Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

<p>Abstract</p> <p>Background</p> <p>Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL).</p> <p>Methods</p> <p>In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.</p> <p>Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking.</p> <p>Results</p> <p>Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.</p> <p>DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69% in 20 out of 22 settings. PFS was proposed in association with QoL in metastatic primary liver and stomach cancers (both 81%). This composite endpoint was ranked second in metastatic oesophageal (69%), colorectal (56%) and anal (56%) cancers, whereas QoL alone was also suggested in most metastatic situations.</p> <p>Other endpoints frequently suggested were R0 resection in the neoadjuvant settings (oesophagus (69%), stomach (56%), pancreas (75%) and biliary tract (63%)) and response. An unexpected endpoint was metastatic PFS in non operable oesophageal (31%) and pancreatic (44%) cancers. Quality and results of surgical procedures like sphincter preservation were also cited as eligible surrogate endpoints in rectal (19%) and anal (50% in case of localized disease) cancers. Except for alpha-FP kinetic in hepatocellular carcinoma (13%) and CA19-9 decline (6%) in pancreas, few endpoints based on biological or tumour markers were proposed.</p> <p>Conclusion</p> <p>The overall results should help prioritise the endpoints to be statistically evaluated as surrogate for OS, so that trialists and clinicians can rely on endpoints that ensure relevant clinical benefit to the patient.</p

Chimioembolisation des carcinomes hépatocellulaires (essai d'optimisation de la procédure)

Avec environ 700 000 décès en 2008, le carcinome hépatocellulaire se situe au 3ème rang de la mortalité par cancers dans le monde. La chimioembolisation est le traitement recommandé chez les patients atteints d un carcinome hépatocellulaire de stade intermédiaire B de la classification Barcelona Clinic Liver Cancer. Cette technique de radiologie interventionnelle consiste en l injection intraartérielle d un agent anticancéreux à l aide d un vecteur (lipiodol ou microsphères d embolisation) complétée par une occlusion artérielle lorsque le lipiodol est utilisé. La médiane de survie des patients traités par chimioembolisation pour un carcinome hépatocellulaire n excède pas 2 ans et il n existe aucun consensus sur la procédure optimale.L objectif de notre travail est d essayer d améliorer la procédure de chimioembolisation en optimisant d une part l agent anticancéreux et d autre part, son vecteur.Il a été démontré au cours d un travail de sélection in vitro, que l idarubicine est l agent anticancéreux le plus cytotoxique sur 3 lignées humaines de carcinome hépatocellulaire. Cette anthracycline présente une cytotoxicité supérieure à 10 autres agents anticancéreux dont ceux utilisés en pratique clinique pour la chimioembolisation des carcinomes hépatocellulaires.L essai de chimioembolisation de phase II randomisé LIPIOAMIO a montré que l addition d amiodarone utilisé pour stabiliser une émulsion à base de lipiodol et d anthracycline n augmente pas signicativement la survie des patients atteints d un carcinome hépatocellulaire non résécable non métastatique. Nous avons par ailleurs montré que l idarubicine était chargeable et donnait une solution stable plusieurs mois avec les microsphères d embolisation DC Bead . Un essai de phase I est en cours pour déterminer la dose limitante de l idarubicine administrée dans une solution de microsphères DC Bead au cours d une séance de chimioembolisation chez des patients atteints d un carcinome hépatocellulaire non résécable, non métastatique. Quelques résultats préliminaires de cet essai sont présentés dans le manuscrit.With 700,000 deaths in 2008, hepatocellular carcinoma is the 3rd most common cause of cancer-related death worldwide. Transarterial chemoembolization is the standard treatment for intermediate-stage hepatocellular carcinoma. This intraarterial treatment is performed by injecting an anticancer drug carried by ethiodized oil or by drug-eluting beads and followed by the occlusion of the artery when ethiodized oil is used. Median survival of patients remains < 2 years, and there is no consensus about the optimal treatment regimen. The aim of our work was to improve the efficacy of transarterial chemoembolization in optimizing the anticancer drug and its carrier.We have demonstrated that idarubicin was the most cytotoxic anticancer drug in an in vitro screening study of 11 anticancer drugs on 3 human hepatocellular carcinoma cell lines. Idarubicin was more cytotoxic in our experiment than the anticancer drugs which are currently used for transarterial chemoembolization of hepatocellular carcinoma.The randomized LIPIOAMIO phase II trial has shown that the addition of amiodarone to stabilize an emulsion composed of an anthracycline and of ethiodized oil injected for transarterial chemoembolization does not improve significantly survival of patients with a non resectable, non metastatic hepatocellular carcinoma. We have also demonstrated that idarubicin could be loaded in drug-eluting DC Bead and that the resulting solution was stable during several months.We designed the dose-escalation IDASPHERE phase I trial to determine the limiting dose of idarubicin administred in a solution of drug-eluting DC Bead during a transarterial chemoembolization session in patients with non resectable, non metastatic hepatocellular carcinoma. First results of the trial are presented in the manuscript.DIJON-BU Doc.électronique (212319901) / SudocSudocFranceF

Prognostic significance of anti-p53 and anti-KRas circulating antibodies in esophageal cancer patients treated with chemoradiotherapy

<p>Abstract</p> <p>Background</p> <p>P53 mutations are an adverse prognostic factor in esophageal cancer. P53 and KRas mutations are involved in chemo-radioresistance. Circulating anti-p53 or anti-KRas antibodies are associated with gene mutations. We studied whether anti-p53 or anti-KRas auto-antibodies were prognostic factors for response to chemoradiotherapy (CRT) or survival in esophageal carcinoma.</p> <p>Methods</p> <p>Serum p53 and KRas antibodies (abs) were measured using an ELISA method in 97 consecutive patients treated at Saint Louis University Hospital between 1999 and 2002 with CRT for esophageal carcinoma (squamous cell carcinoma (SCCE) 57 patients, adenocarcinoma (ACE) 27 patients). Patient and tumor characteristics, response to treatment and the follow-up status of 84 patients were retrospectively collected. The association between antibodies and patient characteristics was studied. Univariate and multivariate survival analyses were conducted.</p> <p>Results</p> <p>Twenty-four patients (28%) had anti-p53 abs. Abs were found predominantly in SCCE (p = 0.003). Anti-p53 abs were associated with a shorter overall survival in the univariate analysis (HR 1.8 [1.03-2.9], p = 0.04). In the multivariate analysis, independent prognostic factors for overall and progression-free survival were an objective response to CRT, the CRT strategy (alone or combined with surgery [preoperative]) and anti-p53 abs. None of the long-term survivors had p53 abs. KRas abs were found in 19 patients (23%, no difference according to the histological type). There was no significant association between anti-KRas abs and survival neither in the univariate nor in the multivariate analysis. Neither anti-p53 nor anti-KRas abs were associated with response to CRT.</p> <p>Conclusions</p> <p>Anti-p53 abs are an independent prognostic factor for esophageal cancer patients treated with CRT. Individualized therapeutic approaches should be evaluated in this population.</p

Oesophageal cancer: Exploring controversies overview of experts' opinions of Austria, Germany, France, Netherlands and Switzerland

Background: Oesophageal carcinoma is a rare disease with often dismal prognosis. Despite multiple trials addressing specific issues, currently, many questions in management remain unanswered. This work aimed to specifically address areas in the management of oesophageal cancer where high level evidence is not available, performing trials is very demanding and for many questions high-level evidence will not be available in the forseeable future. Methods: Two experts of each national, oesophageal cancer research group from Austria, France, Germany, the Netherlands and Switzerland were asked to provide statements to controversial issues. After an initial survey, further questions were formulated and answered by all experts. The answers were then discussed and qualitatively analysed for consensus and controversy. Results: Topics such as indications for PET-CT, reasons for induction chemotherapy, radiotherapy dose, the choice of definitive chemo-radiotherapy versus surgery in squamous cell cancer, the role of radiotherapy in adenocarcinoma and selected surgical issues were identified as topics of interest and discussed. Conclusion: Areas of significant controversy exist in the management of oesophageal cancer, mostly due to high-level evidence. This is not expected to change in the upcoming years

Evaluation de la prothèse Cordis Smart Control posée par voie transhépatique dans les sténoses biliaires malignes (étude prospective monocentrique sur 37 patients)

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Evaluation de la réunion de concertation pluridisciplinaire d'oncologie digestive et de la qualité de la prise en charge initiale des cancers digestifs, enregistrés au CHU de Dijon en 2010

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

MODALITES DE PRISE EN CHARGE DES CANCERS DIGESTIFS DANS LE SERVICE D'HEPATOGASTROENTEROLOGIE DU CHU DE DIJON (COMPARAISON ENTRE 1993 ET 1998)

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude des complications en rapport avec la pose et l'utilisation des chambres implantables pour la chimiothérapie des tumeurs solides de l'adulte (: étude rétrospective sur les années 2006 et 2007 au CHU de Dijon)

DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

Quel est le pourcentage des malades atteints de cancers digestifs inclus dans les essais cliniques? (facteurs liés à l'inclusion-impact des réunions pluridisciplinaires en cancérologie. Etude prospective sur 6 mois dans un service d'hépatogastroentérologie de CHU)

DIJON-BU Médecine Pharmacie (212312103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF