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

Impact of Radiotherapy, Chemotherapy and Surgery in Multimodal Treatment of Locally Advanced Esophageal Cancer

Objectives: It was the aim of this study to assess our institutional experience with definitive chemoradiation (CRT) versus induction chemotherapy followed by CRT with or without surgery (C-CRT/S) in esophageal cancer. Methods: We retrospectively analyzed 129 institutional patients with locally advanced esophageal cancer who had been treated by either CRT in analogy to the RTOG 8501 trial (n = 78) or C-CRT/S (n = 51). Results: The median, 2-and 5-year overall survival (OS) of the entire collective was 17.6 months, 42 and 24%, respectively, without a significant difference between the CRT and C-CRT/S groups. In C-CRT/S patients, surgery statistically improved the locoregional control (LRC) rates (2-year LRC 73.6 vs. 21.2%; p = 0.003); however, this was translated only into a trend towards improved OS (p = 0.084). The impact of escalated radiation doses (>= 60.0 vs. <60.0 Gy) on LRC was detectable only in T1-3 N0-1 M0 patients of the CRT group (2-year LRC 77.8 vs. 42.3%; p = 0.036). Conclusion: Definitive CRT and a trimodality approach including surgery (C-CRT/S) had a comparable outcome in this unselected patient collective. Surgery and higher radiation doses improve LRC rates in subgroups of patients, respectively, but without effect on OS. Copyright (C) 2012 S. Karger AG, Base

Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial

BACKGROUND: The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. METHODS: In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials.gov, NCT00126256. FINDINGS: 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10·5 months (95% CI 9·6-11·5) in the sequential group and 10·3 months (9·0-11·9) in the combination group (hazard ratio 0·95, 95% CI 0·77-1·16; p=0·61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p&lt;0·0001) and non-haematological adverse events (26 events vs 186 events; p&lt;0·0001) occurred in the sequential group than in the combination group. INTERPRETATION: Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. FUNDING: Sanofi-Aventis France

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

High-dose chemoradiotherapy followed by surgery versus surgery alone in esophageal cancer: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival.</p> <p>Methods</p> <p>Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n = 62). The data were collected retrospectively. Sixty-seven patients had adenocarcinomas, 39 squamous cell carcinomas and one undifferentiated carcinoma. CRT was given as three intensive chemotherapy courses by cisplatin 100 mg/m²on day 1 and 5-fluorouracil 1000 mg/m²/day, from day 1 through day 5 as continuous infusion. One course was given every 21 days. The last two courses were given concurrent with high-dose radiotherapy, 2 Gy/fraction and a median dose of 66 Gy. Kaplan-Meier survival analysis with log rank test was used to obtain survival data and Cox Regression multivariate analysis was used to define prognostic factors for overall survival.</p> <p>Results</p> <p>Toxicity grade 3 of CRT occurred in 30 (48.4%) patients and grade 4 in 24 (38.7%) patients of 62 patients. One patient died of neutropenic infection (grade 5). Fifty percent (31 patients) in the CRT group did undergo the planned surgery. Postoperative mortality rate was 9% and 10% in the surgery alone and CRT+ surgery groups, respectively (p = 1.0). Median overall survival was 11.1 and 31.4 months in the surgery alone and CRT+ surgery groups, respectively (log rank test, p = 0.042). In the surgery alone group one, 3 and 5 year survival rates were 44%, 24% and 16%, respectively and in the CRT+ surgery group they were 68%, 44% and 29%, respectively. By multivariate analysis we found that age of patient, performance status, alcoholism and > = 4 pathological positive lymph nodes in resected specimen were significantly associated with overall survival, whereas high-dose preoperative CRT was not.</p> <p>Conclusion</p> <p>We found no significant survival advantage in esophageal cancer stage IIA-III following preoperative high-dose CRT compared to surgery alone. Patient's age, performance status, alcohol abuse and number of positive lymph nodes were prognostic factors for overall survival.</p

Feasibility of intensity-modulated and image-guided radiotherapy for locally advanced esophageal cancer

BACKGROUND:In this study the feasibility of intensity-modulated radiotherapy (IMRT) and tomotherapy-based image-guided radiotherapy (IGRT) for locally advanced esophageal cancer was assessed.METHODS:A retrospective study of ten patients with locally advanced esophageal cancer who underwent concurrent chemotherapy with IMRT (1) and IGRT (9) was conducted. The gross tumor volume was treated to a median dose of 70Gy (62.4-75Gy).RESULTS:At a median follow-up of 14months (1-39 months), three patients developed local failures, six patients developed distant metastases, and complications occurred in two patients (1 tracheoesophageal fistula, 1 esophageal stricture requiring repeated dilatations). No patients developed grade 3-4 pneumonitis or cardiac complications.CONCLUSIONS:IMRT and IGRT may be effective for the treatment of locally advanced esophageal cancer with acceptable complications.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer

International audienceBackground: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil. Methods: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts. Results: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively. Conclusion: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial