Liver transarterial chemoembolization and sunitinib for unresectable hepatocellular carcinoma: Results of the PRODIGE 16 study.

BACKGROUND: Trans-arterial chemoembolization (TACE) is one first-line option therapy for patients with hepatocellular carcinoma (HCC) not suitable for surgical resection. AIMS: We evaluated the effects of sunitinib plus doxorubicin-TACE on bleeding or liver failure. METHODS: Seventy-eight patients with HCC were included in this randomized, double-blind study. They received one to three TACE plus either sunitinib or placebo four weeks out of six for one year. The occurrence of severe bleeding or liver failure was assessed during the week after the TACE. The safety and survival outcomes were evaluated. RESULTS: No bleeding complication was reported. One and two liver failures were respectively observed in sunitinib and placebo patients. Compliance to sunitinib treatment was acceptable. Sunitinib dose reduction occurred in 37% of patients due to acute toxicity. Main grade 3-4 toxicities were: thrombocytopenia, neutropenia, increased bilirubin, increased ALT and asthenia. In the sunitinib group, the median PFS and OS were 9.05 [5.81;11.63] and 25.0 [13.5;36.8] months, respectively. In the placebo group, the median PFS and OS were 5.51 [4.14;7.79] and 20.5 [15.1;30.6] months, respectively. CONCLUSIONS: TACE plus sunitinib in the first-line therapy for patients with HCC not suitable for surgical resection was feasible. CLINICALTRIALS. GOV NUMBER: NCT01164202.

Fatty acid composition of the erythrocyte membrane and risk of hepatocellular carcinoma in cirrhotic patients.

BACKGROUND: Disturbances in fatty acid (FA) metabolism have been reported in cirrhosis, but the role of FAs in the development of hepatocellular carcinoma (HCC) is still unclear. Biomarkers are a promising means to explore the associations between exogenous intake or endogenous production of FAs and cancer risk. AIM: To estimate the relationship between fatty acid content in erythrocyte membranes and HCC risk in cirrhotic patients METHODS: The "CiRCE" case-control study recruited cirrhotic patients from six French hospitals between 2008 and 2012. Cases were cirrhotic patients with HCC (n = 349); controls were cirrhotic patients without HCC at inclusion (n = 550). FA composition of phospholipids in erythrocyte membranes was determined by high performance gas chromatography. Odds ratios for HCC risk according to FA concentrations were estimated with multivariable logistic regression. RESULTS: HCC patients were older and more often men (P < 0.001). In both groups, saturated FAs represented more than 39% of all FAs in erythrocyte membranes, mono-unsaturated FAs around 14%, and polyunsaturated FAs around 46%. High levels of C15:0 + C17:0, C20:1 n-9, C18:2 n-6 and C20:2 n-6 were associated with higher risk of HCC. The levels of C18:0 and C20:4 n-6 were lower in HCC cases than in controls. CONCLUSIONS: The FA composition of erythrocyte membranes differed according to the presence of HCC with higher levels of saturated FAs, linoleic and eicosadienoic acids, and lower levels of stearic and arachidonic acids. These alterations may reflect particular dietary patterns and/or altered FA metabolism. Further investigations are warranted.

Intra-arterial hepatic beads loaded with irinotecan (DEBIRI) with mFOLFOX6 in unresectable liver metastases from colorectal cancer: a Phase 2 study.

BACKGROUND: Chemo-embolisation with drug-eluting beads loaded with irinotecan (DEBIRI) increased survival as compared with intravenous irinotecan in chemorefractory patients with liver-dominant metastases from colorectal cancer (LMCRC). First-line DEBIRI with systemic chemotherapy may increase survival and secondary resection. METHODS: In the FFCD-1201 single-arm Phase 2 study, patients with untreated, non-resectable LMCRC received DEBIRI plus mFOLFOX6. Four courses of DEBIRI were performed alternating right and left lobe or two sessions with both lobes treated during the same session. RESULTS: Fifty-seven patients were enrolled. Grade 3-5 toxicities were more frequent when both lobes were treated during the same session (90.5% versus 52.8%). Nine-month PFS rate was 53.6% (95% CI, 41.8-65.1%). The objective response rate (RECIST 1.1) was 73.2%, and the secondary R0 surgery was 33%. With a median follow-up of 38.3 months, median OS was 37.4 months (95% CI, 25.7-45.8), and median PFS 10.8 months (95% CI, 8.2-12.3). CONCLUSIONS: Front-line DEBIRI + mFOLFOX6 should not be recommended as the hypothesised 9-month PFS was not met. However, high response rate, deep responses, and prolonged OS encourage further evaluation in strategies integrating biologic agent, in particular in patients with secondary surgery as the main goal. CLINICAL TRIAL REGISTRATION: NCT01839877.

Early evaluation using a radiomic signature of unresectable hepatic metastases to predict outcome in patients with colorectal cancer treated with FOLFIRI and bevacizumab.

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

Hepatic arterial chemotherapy with raltitrexed and oxaliplatin versus standard chemotherapy in unresectable liver metastases from colorectal cancer after conventional chemotherapy failure (HEARTO): a randomized phase-II study.

BACKGROUND: Hepatic arterial infusion (HAI) of chemotherapy could be used in patients with liver-only metastatic colorectal cancer (mCRC) to fight against chemoresistance. We previously reported the efficacy of raltitrexed plus oxaliplatin (HAI) in a retrospective series. We performed a randomized two-stage phase-II study to evaluate the efficacy of HAI of the combination of raltitrexed and oxaliplatin in refractory mCRC with only liver metastases in comparison with standard of care. PATIENTS AND METHODS: Eligible patients had unresectable mCRC and were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type KRAS). Patients were randomized between HAI raltitrexed (3 mg/m2 over 1 h) followed by oxaliplatin (130 mg/m2 over 2 h) every 3 weeks and standard of care in a 2:1 ratio. A total of 57 patients (38 in the experimental arm and 19 in the standard of care arm) were to be included. The main objective was to demonstrate 6-month PFS of 45% by intention-to-treat analysis in the experimental arm, compared to theoretical PFS of 20%, with a unilateral alpha risk of 5% and beta risk of 10%. RESULTS: After inclusion of 27 patients, the trial was terminated due to insufficient accrual. In the experimental arm, 11 and 4 patients experienced grade 3 and 4 toxicities, respectively. The most frequent grade 3-4 toxicities were neutropenia, liver toxicity, and abdominal pain. Median progression-free survival was 6.7 months (95% Confidence Interval; 3.9-7.2) in the HAI group and 2.2 months (95% CI 1.2-4.3) with standard of care [HR 0.32 (95% CI 0.14-0.76), p = 0.01]. Median overall survival did not differ between the two groups, at 11.2 months (95% CI 4.8-17.6) for the HAI group and 11.9 months (95% CI 2.8-14.3) for standard of care [HR 0.86 (95% CI 0.36-2.04), p = 0.73]. CONCLUSION: Although stopped prematurely, this randomized trial provides evidence for the benefit and safety of HAI of a combination of raltitrexed and oxaliplatin in liver-only mCRC with chemoresistant disease.

Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma.

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

Low Cross-Reactivity Between Cisplatin and Other Platinum Salts.

BACKGROUND: Hypersensitivity reactions to platinum salts (PS) (cisplatin [CI], carboplatin [CA], and oxaliplatin [OX]) can be severe and their incidence is increasing due to their widespread use in cancer treatment. OBJECTIVE: To determine the rate of cross-reactivity between PS and whether CI can be administered without prior allergy testing in patients with a history of CA or OX hypersensitivity. METHODS: From September 2002 to April 2016, patients with suspected immediate PS hypersensitivity were tested and cross-reactivity between the 3 PS was evaluated. We then studied patients who were given CI without desensitization after immediate hypersensitivity to other PS. RESULTS: A total of 155 patients were included. Skin tests were positive in 97 patients (OX: 51, CA: 43, and CI: 3). Cross-reactivity to CA in OX-allergic patients was 45% (23 of 51) (95% confidence interval [CI]: 36% to 66%) and cross-reactivity to OX in CA-allergic patients was 37% (16 of 43) (95% CI: 23% to 53%). In contrast, cross-reactivity to CI was 0% (0 of 51) (95% CI: 0% to 7%) in OX-allergic patients and 7% (3 of 43) (95% CI: 2% to 17%) in CA-allergic patients. All these 3 patients had previously been exposed to CI in previous courses of chemotherapy. CI was initiated in 24 patients with proven hypersensitivity to CA or OX and had no hypersensitivity reactions. CONCLUSION: Initiating CI in patients with proven immediate hypersensitivity to CA or OX appeared to be safe in our study.

Gemcitabine and Oxaliplatin Chemotherapy or Surveillance in Resected Biliary Tract Cancer (PRODIGE 12-ACCORD 18-UNICANCER GI): A Randomized Phase III Study.

PURPOSE: No standard adjuvant treatment currently is recommended in localized biliary tract cancer (BTC) after surgical resection. We aimed to assess whether gemcitabine and oxaliplatin chemotherapy (GEMOX) would increase relapse-free survival (RFS) while maintaining health-related quality of life (HRQOL) in patients who undergo resection. PATIENTS AND METHODS: We performed a multicenter, open-label, randomized phase III trial in 33 centers. Patients were randomly assigned (1:1) within 3 months after R0 or R1 resection of a localized BTC to receive either GEMOX (gemcitabine 1,000 mg/m2 on day 1 and oxaliplatin 85 mg/m2 infused on day 2 of a 2-week cycle) for 12 cycles (experimental arm A) or surveillance (standard arm B). Primary end points were RFS and HRQOL. RESULTS: Between July 2009 and February 2014, 196 patients were included. Baseline characteristics were balanced between the two arms. After a median follow-up of 46.5 months (95% CI, 42.6 to 49.3 months), 126 RFS events and 82 deaths were recorded. There was no significant difference in RFS between the two arms (median, 30.4 months in arm A v 18.5 months in arm B; hazard ratio [HR], 0.88; 95% CI, 0.62 to 1.25; P = .48). There was no difference in time to definitive deterioration of global HRQOL (median, 31.8 months in arm A v 32.1 months in arm B; HR, 1.28; 95% CI, 0.73 to 2.26; log-rank P = .39). Overall survival was not different (median, 75.8 months in arm A v 50.8 months in arm B; HR, 1.08; 95% CI, 0.70 to 1.66; log-rank P = .74). Maximal adverse events were grade 3 in 62% (arm A) versus 18% (arm B) and grade 4 in 11% versus 3% ( P < .001). CONCLUSION: There was no benefit of adjuvant GEMOX in resected BTC despite adequate tolerance and delivery of the regimen.

Impact of Cytomegalovirus Infection on the Outcome of Patients With Cirrhosis: A Preliminary Study.

GOALS: The aims of this study were to evaluate whether cytomegalovirus (CMV) infection is associated with hepatocellular carcinoma (HCC) and liver-related mortality in cirrhotic patients. BACKGROUND: In cirrhotic patients, the determinants of HCC and liver-related death are imperfectly known. CMV infection, by its prooncogenic and proinflammatory properties, may favor both the development of HCC and deleterious systemic inflammation. STUDY: In the 1178 patients included between June 2008 and December 2012 in the CIrrhose et Risque de Carcinome Hépatocellulaire dans le grand-Est (CIRCE) study, a French multicenter case-control study designed to identify risk factors of HCC among cirrhotic patients, we identified 432 patients with interpretable CMV serological status at baseline. They included 159 cases with HCC and 273 controls. We measured factors associated with HCC at baseline and subsequent HCC in controls, and predictors of overall and liver-related death in the whole study population. RESULTS: During a median follow-up of 31 months, 25 cases of HCC developed in controls, and 209 deaths (163 liver-related) were recorded. There were 247 (57.2%) CMV-seropositive patients. CMV seropositivity was not associated with more frequent HCC at baseline or during follow-up, but among CMV-positive patients with HCC, the proportion of multinodular, infiltrative, or metastatic tumors at diagnosis was higher (73.8% vs. 57.3%; P=0.029), inducing higher mortality (74% vs. 52% at 3 years; P=0.004). By Cox-regression adjusted for age, gender, Model for End-stage Liver Disease (MELD) score, HCC at baseline, and diabetes, CMV seropositivity independently predicted all-cause (hazard ratio=1.45; 95% confidence interval, 1.08-1.94; P=0.013) and liver-related mortality (hazard ratio=1.56; 95% confidence interval, 1.04-2.30; P=0.031). CONCLUSIONS: In this preliminary study, CMV-seropositive cirrhotic patients were at higher risk of liver-related death caused by more aggressive HCCs or severe cirrhosis complications. These findings warrant confirmation.

Intra-arterial idarubicin_lipiodol without embolisation in hepatocellular carcinoma: The LIDA-B phase I trial.

BACKGROUND & AIMS: Idarubicin shows high cytotoxicity against hepatocellular carcinoma (HCC) cells, a high hepatic extraction ratio, and high lipophilicity leading to stable emulsions with lipiodol. A dose-escalation phase I trial of idarubicin_lipiodol (without embolisation) was conducted in patients with cirrhotic HCC to estimate the maximum-tolerated dose (MTD) and to assess the safety, efficacy, and pharmacokinetics of the drug, and the health-related quality of life achieved by patients. METHODS: Patients underwent two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation. The idarubicin dose was escalated according to a modified continuous reassessment method. The MTD was defined as the dose closest to that causing dose-limiting toxicity (DLT) in 20% of patients. RESULTS: A group of 15 patients were enrolled, including one patient at 10 mg, four patients at 15 mg, seven patients at 20 mg, and three patients at 25 mg. Only two patients experienced DLT: oedematous ascitic decompensation and abdominal pain at 20 and 25 mg, respectively. The calculated MTD of idarubicin was 20 mg. The most frequent grade ≥3 adverse events were biological. One month after the second session, the objective response rate was 29% (complete response, 0%; partial response, 29%) based on modified Response Evaluation Criteria In Solid Tumours. The median time to progression was 5.4 months [95% confidence limit (CI) 3.0-14.6 months] and median overall survival was 20.6 months (95% CI 5.7-28.7 months). Pharmacokinetic analysis of idarubicin showed that the mean Cmax of idarubicin after intra-arterial injection of the idarubicin-lipiodol emulsion is approximately half the Cmax after intravenous administration. Health-related quality of life results confirmed the good safety results associated with use of the drug. CONCLUSIONS: The MTD of idarubicin was 20 mg after two chemolipiodolisation sessions. Encouraging safety results, and patient responses and survival were observed. A phase II trial has been scheduled. LAY SUMMARY: There is a need for transarterial regimens that improve the responses and survival of patients with unresectable HCC. In this phase I trial, we showed that two sessions of treatment with a transarterial idarubicin_lipiodol emulsion without embolisation was well tolerated and gave promising efficacy in terms of tumour control and patient survival.

BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease.

The molecular mechanisms of hepatocellular carcinoma (HCC) carcinogenesis are still not fully understood. DNA repair defects may influence HCC risk. The aim of the study was to look for potential genetic variants of DNA repair genes associated with HCC risk among patients with alcohol- or viral-induced liver disease. We performed four case-control studies on 2,006 European- (Derivation#1 and #2 studies) and African-ancestry (Validation#1 and #2 studies) patients originating from several cohorts in order to assess the association between genetic variants on DNA repair genes and HCC risk using a custom array encompassing 94 genes. In the Derivation#1 study, the BRIP1 locus reached array-wide significance (Chi-squared SV-Perm, P=5.00×10-4) among the 253 haplotype blocks tested for their association with HCC risk, in patients with viral cirrhosis but not among those with alcoholic cirrhosis. The BRIP1 haplotype block included three exonic variants (rs4986763, rs4986764, rs4986765). The BRIP1 'AAA' haplotype was significantly associated with an increased HCC risk [odds ratio (OR), 2.01 (1.19-3.39); false discovery rate (FDR)-P=1.31×10-2]. In the Derivation#2 study, results were confirmed for the BRIP1 'GGG' haplotype [OR, 0.53 (0.36-0.79); FDR-P=3.90×10-3]. In both Validation#1 and #2 studies, BRIP1 'AAA' haplotype was significantly associated with an increased risk of HCC [OR, 1.71 (1.09-2.68); FDR-P=7.30×10-2; and OR, 6.45 (4.17-9.99); FDR-P=2.33×10-19, respectively]. Association between the BRIP1 locus and HCC risk suggests that impaired DNA mismatch repair might play a role in liver carcinogenesis, among patients with HCV- or HBV-related liver disease.

Geriatric factors analyses from FFCD 2001-02 phase III study of first-line chemotherapy for elderly metastatic colorectal cancer patients.

AIM: Several predictors of metastatic colorectal cancer (mCRC) outcomes have been described. Specific geriatric characteristics could be of interest to determine prognosis. METHOD: Elderly patients (75+) with previously untreated mCRC were randomly assigned to receive infusional 5-fluorouracil-based chemotherapy, either alone (FU) or in combination with irinotecan (IRI). Geriatric evaluations were included as an optional procedure. The predictive value of geriatric parameters was determined for the objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: From June 2003 to May 2010, the FFCD 2001-02 randomised trial enrolled 282 patients. A baseline geriatric evaluation was done in 123 patients; 62 allocated to the FU arm and 61 to the IRI arm. The baseline Charlson index was ≤1 in 75%, Mini-Mental State Examination was ≤27/30 in 31%, Geriatric Depression Scale was >2 in 10% and Instrumental Activities of Daily Living (IADL) was impaired in 34% of the patients. Multivariate analyses revealed that no geriatric parameter was predictive for ORR or PFS. Normal IADL was independently associated with better OS. The benefit of doublet chemotherapy on PFS differed in subgroups of patients ≤80 years, with unresected primary tumour, leucocytes >11,000 mm3 and carcinoembryonic antigen >2N. There was a trend towards better OS in patients with normal IADL. CONCLUSION: The autonomy score was an independent predictor for OS. A trend toward a better efficacy of doublet chemotherapy in some subgroups of patients was reported and should be further explored.

An explorative study to assess the association between health-related quality of life and the recommended phase II dose in a phase I trial: idarubicin-loaded beads for chemoembolisation of hepatocellular carcinoma.

OBJECTIVES: The objective of this study was to explore the association between health-related quality of life (HRQoL) and the recommended phase 2 dose in a phase I clinical trial according to the Time to HRQoL deterioration approach (TTD). SETTING: This is a phase I dose-escalation trial of transarterial chemoembolisation (TACE) with idarubicin-loaded beads performed in cirrhotic patients with hepatocellular carcinoma. Patients had to complete the EORTC QLQ-C30 HRQoL questionnaire at baseline and at days 15, 30 and 60 after TACE. PARTICIPANTS: Patients aged ≥18 years with HCC unsuitable for curative treatments were evaluated for the study (N=21). PRIMARY AND SECONDARY OUTCOME MEASUREMENTS: The primary objective was to determine the maximum tolerated dose (MTD) of idarubicin loaded after a single TACE session. MTD was defined as the dose level closest to that causing dose-limiting toxicity in 20% of patients. HRQoL was the secondary end point. RESULTS: Between March 2010 and March 2011, 9, 6 and 6 patients were included at idarubicin dose levels of 5, 10 and 15 mg, respectively. Calculated MTD of idarubicin was 10 mg. At the 10 mg idarubicin dose, patients presented a longer TTD than at 5 mg, for global health status (HR=0.91 (95% CI 0.18 to 4.72)), physical functioning (HR=0.38 (0.04 to 3.22)), fatigue (HR=0.67 (0.18 to 2.56)) and pain (HR=0.47 (0.05 to 4.24)). CONCLUSIONS: These HRQoL results were consistent with the estimated MTD, with a median TTD for global health status of 41 days (21 to NA) at 5 mg, 23 days (20 to NA) at 10 mg and 25 days (17 to NA) at 15 mg. These results show the importance of studying HRQoL in phase I trials. TRIAL REGISTRATION NUMBER: NCT01040559; Post-results.

Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone.

BACKGROUND: Two randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended. METHODS: Eligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations. FINDINGS: Of the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p=0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p=0.58). Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR)=0.39 [0.25-0.61]; p<0.0001), and again was not different from that in responding, randomised patients (p=0.40). INTERPRETATION: In patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.

Role of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography in gastrointestinal cancers.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) has become a routine imaging modality for many malignancies and its use is currently increasing. In the present review article, we will summarize the evidence for FDG-PET/CT use in digestive cancers (excluding neuroendocrine tumours), and review the existing recommendations. While PET/CT is nowadays considered to be an important tool in the initial workup of oesophageal and anal cancers, new data are emerging regarding its use in assessing therapeutic efficacy, radiotherapy treatment planning, and detection of recurrence in case of isolated tumour marker elevation. Moreover, PET/CT may help decision making by detecting distant metastatic sites especially in potentially resectable metastatic colorectal cancer and, to a lesser extent, in localized gastric and pancreatic cancers. Finally, incidental focal colonic FDG uptakes require exploration by colonoscopy, as they are often associated with premalignant or malignant lesions.

Gemcitabine plus cisplatin versus chemoradiotherapy in locally advanced biliary tract cancer: Fédération Francophone de Cancérologie Digestive 9902 phase II randomised study.

BACKGROUND: Chemoradiotherapy (CHRT) is often advocated for locally-advanced biliary tract cancer (LABTC). However there was not comparative study with chemotherapy alone (CH). PATIENTS AND METHODS: Patients with hilar or extrahepatic non-metastatic, LABTC could be included in this phase II trial. The inclusion criteria required World Health Organisation (WHO) performance status ⩽ 2, bilirubinemia ⩽ 50 µM/L after biliary drainage if necessary, and possibility of external radiotherapy. Fluorouracil (5 FU) infusion and cisplatin, were given in association to radiotherapy (50 Gy) in the CHRT arm. Gemcitabine+oxaliplatin (GEMOX) was planned for 6 months in the CH arm. End-points were progression-free survival (PFS), overall survival (OS), toxicity and rate of biliary complications. RESULTS: The trial was closed before completion due to slow recruitment. Eighteen and 16 patients were included in the CHRT and CH arms, respectively. Median follow up was 27.9 months (± 2.8). Grade III-IV toxicities were mostly haematological (23% and 25%), and gastrointestinal (11% and 6%), in the CHRT and CH arm, respectively. Biliary complications occurred in 28% of patients in the CHRT arm and 44% of patients in the CH arm (risk ratio (RR): 1.60 [0.65-3.92]). Median PFS was 5.8 months in the CHRT group and 11.0 months in the CH group (hazard ratio (HR): 0.65 [0.32-1.33]). Median OS was 13.5 months in the CHRT group and 19.9 months in the CH group (HR: 0.69 [0.31-1.55]). CONCLUSIONS: Combination of gemcitabine plus cisplatin seems to be at least as efficient as chemoradiotherapy (50 Gy plus 5 FU and cisplatin) in LABTC.

Predictive factors of transarterial chemoembolisation toxicity in unresectable hepatocellular carcinoma.

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.

Feasibility of preoperative and postoperative chemoradiotherapy in gastric adenocarcinoma. Two phase II studies done in parallel. Fédération Francophone de Cancérologie Digestive 0308.

BACKGROUND: For resectable gastric cancer, both postoperative chemoradiotherapy and perioperative chemotherapy demonstrate high-level evidence for improved survival in Western populations. To evaluate the feasibility of pre- or postoperative chemoradiotherapy, we proposed two multicentre phase II studies. PATIENTS AND METHODS: Patients with localised, histologically confirmed gastric cancer and Eastern Cooperative Oncology Group (ECOG) performance status <2 judged suitable for curative resection were eligible. Eligible patients were assigned to either preoperative chemoradiotherapy followed by surgical resection or surgical resection followed by chemoradiotherapy depending on each centre. Chemoradiotherapy regimen included four courses of FOLFIRI (5 Fluorouracil, Leucovorin, Irinotecan) regimen then Concurrent fluorouracil at 200 mg/m2/d by continuous infusion 5 days each week. A dose of 50 Gy in 25 fractions in the preoperative study, or 45 Gy in 25 fractions in the postoperative study, was delivered. The primary end-point for both studies was the proportion of patients, who completed the therapeutic sequence. RESULTS: Between September 2007 and January 2010, 63 patients were included in both studies. The postoperative study was stopped for futility at the first step. In the preoperative study, 31 patients (73.8%, confidence interval (CI) 95%: 65.8-90.1%) received complete therapeutic sequence. Serum albumin and dietary restriction evaluated by QLQ-STO22 (Quality of Life-Stomach module) score were significantly linked with chemoradiotherapy feasibility in univariate analysis with respectively Odds-ratio (OR) 1.16 [CI 95%: 1.01-1.33] and 0.17 [0.03-0.89], p=0.04. Median overall survival time was 26.4 months in the preoperative study. CONCLUSION: Feasibility of chemoradiotherapy was not achieved for these studies: 73.8% (CI 95%: 65.8-90.1) and 42.9% (CI 95%: 21.8-66%) in preoperative and postoperative settings respectively.

Development of primary early-onset colorectal cancers due to biallelic mutations of the FANCD1/BRCA2 gene.

Fanconi anaemia (FA) is characterized by progressive bone marrow failure, congenital anomalies, and predisposition to malignancy. In a minority of cases, FA results from biallelic FANCD1/BRCA2 mutations that are associated with early-onset leukaemia and solid tumours. Here, we describe the clinical and molecular features of a remarkable family presenting with multiple primary colorectal cancers (CRCs) without detectable mutations in genes involved in the Mendelian predisposition to CRCs. We unexpectedly identified, despite the absence of clinical cardinal features of FA, a biallelic mutation of the FANCD1/BRCA2 corresponding to a frameshift alteration (c.1845_1846delCT, p.Asn615Lysfs*6) and a missense mutation (c.7802A>G, p.Tyr2601Cys). The diagnosis of FA was confirmed by the chromosomal analysis of lymphocytes. Reverse transcriptase (RT)-PCR analysis revealed that the c.7802A>G BRCA2 variation was in fact a splicing mutation that creates an aberrant splicing donor site and results partly into an aberrant transcript encoding a truncated protein (p.Tyr2601Trpfs*46). The atypical FA phenotype observed within this family was probably explained by the residual amount of BRCA2 with the point mutation c.7802A>G in the patients harbouring the biallelic FANCD1/BRCA2 mutations. Although this report is based in a single family, it suggests that CRCs may be part of the tumour spectrum associated with FANCD1/BRCA2 biallelic mutations and that the presence of such mutations should be considered in families with CRCs, even in the absence of cardinal features of FA.

Adjuvant treatments for gastric cancer: from practice guidelines to clinical practice.

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.