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IF 6.029; International audience; BackgroundA recent prospective randomised trial did not reveal significant differences in median progression-free survival between two chemoradiotherapy (CRT) regimens for inoperable non-metastatic oesophageal cancer patients. This secondary analysis aimed to describe the impact of CRT on health-related quality of life (HRQOL), physical functioning, dysphagia, fatigue and pain and to evaluate whether baseline HRQOL domains can predict overall survival.Patients and methodsA total of 267 patients were randomly assigned to receive with 50 Gy of radiotherapy in 25 fractions six cycles of FOLFOX or four cycles of fluorouracil and cisplatin on day 1. HRQOL was prospectively assessed using the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire version 3.0 with the oesophageal cancer module (QLQ-OES18).ResultsBoth groups showed high baseline compliance. Subsequently, compliance reduced to 41% at the 6-month follow-up. Baseline HRQOL scores showed no statistical differences between treatment arms. During treatment, both groups exhibited lower physical and social functioning and increased fatigue and dyspnoea, although dysphagia moderately improved in the fluorouracil–cisplatin arm only (p = 0.047).During follow-up, HRQOL scores revealed no significant differences between chemotherapy regimens. Linear mixed model exhibited a treatment-by-time interaction effect for dysphagia (p = 0.017) with a greater decrease in dysphagia in the fluorouracil–cisplatin group. Time until definitive deterioration analysis showed no significant differences in global HRQOL, functional or main symptom domains. However, time until definitive deterioration was significantly longer for the fluorouracil and cisplatin arm compared with FOLFOX for appetite loss (p = 0.002), QLQ-OES-18 pain (p = 0.008), trouble swallowing saliva (p = 0.011) and trouble talking (p = 0.020).ConclusionAnalyses of HRQOL scores revealed no statistically significant differences between patients with inoperable non-metastatic oesophageal cancer treated by FOLFOX versus those treated with a fluorouracil–cisplatin regimen as part of definitive CRT.

Since the eighties, several generally small and powerless trials compared surgery alone with surgery preceded or followed by radiotherapy (RT), chemotherapy (CT) or radiochemotherapy (CRT) in esophageal cancer.

Objective: This study aimed to identify predictors of tumor control (TC) in metastatic esophageal squamous cell carcinoma patients receiving first-line chemotherapy. Methods: A development cohort of 68 patients from a prospective multicenter trial (NCT01248299) was used to identify predictors of TC at first radiological tumor assessment and to generate a predictive score for TC. That score was applied in an independent retrospective single-center validation cohort of 60 consecutive patients. Results: Multivariate analysis identified three predictors of TC: body mass index ≥18.5 (OR 4.5, 95% CI 0.91-22.5), absence of bone metastasis (OR 4.6, 95% CI 0.91-23.2) and albumin ≥35 g/l (OR 3.5, 95% CI 1.0-12.1). Based on the presence or absence of these three independent prognosticators, we built a predictive model using a score from 0 to 3. In the development cohort, the TC rates were 14.3 and 78.0% and in the validation cohort 12.5 and 44.2%, for scores of 0-1 and 2-3, respectively. With negative predictive values of 85 and 88% in the development and validation cohorts, respectively, we were able to identify patients with a very low probability of TC. Conclusion: We have developed and validated a score that can be easily determined at the bedside to predict TC in metastatic esophageal squamous cell carcinoma patients.

Background The optimal treatment for oesophageal cancer is a matter of debate. The aim of this study was to describe patterns of care and survival in a well-defined population for squamous cell carcinoma (SCC) and adenocarcinoma (AC) of the oesophagus. Design Data were provided by the Digestive Cancer Registry of Burgundy (France). Recurrence, excess mortality and net survival were calculated. Results Among non-metastatic patients, the proportion of patients resected for cure decreased between 2004 and 2013 from 16% to 9% for SCC and 48% to 22% for AC. The administration of chemoradiation increased from 45 to 53% for SCC and 21 to 30% for AC. A complete clinical response to chemoradiation was reported in 40% of the patients. Five-year net survival did not vary according to histology. It was 55% in the selected group of patients resected for cure, 44% in patients treated with chemoradiation with a complete clinical response. In multivariate analysis, treatment modality only was associated with survival. In metastatic patients, 3-year net survival was 14% for those treated with chemoradiation. Conclusion Chemoradiation has become the most frequently administered treatment. Cancelling or postponing surgery after chemoradiation with complete response should be assessed by a randomized clinical trial.

Inclusion in a randomized therapeutic trial represents an optimal therapeutic strategy.To determine the influence of demographic characteristics and deprivation on the enrolment of patients in digestive cancer clinical trials.Between 2004 and 2010, 4632 patients were recorded by the Burgundy Digestive Cancer Registry. According to a balancing score, the 136 patients included in a clinical trial were matched with 272 patients who met the eligibility criteria for trials. Deprivation was measured by the ecological European deprivation index. A conditional multivariate logistic regression was performed.Patients aged over 75 years were significantly less likely to be included in clinical trials than younger patients (odds ratio 0.33; [0.13-0.87]). Patients treated in private institutions were also less likely to be enrolled than those treated in public institutions (odds ratio 0.04; [0.01-0.16]; p0.001). A relationship between type of institution and the European deprivation index was observed (p=0.017). Deprived patients were less likely to be included in clinical trials when they were managed in private institutions (odds ratio 0.706; [0.524-0.952]; p=0.022). The European deprivation index had no impact when patients were managed in other institutions.The relationship between type of institution and deprivation underlines the necessity for improving patients' chance of being recruited in digestive cancer clinical trials.

Objective: The study objectives were to analyze the impact of the number of lymph nodes (LNs) reported as resected (NLNr) and the number of LNs invaded (NLNi) on the prognosis of esophageal cancer (EC) after neoadjuvant chemoradiotherapy. Background: Pathological LN status is a major disease prognostic factor and marker of surgical quality. The impact of neoadjuvant chemoradiation (nCRT) on LN status remains poorly studied in EC. Methods: Post hoc analysis from a phase III randomized controlled trial comparing nCRT and surgery (group nCRT) to surgery alone (group S) in stage I and II EC (NCT00047112). Only patients who underwent surgical resection were considered (n = 170). Results: nCRT resulted in tumoral downstaging (pT0, 40.7% vs 1.1%, P 3 vs 0) 3.5, 95% CI: 2.0-6.2, P = 15) 0.95, 95% CI: 0.6-1.4, P = 0.807 and HR ( = 23) 1.4, 95% CI: 0.9-2.0, P = 0.131] did not. In Poisson regression analysis, nCRT was an independent predictive variable for reduced NLNr [exp(coefficient) 0.80, 95% CI: 0.66-0.96, P = 0.018]. Conclusions: nCRT is not only responsible for disease downstaging but also predicts fewer LNs being identified after surgical resection for EC. This has implications for the current quality criteria for surgical resection

Purpose To compare epirubicin, cisplatin, and capecitabine (ECX) with fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatments in patients with advanced gastric or esophagogastric junction (EGJ) adenocarcinoma. Patients and Methods This open, randomized, phase III study was carried out in 71 centers. Patients with locally advanced or metastatic gastric or EGJ cancer were randomly assigned to receive either ECX as first-line treatment (ECX arm) or FOLFIRI (FOLFIRI arm). Second-line treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). The primary criterion was time-to-treatment failure (TTF) of the first-line therapy. Secondary criteria were progression-free survival (PFS), overall survival (OS), toxicity, and quality of life. Results In all, 416 patients were included (median age, 61.4 years; 74% male). After a median follow-up of 31 months, median TTF was significantly longer with FOLFIRI than with ECX (5.1 v 4.2 months; P = .008). There was no significant difference between the two groups in median PFS (5.3 v 5.8 months; P = .96), median OS (9.5 v 9.7 months; P = .95), or response rate (39.2% v 37.8%). First-line FOLFIRI was better tolerated (overall rate of grade 3 to 4 toxicity, 69% v 84%; P < .001; hematologic adverse events [AEs], 38% v 64.5%; P < .001; nonhematologic AEs: 53% v 53.5%; P = .81). Conclusion FOLFIRI as first-line treatment for advanced gastric and EGJ cancer demonstrated significantly better TTF than did ECX. Other outcome results indicate that FOLFIRI is an acceptable first-line regimen in this setting and should be explored as a backbone regimen for targeted agents.

Long-term recurrences of rectal cancer raised questions about the possible benefit of prolonging the recommended active 5-year clinical and endoscopic surveillance. The aim of this study was to determine for the first time, incidence and patterns of late 10-year recurrence after curative resection of rectal cancer. The study included 1,222 patients with rectal cancer resected for cure between 1985 and 2000 from those registered in two French population-based digestive cancer registries. Information about local recurrences and distant metastases at 10 years was retrospectively and actively collected up to January 1, 2011. Although the overall 5-year cumulated rate was 39.5 %, the 10-year cumulated rate was 44.1 % (25.6 % for local recurrence and 29.9 % for distant metastases). In multivariate analyses, TNM stage was associated with a higher risk of local recurrence (hazard ratio [HR] stage III vs. stage I = 3.98 [95 % confidence interval, 2.66–5.94]) and of distant metastasis (HR = 3.60 [2.65–4.91]). Preoperative radiotherapy decreased the risk of local recurrence (HR = 0.43 [0.28–0.66]), but not the risk of metastasis. Patients diagnosed between 1995 and 2000 were less prone to develop long-term metastasis than those diagnosed between 1985 and 1989 (HR = 0.66 [0.49–0.88]). Among patients without recurrence 5 years after diagnosis, one patient in 13 developed a recurrence between 5 and 10 years. Late recurrences do exist. A personalised surveillance could be extended until 10 years according to the characteristics of primary tumour and the patient.

Purpose Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC. Methods The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m2 and cisplatin 75 mg/m2. We report the long-term results of the final analysis, after a median follow-up of 93.6 months. Results Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group CRT compared with group S, R0 resection rate was 93.8% versus 92.1% (P = .749), with 3-year overall survival rate of 47.5% versus 53.0% (hazard ratio [HR], 0.99; 95% CI, 0.69 to 1.40; P = .94) and postoperative mortality rate of 11.1% versus 3.4% (P = .049), respectively. Because interim analysis of the primary end point revealed an improbability of demonstrating the superiority of either treatment arm (HR, 1.09; 95% CI, 0.75 to 1.59; P = .66), the trial was stopped for anticipated futility. Conclusion Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC.

Summary Background Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). Methods For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene ( KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. Findings Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2–3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85–1·29; p=0·66), and in patients with KRAS exon 2/ BRAF wild-type (n=984, HR 0·99; 95% CI 0·76–1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82–1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [ vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. Interpretation The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. Funding Federation Francophone de Cancerologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

SummaryBackground A phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads was performed in cirrhotic patients with hepatocellular carcinoma (HCC). Aim To estimate the maximum-tolerated dose (MTD) and to assess safety, efficacy, pharmacokinetics and quality of life. Methods Patients received a single TACE session with injection of 2 mL drug-eluting beads (DEBs; DC Bead 300–500 μm) loaded with idarubicin. The idarubicin dose was escalated according to a modified continuous reassessment method. MTD was defined as the dose level closest to that causing dose-limiting toxicity (DLT) in 20% of patients. Results Twenty-one patients were enrolled, including nine patients at 5 mg, six patients at 10 mg, and six patients at 15 mg. One patient at each dose level experienced DLT (acute myocardial infarction, hyperbilirubinaemia and elevated aspartate aminotransferase (AST) at 5-, 10- and 15-mg, respectively). The calculated MTD of idarubicin was 10 mg. The most frequent grade ≥3 adverse events were pain, elevated AST, elevated γ-glutamyltranspeptidase and thrombocytopenia. At 2 months, the objective response rate was 52% (complete response, 28%, and partial response, 24%) by modified Response Evaluation Criteria in Solid Tumours. The median time to progression was 12.1 months (95% CI 7.4 months – not reached); the median overall survival was 24.5 months (95% CI 14.7 months – not reached). Pharmacokinetic analysis demonstrated the ability of DEBs to release idarubicin slowly. Conclusions Using drug-eluting beads, the maximum-tolerated dose of idarubicin was 10 mg per TACE session. Encouraging responses and median time to progression were observed. Further clinical investigations are warranted (NCT01040559).

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.

Background For gastric cancers, the benefits of adjuvant radiochemotherapy and of perioperative chemotherapy have been demonstrated since 2001 and 2006 respectively. The aim of this study was to evaluate the diffusion of adjuvant treatments in a French population. Methods 334 incident gastric cancers UICC Stage IB, II, III or IVM0 resected for cure and recorded in the Burgundy digestive cancer registry were retrospectively included. Patients were classified as having received an effective adjuvant treatment if they had been treated by adjuvant radiochemotherapy since 2001 or perioperative chemotherapy since 2006. Results The proportion of patients treated with an effective adjuvant treatment increased from 21.8% (2001–2005) to 40.1% (2006–2009). Patients treated in 2006–2009 were twice as likely to receive effective adjuvant treatment as those treated during the period 2001–2005. During the 2004–2009 period, 62.4% of cases were presented in a multidisciplinary team meeting. These patients were almost three times more likely to receive effective adjuvant treatment than patients excluded from multidisciplinary team consultation. Age was a significant factor, independent of comorbidities. Conclusion Administration of adjuvant treatment is still far from being considered a reference regimen in routine practice for R0 resected gastric cancer. The increase in multidisciplinary team meetings should improve the situation.

Colorectal cancer (CRC), the most common digestive cancer in rance, is a major public health problem. There are an estimated 0,000 new cases every year and 200,000 prevalent cases [1]. Its ncidence has increased by more than 50% over the past 20 years 24,000 new cases/year in 1980, 36,600 in 2000). On the other and, over the same period, the number of deaths has remained table (16,000 deaths in 2000), which reflects a major therapeutic rogress [2,3]. Around 75% of patients may benefit from surgical resection ith curative intent [4]. Among them, nearly 30% stage II and over 5% stage III patients present a loco-regional or distant recurrence r a metachronous cancer within 5 years of initial treatment [5]. his high risk of recurrence raises the question of postoperative onitoring in order to detect early recurrences and metachronous ancers at a curable stage. The annual incidence of adenomas is between 3 and 5%, and the umulative risk of metachronous cancer is 2% at 5 years and 7% t 20 years. Endoluminal recurrences and metachronous cancers re rare, therefore intensive endoscopic monitoring is not useful 5,6]. After resection of CRC, the French national thesaurus of good ractices in digestive cancer (TNCD) [7] recommends a colonoscopy ithin 6 months after surgery (if incomplete or of poor quality efore surgery), followed by another at 3 years and then every 5 ears in case of normal results. After excision of more than 3 adeomas or of one at-risk adenoma (size > 1 cm, villous contingent, igh grade dysplasia or in situ carcinoma), the first colonoscopy is erformed after 1 year.

Il estmaintenant prouve que la chimiotherapie (CT) et la radiochimiotherapie (RTCT) preoperatoire augmentent le taux de resection R0 et la survie globale. En plus, la RTCT entraine environ 30 % de reponses completes pathologiques. Par ailleurs, deux essais randomises ont montre que la survie etait similaire apres RTCT a visee curative ou apres RTCT preoperatoire suivie de chirurgie; ces resultats ont ete obtenus dans les cancers epidermoides localement avances, malgre des recidives locales plus frequentes. Dans l’un des essais (FFCD 9102), seuls les repondeurs cliniques a la RTCT etaient randomises entre chirurgie ou non; ainsi, les non-repondeurs pouvaient etre operes sans delai. De fait, les patients randomises et les nonrepondeurs operes avaient une survie non differente. Le benefice de la chirurgie est moins evident pour les recidives plus tardives. Quelques petites etudes non randomisees ont aborde cette question. Les taux de resection R0 y variaient entre 50 et 87 %, avec une survie a cinq ans de 0 a 33%et une mortalite operatoire de 12,5 a 25 %. Un changement radical de strategie se profile dans le cancer de l’oesophage, a savoir commencer par une RTCT a visee curative et n’operer que les nonrepondeurs ou les rechuteurs resecables. Avant de recommander cela, le benefice de la resection « de sauvetage » pour recidive retardee devra etre evalue dans un essai randomise strategique, actuellement en preparation par la FFCD et la FRENCH.

To assess the impact of primary tumour resection on overall survival (OS) of patients diagnosed with stage IV colorectal cancer (CRC).Among the 294 patients with non-resectable colorectal metastases enrolled in the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 phase III trial, which compared different first-line single-agent chemotherapy regimens, 216 patients (73%) presented with synchronous metastases at study entry and constituted the present study population. Potential baseline prognostic variables including prior primary tumour resection were assessed by univariate and multivariate Cox analyses. Progression-free survival (PFS) and OS curves were compared with the logrank test.Among the 216 patients with stage IV CRC (median follow-up, 33 months), 156 patients (72%) had undergone resection of their primary tumour prior to study entry. The resection and non-resection groups did not differ for baseline characteristics except for primary tumour location (rectum, 14% versus 35%; p=0.0006). In multivariate analysis, resection of the primary was the strongest independent prognostic factor for PFS (hazard ratio (HR), 0.5; 95% confidence interval [CI], 0.4-0.8; p=0.0002) and OS (HR, 0.4; CI, 0.3-0.6; p0.0001). Both median PFS (5.1 [4.6-5.6] versus 2.9 [2.2-4.1] months; p=0.001) and OS (16.3 [13.7-19.2] versus 9.6 [7.4-12.5]; p0.0001) were significantly higher in the resection group. These differences in patient survival were maintained after exclusion of patients with rectal primary (n=43).Resection of the primary tumour may be associated with longer PFS and OS in patients with stage IV CRC starting first-line, single-agent chemotherapy.

Purpose The ACCORD 12 trial investigated the value of two different preoperative chemoradiotherapy (CT-RT) regimens in T3-4 Nx M0 resectable rectal cancer. Clinical results are reported after follow-up of 3 years. Patients and Methods Between November 2005 and July 2008, a total of 598 patients were randomly assigned to preoperative CT-RT with CAP45 (45-Gy RT for 5 weeks with concurrent capecitabine) or CAPOX50 (50-Gy RT for 5 weeks with concurrent capecitabine and oxaliplatin). Total mesorectal excision was planned 6 weeks after CT-RT. The primary end point was sterilization of the operative specimen, which was achieved in 13.9% versus 19.2% of patients, respectively (P = .09). Clinical results were analyzed for all randomly assigned patients according to the intention-to-treat principle. Results At 3 years, there was no significant difference between CAP45 and CAPOX50 (cumulative incidence of local recurrence, 6.1% v 4.4%; overall survival, 87.6% v 88.3%; disease-free survival, 67.9% v 72.7%). Grade 3 to 4 toxicity was reported in four patients in the CAP45 group and in two patients in the CAPOX50 group. Bowel continence, erectile dysfunction, and social life disturbance were not different between groups. In multivariate analysis, the sterilization rate (Dworak score) of the operative specimen was the main significant prognostic factor (hazard ratio, 0.32; 95% CI, 0.21 to 0.50). Conclusion At 3 years, no significant difference in clinical outcome was achieved with the intensified CAPOX regimen. When compared with other recent randomized trials, these results indicate that concurrent administration of oxaliplatin and RT is not recommended.

The aim of this study was to select the best candidate drug for transarterial chemoembolization by in-vitro cytotoxic evaluations of 11 anticancer drugs on three human hepatocellular carcinoma (HCC) cell lines. The SNU-398, HepG2, and SNU-449 human HCC cell lines were exposed for 30 min to 11 concentrations of doxorubicin, epirubicin, idarubicin, mitoxantrone, carboplatin, cisplatin, oxaliplatin, 5-fluorouracil, gemcitabine, mitomycin C, or paclitaxel. Cytotoxicity was measured using a quantitative colorimetric assay. For each drug and cell line, we calculated the drug concentration that caused 90% cell death (IC90). To enable comparisons of drugs with different concentration ranges, we computed the cytotoxic index (CyI) as the ratio of maximal drug concentration of more than IC90. Parameters were estimated using nonlinear regression models. Idarubicin was the most active drug on all three cell lines. With SNU-398 cells, the idarubicin CyI was 2.4-fold, 2.5-fold, 57-fold, 148-fold, and more than 58 748-fold higher than the CyIs of mitoxantrone, epirubicin, doxorubicin, gemcitabine, and other drugs, respectively. With HepG2 cells, the idarubicin CyI was 27-fold, 28-fold, 51-fold, and more than 1343-fold higher than the CyIs of doxorubicin, epirubicin, mitoxantrone, and other drugs, respectively. On the resistant SNU-449 cell line, the idarubicin CyI was 2.9-fold and 14-fold higher than the CyIs of paclitaxel and gemcitabine, respectively, the only other drugs effective on this cell line. Among 11 chemotherapeutic agents including doxorubicin, cisplatin, and epirubicin, the most effective on three HCC cell lines was idarubicin. Further clinical investigations are needed to evaluate the safety and efficacy of idarubicin for transarterial chemoembolization in HCC.

Resume Objectif de l’etude Etudier l’apport de la chimioradiotherapie concomitante suivie de chimiotherapie dans le cancer pancreatique localement evolue, par rapport a la chimiotherapie seule. Patients et methodes Cent dix-neuf patients atteints d’un cancer pancreatique localement evolue, avec indice de performance de 0 a 2 selon l’Organisation mondiale de la sante, ont ete randomises entre une chimioradiotherapie concomitante d’induction (60 Gy, 2 Gy/fraction ; perfusion concomitante de 5-fluoro-uracile de 300 mg/m2 par jour, de j1 a j5 pendant six semaines ; cisplatine, 20 mg/m2 par jour, de j1 a j5 pendant la premiere et la cinquieme semaines) et une chimiotherapie d’induction par gemcitabine (1000 mg/m2 par semaine pendant sept semaines). La gemcitabine a ete maintenue dans les deux groupes (1000 mg/m2 par semaine) jusqu’a progression de la maladie ou toxicite. Resultats La survie globale etait plus courte dans le bras chimioradiotherapie concomitante que dans le bras gemcitabine (medianes de survie de 8,6 [intervalle de confiance a 99 % : 7,1-11,4] contre 13 mois [1,7,8,8–18], p = 0,03). Les probabilites de survie a un an etaient respectivement de 32 et 53 %. Ces resultats ont ete confirmes par une analyse per protocol pour les patients ayant recu 75 % ou plus de la dose prevue de radiotherapie. Un nombre plus important d’effets secondaires de grade 3–4 a ete recense dans le bras chimioradiotherapie concomitante, aussi bien durant l’induction (36 contre 22 %) que lors du maintien par gemcitabine (32 contre 18 %). Conclusion Ce schema d’induction intensive par chimioradiotherapie concomitante est plus toxique et moins efficace que la gemcitabine seule.

Resume La chimioembolisation est le traitement de premiere ligne pour les patients atteints d’un carcinome hepatocellulaire (CHC) non resecable, non metastatique. Les microspheres chargees d’anticancereux recemment commercialisees ont pour objectif d’augmenter l’efficacite de la chimioembolisation en permettant un relargage controle et prolonge de l’anticancereux au plus proche de la tumeur. Notre etude monocentrique compare selon deux methodes de valorisation, les couts medicaux hospitaliers directs d’une premiere cure de chimioembolisation conventionnelle et d’une premiere cure de chimioembolisation avec microspheres chez 30 patients atteints de CHC. Le cout moyen valorise par la comptabilite analytique de notre etablissement s’eleve a 4 332 € pour une premiere chimioembolisation conventionnelle et a 3 577 € pour une premiere chimioembolisation avec microspheres. Le cout moyen valorise par les tarifs nationaux s’eleve a 4 507 € (+ 175 €) pour une premiere chimioembolisation conventionnelle et a 2 852 € (− 725 €) pour une premiere chimioembolisation avec microspheres. En conclusion, une premiere cure de chimioembolisation avec microspheres, valorisee d’apres les tarifs d’hospitalisation des GHS, est significativement ( p = 0,006) moins couteuse qu’une chimioembolisation conventionnelle.

Two randomized trials showed that survival was similar after definitive chemoradiation (CRT) or after CRT and surgery in locally advanced esophageal squamous cell cancer, despite more frequent local recurrences. In one trial randomization was done at inclusion, whereas in the other trial a workup was performed after initial CRT; only clinical responders were randomized between surgery and additional CRT. Therefore, clinical non-responders could be operated on without delay. Indeed, randomized patients and nonrandomized operated patients had a similar survival, even if no response was seen on the specimen. However, evidence of benefit is poor in cases of delayed recurrence. Only small nonrandomized studies have considered this issue. R0 resection rates ranged from 50 to 87%, 5-year survival rates from 0 to 33%, and operative mortality from 12.5 to 25%; only R0 resection was associated with long survival. Therefore, the benefit of delayed salvage resection should be assessed in a prospective strategic randomized trial, after a CRT intensive enough to eradicate a sensitive tumor without increasing the risk of eventual surgery. The FFCD (Federation Francophone de Cancerologie Digestive) is working on such a trial in locally advanced operable esophageal carcinoma: CRT and systematic surgery compared with CRT followed by surgery in case of proven persistent tumor or resectable local recurrence. CRT will be improved with induction chemotherapy, new drugs, and up-to-date protracted radiotherapy.

Purpose Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma. Although the 5-fluorouracil (5FU), folinic acid and cisplatin combination (LV5FU2-CDDP) is an option, the optimal order of the regimens must be determined. The first strategic phase III trial comparing LV5FU2-CDDP followed by gemcitabine versus gemcitabine followed by LV5FU2-CDDP was conducted. Methods Patients with metastatic pancreatic adenocarcinoma, performance status (PS) 0–2, without prior chemotherapy were randomly assigned (1:1) to receive either LV5FU2-CDDP followed by gemcitabine at disease progression or toxicity (Arm A), or the opposite sequence (Arm B). 202 patients had to be included and 170 deaths had to be observed to detect an expected improvement in median overall survival (OS) from 6.5 to 10 months in Arm A (two-sided α = 5% and β = 20%). Results 202 patients were included (Arm A, 102; Arm B, 100). Median age, male/female ratio, PS 0–1 and previous surgery were similar in the two arms. After a median follow-up of 44 months, median OS in Arm A was 6.6 months versus 8.0 months in Arm B (p = 0.85). Median progression-free survival was similar between Arms A and B. More grade 3/4 toxicities were observed when LV5FU2-CDDP was administered as a first-line treatment compared with gemcitabine: 79% versus 64% (p = 0.018). Conclusion This trial did not show any strategic advantage to using LV5FU2-CDDP as a first-line treatment and suggests that gemcitabine remains the standard first-line treatment. Sixty-one per cent of patients were able to receive a second line of chemotherapy.

Background The Federation Francophone de Cancerologie Digestive phase III trial in patients with metastatic pancreatic adenocarcinoma comparing 5FU, folinic acid and cisplatin combination followed by gemcitabine (Arm A) versus the opposite sequence (Arm B) failed to demonstrate a benefit in overall survival. To longitudinally compare the quality of life (QoL) we explored different definitions of time until definitive deterioration (TUDD) of QoL scores according to minimal clinically important difference (MCID) cut-offs. Methods QoL was evaluated using the EORTC QLQ-C30 every 8 weeks until death. The following scores were analysed: global health, emotional functioning, physical functioning, fatigue and pain. TUDD was defined as the time interval between randomisation and the first occurrence of a decrease in QLQ-C30 score ⩾5 points without any further improvement in QoL score ⩾5 points or any further available QoL data. Analyses were repeated using a 10 point MCID and/or including death as event. Results From 08/2003 to 05/2006, 102 patients in Arm A and 100 in Arm B were included. Using a 5 and a 10 point MCID, TUDD curves of the 5 scores did not differ according to treatment arm., The median TUDD of global health was 5.2 months (4.3–6.2) in Arm A and 6.1 months (5.1–8.5) in Arm B (log-rank p = 0.50) including death as an event for a 5 point MCID. Multivariate Cox model showed that tumour localisation and progression were independently associated with TUDD (p Conclusions The strategy of chemotherapy did not influence the deterioration of QoL. The TUDD approach seems to provide meaningful clinical results that are adapted to metastatic pancreatic adenocarcinoma trials.

Background & Aims Little is known about the magnitude of the risk of anal and rectal cancer in patients with anal and/or perineal Crohn's disease. We aimed to assess the risk of anal and rectal cancer in patients with Crohn's perianal disease followed up in the Cancers Et Surrisque Associe aux Maladies Inflammatoires Intestinales En France (CESAME) cohort. Methods We collected data from 19,486 patients with inflammatory bowel disease (IBD) enrolled in the observational CESAME study in France, from May 2004 through June 2005; 14.9% of participants had past or current anal and/or perianal Crohn's disease. Subjects were followed up for a median time of 35 months (interquartile range, 29–40 mo). To identify risk factors for anal cancer in the total CESAME population, we performed a case-control study in which participants were matched for age and sex. Results Among the total IBD population, 8 patients developed anal cancer and 14 patients developed rectal cancer. In the subgroup of 2911 patients with past or current anal and/or perianal Crohn's lesions at cohort entry, 2 developed anal squamous-cell carcinoma, 3 developed perianal fistula–related adenocarcinoma, and 6 developed rectal cancer. The corresponding incidence rates were 0.26 per 1000 patient-years for anal squamous-cell carcinoma, 0.38 per 1000 patient-years for perianal fistula–related adenocarcinoma, and 0.77 per 1000 patient-years for rectal cancer. Among the 16,575 patients with ulcerative colitis or Crohn's disease without anal or perianal lesions, the incidence rate of anal cancer was 0.08 per 1000 patient-years and of rectal cancer was 0.21 per 1000 patient-years. Among factors tested by univariate conditional regression (IBD subtype, disease duration, exposure to immune-suppressive therapy, presence of past or current anal and/or perianal lesions), the presence of past or current anal and/or perianal lesions at cohort entry was the only factor significantly associated with development of anal cancer (odds ratio, 11.2; 95% CI, 1.18-551.51; P = .03). Conclusions In an analysis of data from the CESAME cohort in France, patients with anal and/or perianal Crohn's disease have a high risk of anal cancer, including perianal fistula–related cancer, and a high risk of rectal cancer.

The aim of this randomized multicenter phase III trial was to compare chemotherapy and interferon (IFN) in patients with metastatic carcinoid tumors. Patients with documented progressive, unresectable, metastatic carcinoid tumors were randomized between 5-fluorouracil plus streptozotocin (day 1–5) and recombinant IFN-α-2a (3 MU×3 per week). Primary endpoint was progression-free survival (PFS). From February 1998 to June 2004, 64 patients were included. The two arms were well matched for median age, sex ratio, PS 0–1, previous chemotherapy, surgery, or radiotherapy. The median PFS for chemotherapy was 5.5 months versus 14.1 for IFN (hazard ratio=0.75 (0.41–1.36)). Overall survival (OS), tolerance, and effects on carcinoid symptoms were not significantly different. Despite a trend in favor of IFN, there was no difference in PFS and OS in advanced metastatic carcinoid tumors and therapeutic effect of both treatments was mild.

Malgre leur frequence, les modalites de surveillance des cancers colorectaux operes a visee curative restent mal codifiees. La place respective du scanner thoracoabdominopelvien, de l’echographie hepatique et de la radio de thorax est encore a preciser. L’utilite de la surveillance de l’ACE reste discutee.

Objective: Further to a previous study whereby we reported that an in vitro emulsion of pirarubicin, amiodarone, and lipiodol was more stable and cytotoxic than a classic doxorubicin-lipiodol mixture, we designed a pilot study to evaluate efficacy and toxicity of a transarterial chemoembolization (TACE) procedure using a combination of pirarubicin, amiodarone, lipiodol, and gelatin sponge. Methods: The 43 patients included in this study underwent TACE for unresectable hepatocellular carcinoma. Computed tomography scans were performed to assess tumor response (RECIST) and lipiodol uptake after the first session. Median follow-up lasted 30 months. Endpoints were overall and progression-free survival. Survival was estimated using Kaplan Meier estimations and compared using log-rank tests. Univariate and multivariate Cox analyses were used to calculate hazard ratios with their 95% confidence interval (CI). Results: Twenty-seven (67.5%) patients had alcoholic cirrhosis. Mean tumor size was 9.5 cm (1―20 cm) and 37/43 were multifocal or diffuse. Cancer of the liver Italian program score was 0 in 7/40 and 1 in 16/40. Mean number of TACE sessions was 3.5 (1―11). There were 3 treatment-related deaths (2 severe sepsis, 1 bowel perforation). A partial response and a stable disease were observed in 12 (28%) and 29 (67%) patients, respectively. Median overall and progression-free survivals were 29 months (95% CI: 13.8―45) and 15 months (95% CI: 11.5―20.8), respectively. Cancer of the liver Italian program score ≤1 (P = 0.042) and lipiodol uptake >25% (P = 0.003) were independent prognostic factors for better overall survival. Conclusion: This new TACE procedure is safe with a high overall survival rate and certainly deserves phase III investigation to compare it with classic treatments such as doxorubicin-lipiodol TACE.

Resume Le cancer colorectal se situe au premier rang des cancers. Le traitement initial reste la resection chirurgicale a visee curative mais pres de la moitie des patients operes presenteront une recidive locoregionale ou a distance. Ce risque eleve de rechute et les possibilites therapeutiques avaient fait recommander une strategie de surveillance lors de la conference de consensus (Paris, 1998) avec un niveau de preuve faible. La question de la strategie de surveillance afin de detecter les recidives plus precocement et a un stade curable n’est toujours pas resolue et les modalites de suivi font toujours l’objet d’un important debat. Les etudes controlees et les meta-analyses publies depuis, comparant une strategie intensive de surveillance a une strategie moins intensive, seront analysees. Si elles apportent des arguments en faveur de la surveillance, elles ne permettent pas de conclure et d’etablir des recommandations precises. Une etude randomisee multicentrique sur un effectif important pourrait etre conduite pour repondre a ces interrogations.

Adenocarcinoma of the oesophagogastric junction has an ominous prognosis. Until now, oesophageal adenocarcima care was close to the squamous cell cancer one whereas adenocarcinoma of the cardia was mixed with gastric cancers. Results from randomised studies mixed them without making distinctions. Nevertheless, context, natural history and clinical outcome differ. Five-year survival rate is around 40 %, all stages included. Results from several phase-III studies or meta-analysis allowed to define three therapeutic strategies applicable to adenocarcinoma of the oesophagus and the oesophagogastric junction. In Europe, in the case of a resectable tumour, preoperative chemotherapy became a standard treatment since results from the Magic trial. In the United States, post-operative radiochemotherapy according to the "Macdonald" scheme is used in case of a resected tumour with a R0 surgery. Actually, modern techniques of irradiation could reduce the rate of gastro-intestinal toxicities. The survival benefit from preoperative radiochemotherapy is still very controversial with high rates of postoperative morbidity and mortality. We have performed a review of the literature with a methodological analysis of data with a high level of evidence in order to advise perioperative treatment guidelines for patients with a resectable adenocarcinoma of the lower oesophagus or gastro-oesophageal junction. Results from pre- or postoperative strategies and the role of radiotherapy will need to be analysed in the future through a randomised study.

Objective: The objective of this study was to assess the performance of three staging systems (Okuda, Cancer of the Liver Italian Program (CLIP) and Barcelona Clinic Liver Cancer group (BCLC)), for predicting survival in patients with hepatocellular carcinoma (HCC) and to explore how to improve prognostic classification among French patients with HCC whose main etiology is alcoholic cirrhosis. Methods: We have pooled two randomized clinical trials in palliative condition from the Federation Francophone de Cancerologie Digestive. They had included 416 and 122 patients. Performances of Okuda, CLIP and BCLC scores have been compared using Akaike information criterion, discriminatory ability (Harrell's C and the Royston's D statistics), monotonicity of gradients and predictive accuracy (Schemper statistics Vs). To explore how to improve classifications, univariate and multivariate Cox model analyses were carried out. Results: The pooled database included 538 patients. The median survival was 5.3 months (95% confidence interval 4.6-6.2). For all statistics CLIP staging system had a better prognostic ability. Performances of all staging systems were rather disappointing. World Health Organization performance status (WHO PS) for CLIP or a-fetoprotein for BCLC allowed a significant improvement of prognostic information. Conclusion: Our results indicate that CLIP staging seems to be most adapted to palliative setting and that it could be better by associating WHO PS.

International audience; The FFCD 9402 multicentre phase III trial was designed to compare the effects of the combination of Transarterial Lipiodol Chemoembolisation (TACE) and tamoxifen with tamoxifen alone on overall survival and quality of life in the palliative treatment of hepatocellular carcinoma with cirrhosis. From 1995 to 2002, 138 patients were randomised between the two groups. One hundred and twenty three patients were eligible including 61 in the Tamoxifen group and 62 in the TACE group. Baseline characteristics were similar: Child-Pugh class A: 70%, alcoholic cirrhosis: 76%, Okuda stage I: 71%, multinodular tumour: 70% and segmental portal vein thrombosis: 10%. At 2 years, the overall survival was 22% and 25% in the Tamoxifen and TACE groups (P = .68), respectively. Multivariate analysis identified four independent prognostic factors for survival: α-fetoprotein (AFP) > 400 ng/mL (P = .008), abdominal pain (P = .011), hepatomegaly (P = .023) and Child-Pugh score (P = .032). The Spitzer Index level assessing the quality of life during follow-up did not differ between the two groups (P = .70). Amongst patients with stage Okuda I, the 2-year overall survival was 28% in the Tamoxifen group and 32% in the TACE group (P = .58). In this subgroup, two prognostic factors were statistically significant for survival: AFP > 400 ng/mL (P = .004) and Spitzer Index (P = .013) as shown by multivariable analysis.In conclusion, this study suggests that TACE improves neither the survival nor the quality of life in patients with HCC and cirrhosis.

The standard adjuvant treatment for stage III colon cancer in Europe is the 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX-4) regimen, given for 6 months. Cetuximab, a monoclonal antibody directed against the EGF receptor, appears to be effective and safe when combined with oxaliplatin-based regimens, including FOLFOX-4, in patients with metastatic colorectal cancer. PETACC-8, a randomized, multicenter, European Phase III trial, is comparing the efficacy of cetuximab plus FOLFOX-4 with that of FOLFOX-4 alone in patients with stage III colon cancer. The study began in December 2005 and approximately 2000 patients are to be enrolled in nine European countries. The primary end point is disease-free survival time, analyzed after a minimum follow-up of 3 years per patient. Secondary end points include overall survival, treatment compliance, safety and pharmacogenomic parameters.

The aim of the study was to assess the contribution of general practitioners in the surveillance of colorectal cancer, and to examine characteristics and survival of patients with routine general practitioner follow-up. This French registry-based study included 389 patients diagnosed with first colorectal cancer in 1998 and free of disease at least 6 months after curative surgery. For each physician involved, medical records were thoroughly reviewed to collect information about the clinical examinations and follow-up tests prescribed within 3 years after surgery or until death or detection of recurrence. Five-year vital status was obtained through registry records. The proportion of routine clinical examinations performed by general practitioners increased from 35% in the first year to 65% in the third year. Patients having undergone regular general practitioner routine examinations (or =one examination every 6-month period) had significantly less advanced disease (odds ratio: 0.45; 95% confidence interval: 0.21-0.96), preoperative complications (odds ratio: 0.28; 95% confidence interval: 0.08-0.91) and routine examinations by gastroenterologists/oncologists (odds ratio: 0.37; 95% confidence interval: 0.14-0.98) compared with those without general practitioner examinations. Routine general practitioner follow-up had no influence on 3 and 5-year survival. General practitioners detected significantly more recurrences than specialists in patients over 75 and in those presenting symptoms. French general practitioners are widely involved in the surveillance of patients with early-stage colorectal cancer, without any unfavourable impact on the patient's survival. Some suggestions exist that continuing education in oncology may increase the implication of general practitioners in colorectal cancer surveillance.

Summary Objectives To assess the contribution of gastroenterologists (GEs) to the surveillance of colorectal cancer after curative surgery. Patients and methods This registry-based study included 407 patients residing in two French administrative areas diagnosed with newly diagnosed colorectal cancer in 1998 and free of disease six months after curative surgery. All surveillance examinations performed either in the three years after surgery or until death or recurrence were collected retrospectively. Results One hundred nine patients (27%) had a regular clinical check-up with a GE at least once a year. Factors independently associated with GE follow-up were young age (P=0.004), use of adjuvant chemotherapy (P=0.013), and surgeon follow-up (P=0.068). GEs ordered 84% of colonoscopies, 44% of abdominal ultrasound examinations and 52% of abdominal CT scans. They detected 35% of recurrences. A significant proportion of patients (20%) had no regular follow-up, irrespective of the physicians involved. Conclusions GEs play a modest role in the routine follow-up of patients with colorectal cancer, but are largely involved in ordering surveillance tests. They might play an important role in the surveillance of patients who presently have poor access to health care.

Purpose Uncontrolled studies suggest that chemoradiation has similar efficacy as surgery for esophageal cancer. Therefore, a randomized trial was carried out to compare, in responders only, chemoradiation alone with chemoradiation followed by surgery in patients with locally advanced tumors. Patients and Methods Eligible patients had operable T3N0-1M0 thoracic esophageal cancer. Patients received two cycles of fluorouracil (FU) and cisplatin (days 1 to 5 and 22 to 26) and either conventional (46 Gy in 4.5 weeks) or split-course (15 Gy, days 1 to 5 and 22 to 26) concomitant radiotherapy. Patients with response and no contraindication to either treatment were randomly assigned to surgery (arm A) or continuation of chemoradiation (arm B; three cycles of FU/cisplatin and either conventional [20 Gy] or split-course [15 Gy] radiotherapy). Chemoradiation was considered equivalent to surgery if the difference in 2-year survival rate was less than 10%. Results Of 444 eligible patients, 259 were randomly assigned; 230 patients (88.8%) had epidermoid cancer, and 29 (11.2%) had glandular carcinoma. Two-year survival rate was 34% in arm A versus 40% in arm B (hazard ratio for arm B v arm A = 0.90; adjusted P = .44). Median survival time was 17.7 months in arm A compared with 19.3 months in arm B. Two-year local control rate was 66.4% in arm A compared with 57.0% in arm B, and stents were less required in the surgery arm (5% in arm A v 32% in arm B; P < .001). The 3-month mortality rate was 9.3% in arm A compared with 0.8% in arm B (P = .002). Cumulative hospital stay was 68 days in arm A compared with 52 days in arm B (P = .02). Conclusion Our data suggest that, in patients with locally advanced thoracic esophageal cancers, especially epidermoid, who respond to chemoradiation, there is no benefit for the addition of surgery after chemoradiation compared with the continuation of additional chemoradiation.

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. Electronic supplementary material The online version of this article (doi:10.1186/s13014-015-0418-4) contains supplementary material, which is available to authorized users.

High-dose FOLFIRI has an acceptable safety profile and promising efficacy. UDP-glucuronosyltransferase: (UGT1A1) polymorphism may be predictive of toxicity and efficacy of irinotecan. This phase II study aimed to evaluate the combination of high-dose FOLFIRI plus bevacizumab in patients with previously untreated metastatic colorectal cancer (MCRC) based on their UGT1A1 genotype. Patients with the UGT1A1 *1/*1 (group 1) or *1/*28 (group 2) genotype received bevacizumab plus high-dose FOLFIRI every 2 weeks. Using the Bryant and Day design with objective response rate and toxicity as the primary endpoints, 54 patients in each group were required with a planned interim analysis after inclusion of 17 patients per group. We planned to stop the trial at the interim analysis if ≤7 patients exhibited an objective response (OR) and/or ≥3 patients exhibited severe toxicity. At the interim analysis, ORs were higher than the number expected: 52.9% (group 1) and 58.8% (group 2). More than three toxic events occurred in both groups and, according to the interim analysis rule, the trial was closed due to unacceptable toxicity. Recruitment was stopped when 86 patients were included and an analysis on overall population was done for overall survival (OS) and progression-free survival (PFS). The median PFS was 10.7 months (group 1) and 10.4 months (group 2). The median OS was 25.5 months (group 1) and 23.9 months (group 2). This trial does not support the use of the intensive treatment with HD-FOLFIRI plus bevacizumab combination for MCRC in patients with the UGTA1*1/UGT1A1*1 or UGT1A1*1/UGT1A1*28 genotype. Mol Cancer Ther; 14(12); 2782–8. ©2015 AACR.

LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex® arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3–4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3–4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

The aim of this study was to investigate time trends in treatment and prognosis of esophageal cancer in a well-defined French population. Data was obtained from the Burgundy Cancer Registry (France) and three time periods were defined: 1976-90, 1991-96 and 1997-2002. A logistic regression was used to identify factors associated with an R0 resection. A multivariate survival analysis was performed using a Cox model. From 1976 to 2002, 2267 patients were included. The R0 resection rate slightly increased from 20.9% to 25.8% (P=0.019) then remained stable. Operative mortality decreased from 11.7% to 6.7% (NS). Age and subsite significantly influenced the rate of resection for cure whereas period had no effect. Chemotherapy alone was seldom used and radiotherapy alone dramatically dropped over time. Chemoradiation used as adjuvant treatment increased from 16.3% (1976-90) to 30.6% (1997-02) (P0.001) and as sole treatment from 16.0% to 48.5% (P0.001). The 3-year survival rates were respectively 10.1% and 9.7% (NS). Age and stage at diagnosis influenced the prognosis of esophageal cancer whereas time period and histology had no influence. This study claims that esophageal cancer remains a serious cancer problem and no improvement has been seen in the study population in France in its management over time.

Background: The De Gramont regimen (or high-dose LV5FU2, HD-LV5FU2) is considered a standard treatment for metastatic colorectal cancer. The aim of the study was to evaluate the efficacy and the costs of three regimens as compared to HD-LV5FU2: raltitrexed (R), LV5FU2 with a lower dose of folinic acid (LD-LV5FU2), and weekly infusional 5FU (WI-FU). Methods: An economic analysis was performed prospectively as part of a randomized trial comparing first-line chemotherapy regimens in 294 patients with unresectable metastatic colorectal cancer. The primary endpoint was event-free survival (EFS). Direct medical costs were computed from the health system viewpoint using 2001 unit costs. Results: None of the three regimens improved EFS as compared to HD-LV5FU2. R was less effective and more toxic. The mean total cost per patient was € 15,970 for HD-LV5FU2. The cost of R (€ 10,687) was lower than that of HD-LV5FU2 (p = 0.008). The cost of LD-LV5FU2 (€ 14,888) and of WI-FU (€ 13,760) was not significantly different from that of HD-LV5FU2. Conclusion: The lower efficacy and increased toxicity of R made it a clinically inferior regimen despite its easy administration and lower cost. The HD-LV5FU2 protocol remains a better treatment. LD-LV5FU2 appeared a good alternative regimen because it reduced costs without jeopardizing its efficacy. The WI-FU regimen did not show a significant difference in terms of efficacy, but suggested toxicity to be slightly increased.

Summary Objectives The aim of this study was to compare the longitudinal quality of life (QoL) between LV5FU2-irinotecan and LV5FU2 alone or LV5FU2-cisplatin in a randomized Phase II trial in patients with metastatic gastric adenocarcinoma. Methods Among 134 eligible patients, QLQ-C30 scores were collected and described at each 2 monthly follow-up visit during 6 months. The frequencies of QLQ-C30 score improvement were calculated and mixed models for repeated measurements were applied with or without extreme poorest imputation for missing scores. The “survival” until definitive global health score (GHS) deterioration was estimated. Results At the 3rd follow-up, patients with a stable or improved global health ranged from 11% in the LV5FU2-cisplatin arm to 18% in the LV5FU2-irinotecan arm. The irinotecan-based-therapy presented 14 to 15 scores with a better QoL. The time until definitive GHS deterioration was globally similar between treatment arms. Conclusion This study highlights a better impact of LV5FU2-irinotecan and the interest of QoL assessment in phase II trials to complement the risk-benefit judgement.

Purpose Randomized studies on tamoxifen treatment of hepatocellular carcinoma (HCC) produced conflicting results. The aim of this study was to assess the efficacy of tamoxifen administration in improving overall survival of patients with advanced HCC. Patients and Methods A total of 420 patients with HCC who were not suitable for surgery or local treatment were randomly assigned between April 1995 and May 2000: 210 in the control group and 210 in the tamoxifen group (20 mg/d orally). Patients with WHO performance status greater than 2, belonging to Child-Pugh class C, or with serum creatinine greater than 130 μmol/L were not eligible. Results Tolerance was good and the main reported adverse effects were thrombophlebitis (three patients), nausea (two patients), and hot flushes (three patients). Outcome did not differ between the two treatment arms: estimated median survival was 4.8 and 4.0 months in the tamoxifen and in the control groups, respectively (P = .25). Univariate analysis showed significant association of survival with age, Okuda stage, WHO performance status, Child-Pugh class, intrahepatic tumor stage, alpha-fetoprotein serum concentration, and presence of extrahepatic spread, portal vein thrombosis, hepatomegaly, or hepatalgia. In a Cox proportional hazards model we found a significant beneficial effect of tamoxifen on survival in patients belonging to Okuda I or II stages. Conclusion In this large study, tamoxifen did not improve the survival of patients with advanced HCC, but there is a suggestion that patients without major hepatic insufficiency seem to have some survival benefit. New trials involving this specific population are warranted.

We report on four patients with severe polyneuropathy associated with intestinal pseudoobstruction (MNGIE). Three patients presented characteristic supranuclear ophthalmoplegia, and hyperdense signals on T2 weighted cerebral MRI and dystrophic mitochondria in Schwann cells and in endothelial cells in nerve biopsy specimens. Two of these patients had a Charcot-Marie-Tooth (CMT) presentation. All three were heterozygous for a recessively transmitted double substitution in the TP gene: Glu286Lys/Glu289Ala, Asp156Gly/Leu177Pro and Glu289Ala/Gly387Asp. The fourth patient, who was the only patient of this series with an affected sib, had no oculomotor manifestations, nor T2 hyperdense signals on brain MRI, and no TP gene mutation and or morphological abnormalities of mitochondria on electron microscopic examination. He was the only patient of this series with an affected sib. The three patients with the full MNGIE syndrome died before the age of 30 years. Detailed results of nerve pathology show that severe axonal degeneration is associated with segmental abnormalities of the myelin sheath in this syndrome which appears genetically heterogeneous. Our findings suggest that only ophthalmoplegia and hyperdense signals on cerebral MRI are directly related to the mitochondriopathy.

Purpose To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study. Patients and Methods One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m2 (2-hour infusion) followed by FU 400 mg/m2 (bolus) and FU 600 mg/m2 (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m2 (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m2 (2-hour infusion) on day 1 (arm C). Results The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively. Conclusion Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.

Gastroenterology and Digestive Oncology, CHU Avicenne, APHP, Bobigny, France Oncology, Centre Antoine Lacassagne, Nice, France Oncogeriatry, ICM Val d’Aurelle, Montpellier, France Oncology, CH Senlis, Senlis, France Federation Francophone de Cancerologie Digestive, Burgundy University, INSERM U866, Dijon, France Geriatry, CHU Henri Mondor, APHP, Creteil, France Geriatry, Centre Gerontologique Departemental, Marseille, France Gastroenterology, CH de la Roche sur Yon, La Roche sur Yon, France Oncology, CHU Saint-Antoine, APHP, Paris, France rance Hepato-Gastroenterology and Digestive Oncology, CHU La Timone, APHM, Marseille, F

3550 Background: In the early 2000s, classic LV5FU2 (C) (folinic acid, 5FU bolus, then 5FU infusion on D1 and D2) was replaced with simplified LV5FU2 (S) (folinic acid and 5FU bolus on D1 only), considered as effective and less toxic. No trial proved this assertion. The LV5FU2 companion in the FOLFIRI or FOLFOX regimen was C or S. The FFCD 2001-02 study compared in a 2 x 2 factorial design, in not-pretreated elderly patients (75+) with metastatic colorectal cancer, C or S, with or without irinotecan. No significant differences in PFS and OS were observed in the comparison with or without irinotecan. The median OS was 15.2 months in C versus 11.4 months in S, HR = 0.71 (0.55–0.92) and objective response rate was 37.1% in C vs S 25.6% in S, p = 0.004. The aim of this study was to present the factors associated with these differences. Methods: Prognostic factors associated with OS were studied using a Cox model. The multivariate analysis used the significantly different items from the univariate analysis and the differences observed at the inclusion. For each of these items, a subgroup analysis was performed. The second- and third-line treatments were analysed. Results: The 282 patients from the intent-to-treat study were included in the model. In OS, the prognostic factors were C versus S, number of metastatic sites, alkaline phosphatases (AP) and CEA. The interaction test in each subgroup for OS was not significant but C was significantly better in the following subgroup: age > 80 years, male, Karnofsky 100%, 1-2 Charlson index, AP ≤ 2N, leucocyte count > 11,000, CEA > 2N, CA 19-9 ≤2N. No differences were observed in the NCI toxicities but 130 serious adverse events in S versus 102 in C. A second-line was used for 55% patients in C, 46% in S, 81% of them with oxaliplatin or irinotecan in C, 76% after S. The third-line administration (20%) and targeted therapy (15%) were similar in C and S. Conclusions: C-LV5FU2 was superior both in subgroups with better and lower prognostics and this difference cannot be explained by an imbalance between the populations. The toxicity was not higher and a second-line was more often possible after C. The switch from C to S without scientific proof was perhaps a mistake in our practices. Clinical trial information: NCT00303771.