
The association between liver cirrhosis (LC) and diabetes mellitus (DM) is well known. However, the impact of the severity or etiology of LC on the occurrence of DM is relatively unknown. We aimed to determine the prevalence and clinical correlates of DM in a large cohort of patients with cirrhosis. A total of 1,068 patients with LC were included in this cross sectional study (CIRCE study). The diagnosis of cirrhosis irrespective of its etiology was based on histological confirmation by liver biopsy or, in the absence of biopsy, on typical clinical, morphological and biological data. Data related to the cirrhosis etiology: alcohol, viral markers of hepatitis B, C, iron load parameters and autoimmune markers were collected for each patient. Venous blood samples were taken in the morning after 12-h overnight fasting. There were 383 patients with cirrhosis associated with hepatocellular carcinoma (HCC). DM was found in 412 (39.7 %) patients. Patients with DM were older and more likely to be overweight and male, with a family history of DM and a diagnosis of HCC. DM was not associated with a history of stroke or myocardial infarction. Cirrhosis secondary to hepatitis infection was less strongly associated with DM than with NASH or alcoholic cirrhosis. The severity of LC was not associated with DM. In multivariate analysis, the factors associated with DM were age, BMI, a family history of DM, and statin use. There was a significant interaction between HCC and cirrhosis etiology for the risk of DM. Cirrhosis secondary to hepatitis was associated with a lesser presence of DM only in patients with HCC (interaction p = 0.0015). LC was strongly associated with DM, with around 40 % of diabetic patients. In the group of patients with LC without HCC, diabetes was not associated with the etiology of cirrhosis.
Assuntos
Diabetes Mellitus/etiologia , Cirrose Hepática/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Estudos Transversais , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Feminino , França/epidemiologia , Humanos , Cirrose Hepática/patologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.