Publications by authors named "Denis Smith"

58 Publications

Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.

N Engl J Med 2020 12;383(23):2207-2218

From Sorbonne Université and Hôpital Saint Antoine, Paris (T.A.), Bordeaux University Hospital, Bordeaux (D.S.), and Léon Bérard Center, Lyon (C.F.) - all in France; University College Hospital, NHS Foundation Trust, London (K.-K.S.); Asan Medical Center, University of Ulsan, Seoul, South Korea (T.W.K.); Herlev and Gentofte Hospital, Herlev (B.V.J.), and University Hospital of Southern Denmark, Vejle (L.H.J.) - both in Denmark; Amsterdam University Medical Center, University of Amsterdam, Amsterdam (C.P.); Hospital Universitario 12 de Octubre, Imas12, Madrid (R.G.-C.), Hospital Regional Universitario, Malaga (M.B.), Hospital Universitario Marques de Valdecilla, Santander (F.R.), and Vall d'Hebron Institute of Oncology, Barcelona (E.E.) - all in Spain; Western Health, St. Albans, VIC, Australia (P.G.); Sarah Cannon Research Institute-Tennessee Oncology, Nashville (J.B.); Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (D.T.L.); National Cancer Center Hospital East, Kashiwa, Japan (T.Y.); University Hospital Gasthuisberg and KU Leuven, Leuven, Belgium (E.V.C.); MSD China, Beijing (P.Y.); Merck, Kenilworth, NJ (M.Z.H.F., P.M.); and Memorial Sloan Kettering Cancer Center, New York (L.A.D.).

Background: Programmed death 1 (PD-1) blockade has clinical benefit in microsatellite-instability-high (MSI-H) or mismatch-repair-deficient (dMMR) tumors after previous therapy. The efficacy of PD-1 blockade as compared with chemotherapy as first-line therapy for MSI-H-dMMR advanced or metastatic colorectal cancer is unknown.

Methods: In this phase 3, open-label trial, 307 patients with metastatic MSI-H-dMMR colorectal cancer who had not previously received treatment were randomly assigned, in a 1:1 ratio, to receive pembrolizumab at a dose of 200 mg every 3 weeks or chemotherapy (5-fluorouracil-based therapy with or without bevacizumab or cetuximab) every 2 weeks. Patients receiving chemotherapy could cross over to pembrolizumab therapy after disease progression. The two primary end points were progression-free survival and overall survival.

Results: At the second interim analysis, after a median follow-up (from randomization to data cutoff) of 32.4 months (range, 24.0 to 48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (median, 16.5 vs. 8.2 months; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.80; P = 0.0002). The estimated restricted mean survival after 24 months of follow-up was 13.7 months (range, 12.0 to 15.4) as compared with 10.8 months (range, 9.4 to 12.2). As of the data cutoff date, 56 patients in the pembrolizumab group and 69 in the chemotherapy group had died. Data on overall survival were still evolving (66% of required events had occurred) and remain blinded until the final analysis. An overall response (complete or partial response), as evaluated with Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was observed in 43.8% of the patients in the pembrolizumab group and 33.1% in the chemotherapy group. Among patients with an overall response, 83% in the pembrolizumab group, as compared with 35% of patients in the chemotherapy group, had ongoing responses at 24 months. Treatment-related adverse events of grade 3 or higher occurred in 22% of the patients in the pembrolizumab group, as compared with 66% (including one patient who died) in the chemotherapy group.

Conclusions: Pembrolizumab led to significantly longer progression-free survival than chemotherapy when received as first-line therapy for MSI-H-dMMR metastatic colorectal cancer, with fewer treatment-related adverse events. (Funded by Merck Sharp and Dohme and by Stand Up to Cancer; KEYNOTE-177 ClinicalTrials.gov number, NCT02563002.).
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http://dx.doi.org/10.1056/NEJMoa2017699DOI Listing
December 2020

Comparison of 18FDG-PET/CT and conventional follow-up methods in colorectal cancer: A randomised prospective study.

Dig Liver Dis 2021 Feb 2;53(2):231-237. Epub 2020 Nov 2.

Department of Medical Oncology, University Hospital, Limoges, France.

Background: A surveillance program was performed in colorectal cancer (CRC) patients after surgery, to diagnose asymptomatic recurrence.

Aims: To assess whether 18-FDG positron emission tomography/CT (PET/CT) improved the detection of recurrence during a 3-year follow-up.

Methods: A multicentre, two-arm randomised prospective trial comparing different 36-month follow-up strategies. Complete colonoscopy was performed at baseline and after 3 years and clinical exams with imaging every 3 months. The conventional arm (A) received carcinoembryonic antigen, liver echography, and alternated between lung radiography and computed tomography (CT) scans. The experimental arm (B) received PET/CT.

Results: A total of 365 patients with colon (79.4%) or rectal cancer (20.6%), stages II (48.2%) or III (50.8%), were enroled in this study. At 36 months, intention-to-treat analysis revealed recurrence in 31 (17.2%) patients in arm A and 47 (25.4%) in arm B (p = 0.063). At 3 years, 7 of 31 relapses (22.5%) in arm A were surgically treated with curative intent, compared to 17 of 47 (36.2%) in arm B (p = 0.25). The rates of recurrence and new cancers were higher in arm B than arm A (p = 0.038).

Conclusions: PET/CT follow-up every 6 months did not increase the rate of recurrence at 3 years or the rate of surgically treated recurrence compared with conventional follow-up.
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http://dx.doi.org/10.1016/j.dld.2020.10.012DOI Listing
February 2021

Evaluation of Nurses' and Patients' Overall Satisfaction with New and Previous Formulations of Octreotide Long-acting Release (Sandostatin LAR): A French Observational Study.

Adv Ther 2020 09 18;37(9):3901-3915. Epub 2020 Jul 18.

Hepatogastroenterology and Digestive Oncology Unit, University Hospital of Reims, Reims, France.

Introduction: The first long-acting release (LAR) formulation of octreotide was marketed in France in the late 1990s. An injectable formulation of Sandostatin LAR (Novartis SAS) with a new diluent has been developed to facilitate its preparation and administration and to improve its use in practice.

Methods: We conducted an observational, cross-sectional and multicenter study in France whose main outcome was to compare nurses' satisfaction with the preparation and administration of both previous and new formulations of octreotide LAR. Secondary outcomes included assessment of patient satisfaction (quality of life and pain felt during the injection) and product tolerance. Data were collected at two time points (one for the first formulation group and one for the second formulation group) through paper questionnaires administered to physicians, patients and nurses including a visual analog scale (VAS) from 0 (unsatisfied) to 10 (very satisfied).

Results: Results showed that overall nurse satisfaction improved from 5.3 (95% CI 4.9-5.8) with the previous formulation to 7.5 (95% CI 7-7.9) with the new formulation (p < 0.0001). Regarding secondary outcomes, the simplicity of the injection increased (84% for the previous formulation and 94% for the new formulation) and the purge problem disappeared (36% for the previous formulation and 4% for the new formulation).

Conclusion: The improvement due to the new formulation of Sandostatin LAR was reported in terms of handling, ease of use and overall nurse satisfaction. The new formulation greatly reduced treatment administration problems associated with the previous formulation, while maintaining low injection site pain and an equivalent safety profile in both indications.
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http://dx.doi.org/10.1007/s12325-020-01429-4DOI Listing
September 2020

Effectiveness of first-line cetuximab in wild-type RAS metastatic colorectal cancer according to tumour BRAF mutation status from the EREBUS cohort.

Br J Clin Pharmacol 2021 Mar 15;87(3):1120-1128. Epub 2020 Sep 15.

Hepato-Gastro-Enterology and Digestive Oncology Department, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France.

Aims: Poor efficacy has been reported for patients with BRAF mutations for metastatic colorectal cancer (mCRC).

Methods: EREBUS is a French cohort study of wild-type (wt) KRAS unresectable mCRC patients initiating a first-line treatment with cetuximab from 2009 to 2010, followed for two years (five years for vital status). Molecular genetics platforms have provided additional RAS and BRAF mutation testing results. Progression-free survival (PFS) and overall survival (OS) were assessed according to tumour mutation (mt) status: RASmt/BRAFany, RASwt/BRAFmt and RASwt/BRAFwt. Multivariate Cox analyses were used to evaluate association between mutation status and death or progression.

Results: A total of 389 patients were included in 65 centres and with a known tumour mutation status: 64 RASmt/BRAFany (21%), 33 RASwt/BRAFmt (13%) and 213 RASwt/BRAFwt (87%). Respective baseline characteristics were: median age 65, 64 and 63 years, male gender 63%, 64% and 69%, Eastern Cooperative Oncology Group performance status ≤ 1 75%, 76% and 79%, and liver-only metastases 39%, 33% and 40%. Median progression-free survival was 8.0 months [5.9-9.3] for patients with RASmt/BRAFany, 6.0 months [2.3-7.2] for patients with RASwt/BRAFmt, and 10.4 months [9.5-11.0] for patients with RASwt/BRAFwt. Respectively, median overall survival was 18.4 months [10.9-23.3], 9.7 months [6.9-16.6] and 29.3 months [26.3-36.1]. In multivariate analyses, progression (HR = 2.71 [1.79-4.10]) and death (HR = 2.79 [1.81-4.30]) were more likely for RASwt/BRAFmt vs RASwt/BRAFwt patients.

Conclusions: BRAF mutations were associated with markedly poorer outcomes in initially unresectable RASwt mCRC patients treated by cetuximab in first-line treatment.
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http://dx.doi.org/10.1111/bcp.14472DOI Listing
March 2021

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

Br J Cancer 2020 08 8;123(4):518-524. Epub 2020 Jun 8.

Département de Gastroentérologie et d'Oncologie Digestive, Hôpital Européen George Pompidou, Paris, France.

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.
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http://dx.doi.org/10.1038/s41416-020-0917-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7435188PMC
August 2020

Management of colon cancer patients: A comprehensive analysis of the absence of multidisciplinary team meetings in two French departments.

Clin Res Hepatol Gastroenterol 2020 Apr 28:101413. Epub 2020 Apr 28.

Gironde General Cancer Registry, 33000 Bordeaux, France; Inserm Bordeaux Population Health, Research Center U1219, Epicene Team, university of Bordeaux, 33000 Bordeaux, France; Medical Information Service, Public Health Department, university Bordeaux hospital, 33000 Bordeaux, France.

Background: The care management of colorectal cancers has evolved, particularly since the implementation of multidisciplinary team meetings (MDTm). The aim of this study was to identify factors associated with the non-presentation of colon cancer patients in MDTm (no-MDTm) and to assess the association between no-MDTm and the diagnostic and therapeutic care management, in two areas in France, in 2010.

Methods: Patients over 18 years diagnosed for invasive colon cancer in Gironde and Tarn during 2010 were included from the cancer registries of these two departments. We used five indicators to evaluate the care management of colon cancer patients (about diagnosis, treatment and selection of patients for chemotherapy).

Results: No-MDTm patients were more likely to die early after diagnosis (OR=2.94, 95% CI=[1.52-5.66]). Elderly patients and those living in more disadvantaged areas were less often presented in MDTm (OR=2.10, 95% CI=[1.06-4.18]; OR=1.96, 95% CI=[1.23-3.14]). After adjusting for patient-related variables (age, comorbidities, deprivation) and tumor (stage at diagnosis), we found that thoracic CT scan was less often performed among no-MDTm patients (OR=0.40, 95% CI=[0.24-0.65]). There was no association between the absence of MDTm and the therapeutic care management indicators.

Conclusion: In conclusion, therapeutic care management was not associated with the absence of MDTm but with patient and tumor characteristics, including age, comorbidities and level of deprivation, that influence the non-presentation in MDTm.
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http://dx.doi.org/10.1016/j.clinre.2020.02.020DOI Listing
April 2020

Single-arm phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients over 70 with previously treated metastatic colorectal adenocarcinoma FFCD 1404 - REGOLD.

J Geriatr Oncol 2020 11 22;11(8):1255-1262. Epub 2020 Apr 22.

Gastroenterology and Digestive Oncology Department, University Hospital Dijon, Dijon, France; EPICAD INSERM LNC-UMR 1231, Université de Bourgogne et Franche Comté, Dijon, France.

Background: Regorafenib significantly increases overall survival (OS) in patients with metastatic colorectal cancer previously treated but gives toxicities.

Objectives: to assess the efficacy and safety of regorafenib at it's approved dose in the older population.

Patients And Methods: This multicenter single-arm phase II enrolled patients ≥70 years old after the failure of fluoropyrimidine-based chemotherapy, anti-VEGF, and anti-EGFR treatment. The primary endpoint was disease control rate (DCR) 2 months after initiation of regorafenib (160 mg/day, 3 weeks on/1 week off).

Results: Forty-three patients were enrolled, with a median age of 77 years. The 2 months DCR was 31.4% in the 35 evaluable patients. For the 42 patients that received at least one dose of regorafenib, median progression-free survival and OS were 2.2 and 7.5 months. The median time to autonomy degradation and quality of life degradation was 3.1 and 3.2 months, respectively. A grade 3-4 treatment-related adverse events was observed in 35/42 patients, notably: fatigue (45.2%), hand-foot skin reaction (19.0%), hypertension (21.4%), and diarrhea (7.1%). There is a trend to achieve DCR in patients ≤80 years and a trend to discontinue the study due to toxicity in patients with ECOG ≥1, over 80 years and with impaired baseline autonomy.

Conclusion: Treatment with regorafenib in pretreated patients ≥70 years is feasible and demonstrate similar efficacy that was observed in previous studies in young patients. Fatigue is the most frequent severe adverse event. However, caution should be taken for older patients with ECOG ≥1, over 80 years, and with impaired baseline autonomy.
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http://dx.doi.org/10.1016/j.jgo.2020.04.001DOI Listing
November 2020

Atezolizumab plus modified docetaxel-cisplatin-5-fluorouracil (mDCF) regimen versus mDCF in patients with metastatic or unresectable locally advanced recurrent anal squamous cell carcinoma: a randomized, non-comparative phase II SCARCE GERCOR trial.

BMC Cancer 2020 Apr 25;20(1):352. Epub 2020 Apr 25.

Department of Oncology, University Hospital of Besançon, 3 Boulevard Alexander Flemingn, F-25030, Besançon, France.

Background: Modified docetaxel, cisplatin, and 5-fluorouracil (mDCF) regimen has become a new standard for the treatment of metastatic or unresectable locally advanced recurrent squamous cell carcinoma of the anus (SCCA) after demonstrating improved efficacy (12-month PFS of 47%) in the Epitopes-HPV02 trial. Antibodies targeting the checkpoint inhibitor (CKI) programmed cell death protein-1 (PD1) have demonstrated the efficacy as monotherapies in second-line treatment of SCCA. The aim of this study is to evaluate the combination of atezolizumab and mDCF as first-line chemotherapy in a non-comparative multicentre randomized phase II study of advanced SCCA patients.

Methods: Patients with chemo-naive advanced histologically proven SCCA, metastatic or unresectable locally advanced recurrence, and Eastern Cooperative Oncology Group-performance status (ECOG-PS) < 2 will be eligible. The primary endpoint is a 12-month PFS rate. Using one-arm non-parametric survival with unilateral alpha type I error of 5% and a statistical power of 80%, the upper critical value for the 12-month PFS rate is 47% to reject H0. Assuming 5% lost to follow-up, 99 patients will be randomized on a 2:1 basis, 66 to the experimental arm (arm A, mDCF plus atezolizumab) and 33 to the standard arm (arm B, mDCF). In both arms, 8 cycles of mDCF will be administered. In arm A, patients receive mDCF with a fixed dose of atezolizumab (800 mg every 2 weeks) and are followed up to 1 year. Secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and an extensive biomarker programme and its correlation with the treatment efficacy.

Discussion: Although the Epitopes-HPV02 trial has changed long-lasting prognosis of patients with SCCA in advanced stage disease, more than 50% of patients will progress at 12 months. The purpose of the SCARCE trial to establish the addition of atezolizumab to mDCF as a new standard in this rare disease. Associated biomarker studies and the control arm could contribute to better understanding of the potential synergic and tumour resistance mechanisms in SCCA.

Trial Registration: NCT03519295.
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http://dx.doi.org/10.1186/s12885-020-06841-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7183720PMC
April 2020

Efficacy and Safety of Bevacizumab Combined With First-Line Chemotherapy in Elderly (≥75 Years) Patients With Metastatic Colorectal Cancer: A Real-World Study.

Clin Colorectal Cancer 2020 09 13;19(3):e100-e109. Epub 2020 Apr 13.

Soins de support en oncologie/onco-gériatrie, Institut Curie, Paris, France.

Background: Although elderly patients are the first concerned by colorectal cancer (CRC), they are underrepresented in clinical trials. The real-world CASSIOPEE study was thus conducted in elderly patients treated for metastatic CRC (mCRC).

Methods: This French prospective, multicenter, noninterventional study aimed to estimate 1-year progression-free survival (PFS) and overall survival (OS), and describe treatments, patient autonomy (Instrumental Activities of Daily Living; Balducci scale), and safety over 24 months, in patients older than 75 with mCRC, starting first-line bevacizumab plus chemotherapy (NCT01555762).

Results: From 2012 to 2014, 402 patients were included (safety population: n = 383, efficacy population: n = 358). Patient characteristics were as follows: mean age, 81 ± 4 years (<80 years, 46%; 80-85 years, 44%; >85 years, 10%); men, 52%; colon primary tumor, 80%; main metastatic site, liver 66%; Eastern Cooperative Oncology Group performance 0-1, 81%. Median PFS was 9.1 months (95% confidence interval [CI]: 8.3-10.2). It was superior for patients ≤85 years (<80 years: 9.3 months; 80-85 years: 9.5 months) compared with patients >85 years (8.3 months). Median OS was 19.0 months (95% CI, 16.5-21.5) and decreased in the 2 oldest groups (20.6, 17.8, and 13.0 months). Autonomy assessments decreased over time leading to nonconclusive results. Twenty-six percent of patients experienced serious adverse events (SAEs): 7% bevacizumab-related SAEs, and 6% bevacizumab-targeted SAEs. Two fatal bevacizumab-related adverse events were reported (hemorrhagic stroke and intestinal ischemia).

Conclusions: This large French real-world study showed that medically fit older patients with mCRC could have a benefit/risk balance similar to that of younger patients when treated with first-line bevacizumab plus chemotherapy. Improvements in geriatric assessments are needed to better define this population.
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http://dx.doi.org/10.1016/j.clcc.2020.02.009DOI Listing
September 2020

Digestive Neuroendocrine Neoplasms (NEN): French Intergroup clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN, TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR).

Dig Liver Dis 2020 05 28;52(5):473-492. Epub 2020 Mar 28.

Department of Hepato-Gastroenterology and Digestive Oncology, Robert Debré University Hospital, Reims, France. Electronic address:

Introduction: This document is a summary of the French Intergroup guidelines regarding the management of digestive neuroendocrine neoplasms (NEN) published in February 2020 (www.tncd.org).

Methods: All French medical societies involved in the management of NEN took part in this work. Recommendations were graded into four categories (A, B, C or D), according to the level of evidence found in the literature until May 2019.

Results: The management of NEN is challenging because of their heterogeneity and the increasing complexity of diagnostic and therapeutic procedures. Pathological analysis is required for their diagnostic and prognostic characterization, which mainly relies on differentiation, grade and stage. The two main emergency situations are functioning syndromes and poorly-differentiated carcinoma. Chromogranin A is the main biochemical marker of NET, although of limited clinical interest. Initial characterization relies on morphological and isotopic imaging. The treatment of localized NET relies on watchful follow-up and local or surgical resection depending on its supposed aggressiveness. Treatment options for metastatic disease include surgery, somatostatin analogues, chemotherapy, targeted therapies, organ-driven locoregional therapies and peptide-receptor radionuclide therapy. As specific predictive factors of treatment efficacy are yet to be identified and head-to-head comparisons have not or only rarely been performed, the therapeutic strategy currently depends on prognostic factors. Cumulative toxicity and the impact of treatment on quality of life must be considered since survival is relatively long in most patients with NET.

Conclusion: These guidelines are proposed to achieve the most beneficial therapeutic strategy in clinical practice as the therapeutic landscape of NEN is becoming ever more complex. These recommendations are permanently being reviewed.
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http://dx.doi.org/10.1016/j.dld.2020.02.011DOI Listing
May 2020

Organ preservation with chemoradiotherapy plus local excision for rectal cancer: 5-year results of the GRECCAR 2 randomised trial.

Lancet Gastroenterol Hepatol 2020 05 7;5(5):465-474. Epub 2020 Feb 7.

Department of Colorectal Surgery, Haut-Lévèque Hospital, CHU Bordeaux, France.

Background: GRECCAR 2 was the first multicentre, randomised trial to compare local excision with total mesorectal excision in downstaged low rectal cancer. Encouraging oncological results were noted at 3 years' follow-up but needed to be corroborated with longer follow-up. In this study, we aimed to report the 5-year oncological outcomes, including local recurrence, metastatic disease, and survival.

Methods: Patients age 18 years and older with T2T3 low rectal cancer, of maximum size 4 cm, who were clinically good responders after chemoradiotherapy (residual tumour ≤2 cm) were randomly assigned before surgery to either local excision or total mesorectal excision. Randomisation was centralised and not stratified and used permuted blocks of size eight. In the local excision group, a completion total mesorectal excision was performed if pathological tumour stage was ypT2-3. The primary objective of this study was to assess the 5-year oncological outcomes of local recurrence, metastatic disease, disease-free survival, overall survival, and cancer-specific mortality, which were the secondary endpoints of GRECCAR 2. We used Kaplan-Meier estimates and Cox modelling to estimate and compare recurrence and survival in modified intention-to-treat and as-treated populations. This trial was registered with ClinicalTrials.gov, number NCT00427375.

Findings: Between March 1, 2007, and Sept 24, 2012, 148 patients who were good clinical responders were randomly assigned to treatment, three patients were excluded after randomisation (because they had metastatic disease, tumour >8 cm from anal verge, or withdrew consent), leaving 145 for analysis: 74 in the local excision group and 71 in the total mesorectal excision group. Median follow-up was 60 months (IQR 58-60) in the local excision group and 60 months (57-60) in the total mesorectal excision group. 23 patients died and five were lost to follow-up. In the local excision group, 26 had a completion total mesorectal excision for ypT2-3 tumour. In the modified intention-to-treat analysis, there was no difference between the local excision and total mesorectal excision groups in 5-year local recurrence (7% [95% CI 3-16] vs 7% [3-16]; adjusted hazard ratio [HR] 0·71 [95% CI 0·19-2·58]; p=0·60), metastatic disease (18% [CI 11-30] vs 19% [11-31]; 0·86 [0·36-2·06]; p=0·73), overall survival (84% [73-91] vs 82% [71-90]; 0·92 [0·38-2·22]; p=0·85), disease-free survival (70% [58-79] vs 72% [60-82]; 0·87 [0·44-1·72]; p=0·68), or cancer-specific mortality (7% [3-17] vs 10% [5-20]; 0·65 [0·17-2·49]; p=0·53).

Interpretation: The 5-year results of this multicentre randomised trial corroborate the 3-year results, providing no evidence of difference in oncological outcomes between local excision and total mesorectal excision. Local excision can be proposed in selected patients having a small T2T3 low rectal cancer with a good clinical response after chemoradiotherapy.

Funding: National Cancer Institute of France.
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http://dx.doi.org/10.1016/S2468-1253(19)30410-8DOI Listing
May 2020

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting.

Materials And Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR).

Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007).

Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF.

Implications For Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.
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http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Everolimus after hepatic arterial embolisation therapy of metastases from gastrointestinal neuroendocrine tumours: The FFCD 1104-EVACEL-GTE phase II study.

Eur J Cancer 2019 12 31;123:92-100. Epub 2019 Oct 31.

Interventional Radiology Department, Gustave Roussy Villejuif & UFR Medecine Kremlin Bicetre Paris Sud University, Villejuif, France.

Background: Hepatic arterial embolisation therapy (HAET) is a treatment of liver metastases of gastrointestinal neuroendocrine tumours (GI-NETs). HAET increases circulating vascular endothelial growth factor levels. Everolimus is a treatment in NETs that may have antiangiogenic activity.

Methods: This phase II study was conducted in patients with predominant and progressive liver metastases from GI-NETs. Everolimus was initiated 7-30 days after HAET. The hypothesis was that everolimus after HAET would increase hepatic progression-free survival (hPFS) rate at 24 months from 35% to 50%.

Results: Among the 74 patients included, 88% had small-bowel primary tumour, 43% had grade I and 57% grade II tumour, and 51% had extrahepatic metastases. Patients underwent one (n = 19), two (n = 54), or three (n = 1) HAET procedures. hPFS at 24 months was 33% (95% confidence interval [CI], 22.5-43.7); 40 (54%) patients had objective response. Median (95% CI) hPFS, PFS, and overall survival were 19 (14-23), 17 (13-22), and 51 (33-60) months. The most common grade III-IV toxicities (>5%) in patients receiving both HAET and everolimus (n = 67) were elevated liver enzymes (55%), fatigue (18%), diarrhoea (16%), anaemia (12%), hypertriglyceridaemia (7%) and mucositis (6%).

Conclusions: The primary end-point was not reached. This sequence allows high liver response with HAET, and everolimus controls the extrahepatic disease.

Trial Registration: NCT01678664 (clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.ejca.2019.09.021DOI Listing
December 2019

Characteristic and outcomes of patients with pathologic complete response after preoperative treatment in borderline and locally advanced pancreatic adenocarcinoma: An AGEO multicentric retrospective cohort.

Clin Res Hepatol Gastroenterol 2019 11 24;43(6):663-668. Epub 2019 Apr 24.

Sorbonne Paris-Cité, Paris Descartes University, hepatogastroenterology and gastrointestinal oncology department, hôpital Européen Georges-Pompidou, 75015 Paris, France. Electronic address:

Introduction: Following publication of improved patients' outcome using first line FOLFIRINOX for metastatic pancreatic adenocarcinoma, many physicians now prescribe it as neo-adjuvant or induction treatment for borderline and locally advanced pancreatic cancer. A pathologic complete response, rarely seen with previous preoperative regimens, is sometimes observed in these patients. The aim of this study was to assess long-term outcomes of patients presenting pathologic complete response after preoperative FOLFIRINOX usually followed by chemo-radiation therapy for non-metastatic pancreatic adenocarcinoma.

Material And Methods: We retrospectively identified all resected patients with pancreatic cancer presenting pathologic complete response after FOLFIRINOX in 9 French centers from the AGEO group between November 2010 and May 2017.

Results: 29 patients were enrolled, 14 had borderline, 14 locally advanced and 1 oligo-metastatic pancreatic cancer. M/F ratio was 1.2 and the mean age was 57 years. All patients were treated with FOLFIRINOX (n = 29), de-escalated to gemcitabine (n = 1) and FOLFIRI (n = 2), and 24 (83 %) received radiation therapy after chemotherapy. Objective response rate to preoperative chemotherapy was 66% (RECIST V1.1). Only 8 patients received postoperative chemotherapy. After a median follow-up of 34 months from surgery, the median overall survival was not reached and the median disease free survival was 48 months. The 1-year and 2-year survival rates were 100% for OS and 96% and 72 % for DFS from surgery, 8 of the 9 observed recurrences were distant metastases.

Conclusions: The promising 1 and 2-year overall survival and disease free survival rates suggest that pathologic complete response is a major prognostic factor in resected pancreatic cancer following preoperative chemo-radiotherapy. A longer follow-up and prospective series are now necessary to confirm these encouraging results and to potentially validate pathologic complete response as a relevant surrogate marker of preoperative treatment efficacy.
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http://dx.doi.org/10.1016/j.clinre.2019.03.007DOI Listing
November 2019

FOLFIRINOX-based neoadjuvant chemoradiotherapy for borderline and locally advanced pancreatic cancer: A pilot study from a tertiary centre.

Dig Liver Dis 2019 07 15;51(7):1043-1049. Epub 2019 Apr 15.

CHU Bordeaux, Department of Radiotherapy, Bordeaux, France; Bordeaux University, INSERM U1035, Bordeaux, France. Electronic address:

Background: Neoadjuvant chemoradiotherapy, potentially relevant to increase resection rate in pancreatic cancer, is still debated.

Aims: To assess tolerance, resection rate and outcomes of patients with non-metastatic pancreatic ductal adenocarcinoma treated by concomitant chemoradiotherapy.

Methods: This monocentric study included all consecutive patients treated from 2010 to 2014 for non-metastatic pancreatic adenocarcinoma. Chemotherapy was followed by chemoradiotherapy in operable patients, surgical resectability being assessed by CT-scan.

Results: Seventy-nine patients were included: 41 patients had borderline and 38 locally advanced tumours. All patients were treated by chemotherapy (FOLFIRINOX), followed by chemoradiotherapy (median dose: 59 Gy, range 45-66 Gy) for 94% of patients. Thirty-seven patients (47%) could subsequently benefit from surgery with a complete R0 resection in 94% of cases, with a postoperative mortality of 5%. Median overall survival was 21.5 months (median follow-up: 48.8 months). Local control, overall and disease-free survival were significantly higher for patients who underwent resection compared to others, with 89.2% vs 59.5% (p = 0.01), 49.7 vs 17.4 months (p < 0.01) and 25.5 vs 9.2 months (p < 0.01), respectively.

Conclusion: Neoadjuvant treatment consisting of FOLFIRINOX chemotherapy followed by chemoradiotherapy is an efficient strategy for patients with borderline and locally advanced pancreatic cancer, resulting in a 43% rate of secondary complete surgical resection associated with high local control, overall and disease-free survival.
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http://dx.doi.org/10.1016/j.dld.2019.03.004DOI Listing
July 2019

Avelumab (anti-PD-L1) as first-line switch-maintenance or second-line therapy in patients with advanced gastric or gastroesophageal junction cancer: phase 1b results from the JAVELIN Solid Tumor trial.

J Immunother Cancer 2019 02 4;7(1):30. Epub 2019 Feb 4.

Brown University, Providence, USA.

Background: We evaluated the antitumor activity and safety of avelumab, a human anti-PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy.

Methods: In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety.

Results: Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5-13.9% and 1.8-16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n = 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4 months (95% CI, 4.0-not estimable) and 3.5 months (95% CI, 2.8-8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3-4.1) and 1.4 months (95% CI, 1.3-1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7-32.4%) and 7.9% (95% CI, 2.6-17.2%), and median OS was 11.1 months (95% CI, 8.9-13.7) and 6.6 months (95% CI, 5.4-9.4), respectively. In the 1 L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4-20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade ≥3 TRAE, including 1 treatment-related death.

Conclusion: Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC.

Trial Registration: ClinicalTrials.gov NCT01772004 ; registered 21 January 2013.
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http://dx.doi.org/10.1186/s40425-019-0508-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362598PMC
February 2019

Patterns of Use, Safety, and Effectiveness of Targeted Therapies in First-Line Treatment of Metastatic Colorectal Cancer According to Age: The STROMBOLI Cohort Study.

Clin Colorectal Cancer 2019 03 29;18(1):e150-e162. Epub 2018 Nov 29.

Univ Bordeaux, Inserm, Bordeaux Population Health Research Center, Team Pharmacoepidemiology, UMR 1219, Bordeaux, France; Bordeaux PharmacoEpi, INSERM CIC1401, Bordeaux, France; CHU de Bordeaux, Pôle de Sante publique, Service de Pharmacologie médicale, Bordeaux, France.

Background: Metastatic colorectal cancer (mCRC) is increasingly treated using targeted therapies. Their real-life evaluation is insufficient, especially in elderly and frail patients. The aim was to describe use, safety, and effectiveness of targeted therapies in first-line mCRC treatment according to age.

Patients And Methods: Two field cohorts of patients initiating bevacizumab or cetuximab for first-line mCRC were pooled. Patients characteristics, use, and safety were compared between younger and elderly patients (<75 vs. ≥75 years). Two-year overall survival (OS) and progression-free survival (PFS) were estimated in both age groups using the Kaplan-Meier method adjusted on factors associated with death or progression identified with Cox multivariate modeling.

Results: Eight hundred patients (n = 411, 51.4% bevacizumab) were included: 498 (62.3%) male, median age 64 years, 118 (14.8%) Eastern Cooperative Oncology Group performance status (ECOG-PS) ≥2. Elderly patients (n = 126, 15.8%) were more often treated with 5-fluorouracil alone than younger. Severe adverse events were equivalent across age groups. ECOG-PS ≥1, abnormal hemoglobin, and abnormal alkaline phosphatases were associated with a higher risk of death; OS adjusted on these factors was similar between elderly and younger patients. ECOG-PS ≥1, lung metastases, abnormal hemoglobin, and abnormal creatinine clearance were associated with a higher risk of progression or death; PFS adjusted on these factors was similar across groups.

Conclusion: Despite treatment adaptations, elderly patients could benefit from targeted therapies as younger without safety warning.
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http://dx.doi.org/10.1016/j.clcc.2018.11.005DOI Listing
March 2019

Prognostic factors in esophageal cancer treated with curative intent.

Dig Liver Dis 2018 10 9;50(10):991-996. Epub 2018 Aug 9.

Bordeaux University of Medicine, Bordeaux, France; Esophageal and Endocrine Surgery Unit, Visceral Surgery Department, Magellan Center, Bordeaux University Hospital, Pessac, France; INSERM, UMR1053 Bordeaux Research in Translational Oncology, BaRITOn, University of Bordeaux, Bordeaux, France. Electronic address:

The overall prognosis of patients with esophageal cancer has improved in recent decades due to surgical and medical progress, but overall survival remains poor. Better patient selection and tailored treatment are needed. Different prognostic factors linked with the patient, tumoral characteristics and treatment with curative intent have been identified and are the purpose of this review. Tumor detection at an earlier stage, the advent of new molecules and therapeutic combinations, and the centralization of management in high-volume centers should help to improve the prognosis of esophageal cancer. Improved imaging techniques and a better prediction strategy should guide future treatments.
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http://dx.doi.org/10.1016/j.dld.2018.08.002DOI Listing
October 2018

Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study.

Lancet Oncol 2018 08 2;19(8):1094-1106. Epub 2018 Jul 2.

Department of Oncology, University Hospital of Besancon, Centre Hospitalier Universitaire de Besançon, Besançon, France; Department of Oncology and Radiotherapy, Hôpital Nord Franche Comté, Montbéliard, France; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France; Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France.

Background: The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma.

Methods: We did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m docetaxel and 75 mg/m cisplatin on day 1 and 750 mg/m per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m docetaxel and 40 mg/m cisplatin on day 1 and 1200 mg/m per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here.

Findings: Between Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded.

Interpretation: Compared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation.

Funding: Besançon University Hospital and Ligue contre le cancer Grand-Est.
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http://dx.doi.org/10.1016/S1470-2045(18)30321-8DOI Listing
August 2018

Oncological outcomes of IBD-associated versus sporadic colorectal cancer in modern era: a matched case-control study.

Int J Colorectal Dis 2018 Jul 19;33(7):963-966. Epub 2018 Apr 19.

CHU of Bordeaux, Colorectal Unit, Department of Surgery, Magellan Hospital, University of Bordeaux, Bordeaux, France.

Aim: Inflammatory bowel diseases (IBD) are associated with an increased risk for colorectal cancer (CRC). However and despite significant advances in the management of IBD and CRC, the prognosis of IBD-related CRC (IBD-CRC) remains controversial. The aim of the present case-control study was to compare the prognosis of IBD-CRC to sporadic CRC.

Methods: Consecutive patients operated for IBD-CRC from 2004 to 2014 were recruited and matched with sporadic CRC (ratio 3:1) from the same center. Matching was performed on gender, tumor stage, and location and period of surgery. Endpoints were postoperative morbidity (Dindo-Clavien III-V), quality of surgery, and long-term oncological outcomes.

Results: Among 1498 CRC patients operated during the study period, 21 patients were identified with IBD-CRC and matched to 63 patients with sporadic CRC (S-CRC). Patients with IBD-CRC were significantly younger (p < 0.001), had multifocal lesions more frequently (p = 0.04), and undergone abdominoperineal excision and coloproctectomy more often (p = 0.001). Postoperative morbidity was not significantly different between the two groups (25 vs. 14%; p = 0.309), as well as the rate of R0 resection (86 vs. 95%; p = 0.162). Five-year disease-free and overall survival were 71 and 81% in patients with IBD-CRC and 69% (p = 0.801) and 78% (p = 0.845) in those with S-CRC, respectively.

Conclusion: In a case-control study of patients operated for CRC within the last decade, the prognosis of cancer associated with IBD is similar to sporadic cancer.
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http://dx.doi.org/10.1007/s00384-018-3049-zDOI Listing
July 2018

Effectiveness of Cetuximab as First-Line Therapy for Patients With Wild-Type KRAS and Unresectable Metastatic Colorectal Cancer in Real-Life Practice: Results of the EREBUS Cohort.

Clin Colorectal Cancer 2018 06 31;17(2):129-139. Epub 2018 Jan 31.

Digestive oncology and Gastroenterology Department, Hôpital Haut-Lévêque, CHU de Bordeaux, Pessac, France. Electronic address:

Introduction: Few real-life data are available on cetuximab benefit. The EREBUS cohort was performed to assess metastases resection rate, use, safety, and survival outcomes in wild-type KRAS (Kirsten rat sarcoma viral oncogene) patients with initially unresectable metastatic colorectal cancer (mCRC) treated by cetuximab in real practice.

Patients And Methods: The study cohort comprised patients initiating cetuximab between January 2009 and December 2010 in 65 French centers, with initially unresectable mCRC and wild-type KRAS. Kaplan-Meier analysis estimated 24-month probability of metastases resection and progression-free survival, and 36-month overall survival (OS). Cox proportional hazards models investigated factors associated with survival outcomes.

Results: Among the 389 patients included, median age was 64 years, 67.4% were male, 77.9% had Eastern Cooperative Oncology Group performance status ≤ 1, and hepatic metastases were most frequent at baseline (n = 146 exclusively, n = 149 not exclusively, n = 94 nonliver only). Median duration of cetuximab use was 4.8 months. Metastases resection was performed in 106 patients (27.2%) (n = 60 liver exclusively, n = 33 not exclusively, n = 13 nonliver only). The 24-month probability (95% confidence interval) of metastases resection occurrence was 33.6% (28.5-39.3). Median progression-free survival was 9.2 (8.5-9.8) months for the total cohort and 13.0 (11.6-15.1) for those resected; median OS was 23.0 (20.6-26.3) months for the total cohort and was not reached after 36 months for those who were resected. The strongest factor associated with higher OS was metastases resection with complete remission (hazard ratio, 0.41; 95% confidence interval, 0.19-0.88).

Conclusion: This cohort study highlights in French real-life practice the benefit of cetuximab in first-line mCRC therapy, notably in case of metastases resection with complete remission.
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http://dx.doi.org/10.1016/j.clcc.2018.01.007DOI Listing
June 2018

Common variants in glucuronidation enzymes and membrane transporters as potential risk factors for colorectal cancer: a case control study.

BMC Cancer 2017 12 28;17(1):901. Epub 2017 Dec 28.

UMR-1248, Inserm, CHU Limoges, Univ. Limoges, Limoges, France.

Background: Associations between polymorphisms of UDP-glucuronosyltransferases (UGTs) or efflux transporters (e.g., P-glycoprotein and MRP2) and different types of cancer have been described, whereas the role of influx transporters (e.g. OATP1B1 and OATP2B1) has been seldom explored. The GenColon study investigated potential associations between variant alleles of UGTs, efflux and influx transporters and CRC.

Methods: Three hundred CRC cases were matched with 300 controls for age, sex and enrolment site. Fifteen SNPs in UGT1A6-9, UGT2B7, ABCB1, ABCC2, SLCO1B1 and SLCO2B1 genes were characterized using Taqman® PCR. Using multivariate conditional logistic regression, we investigated the relationships between CRC and "environmental" risk factors (physical activity, housing and working areas, consumption of red meat, tobacco, alcohol); genetic polymorphisms, in the study population and in the subgroups with "environmental" risk factors.

Results: No significant association was observed for the analyzed SNPs (or haplotypes). However, an increased CRC risk was found in carriers of the UGT1A8 rs1042597-G variant allele (additive risk OR = 3.39[1.29-8.89], p = 0.02951) in the subgroup of meat-consumers (n = 84), and in carriers of the ABCB1 rs1045642-T (exon26) variant allele (additive risk; OR = 1.89[1.10-3.39], p = 0.0257) in the "never alcohol consumption subgroup" (n = 125). In addition, as previously reported, the following CRC risk factors were identified: absence of physical activity (OR = 6.35[3.70-10.9], p < 0.0001), living or working in rural or mix area (OR = 2.50[1.48-4.23], p = 0.0006 and OR = 2.99[1.63-5.48], p = 0.004, respectively) and tobacco exposure >30 years (3.37[1.63-6.96], p = 0.0010).

Conclusions: Variant genotypes of influx transporters (OATP1B1 and 2B1) were not associated with CRC. This study confirmed the influence of lifestyle factors, but not the previously reported detrimental effect of SNPs in intestinal UGTs or efflux transporters, except for a UGT1A8 variant in subjects consuming meat and the exon 26 SNP of ABCB1 in the never alcohol consumption subgroup.

Trial Registration: Registered in Direction Générale de la Santé the 1st July 2008 under the number DGS2008-0144.
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http://dx.doi.org/10.1186/s12885-017-3728-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745594PMC
December 2017

Evaluating bevacizumab in combination with FOLFIRI after the failure of platinum-etoposide regimen in patients with advanced poorly differentiated neuroendocrine carcinoma: The PRODIGE 41-BEVANEC randomized phase II study.

Dig Liver Dis 2018 Feb 6;50(2):195-198. Epub 2017 Dec 6.

Gastrointestinal Oncology Department, Gustave Roussy Institute, Villejuif, France; Gastroenterology & Digestive Oncology, University Hospital Le Bocage, Dijon, France.

Introduction: Patients with gastroenteropancreatic (GEP), metastatic or locally advanced, non-resectable, grade 3 poorly-differentiated neuroendocrine carcinoma (NEC) are treated with cisplatin (or carboplatin)-etoposide in first-line palliative chemotherapy (CT1). However, nearly all patients will develop resistance and there is no standard second-line treatment.

Aim: PRODIGE 41-BEVANEC is an academic randomized, phase II study designed to evaluate the efficacy of bevacizumab in combination with FOLFIRI after failure of CT1 in unknown primary NEC and GEP-NEC.

Materials And Methods: The main eligibility criteria are age ≥18 years, metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 3 GEP-NEC, and documented progressive disease during or after CT1 therapy.

Results: A total of 124 patients will be randomly assigned (1:1) to receive either 5 mg/kg bevacizumab with FOLFIRI, or FOLFIRI alone, every 14 days until disease progression or unacceptable toxicity. The hypothesis is to demonstrate a 6-month overall survival for at least 50% of the patients in bevacizumab arm versus 35% in the control arm (FOLFIRI alone). Secondary endpoints are objective response, response duration, progression-free survival, toxicity, and biochemical response.

Conclusion: The study is currently opened in France (NCT02820857). The first patient was randomized on September 6, 2017.
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http://dx.doi.org/10.1016/j.dld.2017.11.020DOI Listing
February 2018

Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases.

Ultraschall Med 2018 Oct 12;39(5):544-558. Epub 2017 Dec 12.

CNRS GICC UMR 9272, Universite Francois-Rabelais de Tours, France.

Purpose:  To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases.

Materials And Methods:  This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS).

Results:  Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival.

Conclusion:  This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.
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http://dx.doi.org/10.1055/s-0043-122497DOI Listing
October 2018

When is the best moment to apply photobiomodulation therapy (PBMT) when associated to a treadmill endurance-training program? A randomized, triple-blinded, placebo-controlled clinical trial.

Lasers Med Sci 2018 May 29;33(4):719-727. Epub 2017 Nov 29.

Laboratory of Phototherapy in Sports and Exercise, Nove de Julho University, Sao Paulo, SP, Brazil.

Photobiomodulation therapy (PBMT) employing low-level laser therapy (LLLT) and/or light emitting diode therapy (LEDT) has emerged as an electrophysical intervention that could be associated with aerobic training to enhance beneficial effects of aerobic exercise. However, the best moment to perform irradiation with PBMT in aerobic training has not been elucidated. The aim of this study was to assess the effects of PBMT applied before and/or after each training session and to evaluate outcomes of the endurance-training program associated with PBMT. Seventy-seven healthy volunteers completed the treadmill-training protocol performed for 12 weeks, with 3 sessions per week. PBMT was performed before and/or after each training session (17 sites on each lower limb, using a cluster of 12 diodes: 4 × 905 nm super-pulsed laser diodes, 4 × 875 nm infrared LEDs, and 4 × 640 nm red LEDs, dose of 30 J per site). Volunteers were randomized in four groups according to the treatment they would receive before and after each training session: PBMT before + PBMT after, PBMT before + placebo after, placebo before + PBMT after, and placebo before + placebo after. Assessments were performed before the start of the protocol and after 4, 8, and 12 weeks of training. Primary outcome was time until exhaustion; secondary outcome measures were oxygen uptake and body fat. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) significantly increased (p < 0.05) the percentage of change of time until exhaustion and oxygen uptake compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 4th, 8th, and 12th week. PBMT applied before and after aerobic exercise training sessions (PBMT before + PBMT after group) also significantly improved (p < 0.05) the percentage of change of body fat compared to the group treated with placebo before and after aerobic exercise training sessions (placebo before + placebo after group) at 8th and 12th week. PBMT applied before and after sessions of aerobic training during 12 weeks can increase the time-to-exhaustion and oxygen uptake and also decrease the body fat in healthy volunteers when compared to placebo irradiation before and after exercise sessions. Our outcomes show that PBMT applied before and after endurance-training exercise sessions lead to improvement of endurance three times faster than exercise only.
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http://dx.doi.org/10.1007/s10103-017-2396-2DOI Listing
May 2018

Patient-reported tolerance in treatments approved in neuroendocrine tumors: A national survey from the French Group of Endocrine Tumors.

Clin Res Hepatol Gastroenterol 2018 04 20;42(2):153-159. Epub 2017 Nov 20.

Service d'hépatogastroentérologie et d'oncologie, hospices civils de Lyon, hôpital Edouard-Herriot, 5, place d'Arsonval, 69437 Lyon, France. Electronic address:

Background: Patients with advanced neuroendocrine tumors (NETs) benefit from an increasing number of treatments. The patient's preference could help physicians to choose among these options. Our patient-reported survey aims to compare the perceived tolerance of NETs treatments.

Methods: Patients treated by at least three different therapeutic options have evaluated their perceived tolerance from one (very good) to five (very poor) for each single treatment. Referent physician confirmed the type and ranking over time of each treatment.

Results: Two hundred and fourty two treatments have been evaluated by 54 patients. Among patients and NETs characteristics, only a female gender was associated with poor perceived tolerance. Median perceived tolerance increased from 1 (somatostatin analogs, peptide receptor radionuclide therapy (PRRT)), 2 (surgery, radiofrequency ablation and oral chemotherapy), 3 (interferon and everolimus), to 4 (liver embolization, sunitinib and intravenous chemotherapy). In taking somatostatin analogs as reference, the odd ratios for poor perceived tolerance were 1.7 [0.6-5.1] for oral chemotherapy, 2.2 [0.9-5.3] for surgery of the primary tumor, 2.4 [0.6-9.5] for radiofrequency ablation, 2.8 [1.1-7.3] for surgery of metastasis, 3.4 [1.4-7.9] for everolimus, 3.7 [1.6-8.5] for liver embolization, 4.9 [2.2-10.7] for intravenous chemotherapy and 5.9 [2.6-13.1] for sunitinib. Only PRRT had negative odd ratio.

Conclusion: Our retrospective analysis suggests that perceived tolerance differ in between therapeutic options and may help physicians to sequence the therapeutic strategy.
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http://dx.doi.org/10.1016/j.clinre.2017.10.003DOI Listing
April 2018

Docetaxel, Cisplatin, and 5-fluorouracil (DCF) chemotherapy in the treatment of metastatic or unresectable locally recurrent anal squamous cell carcinoma: a phase II study of French interdisciplinary GERCOR and FFCD groups (Epitopes-HPV02 study).

BMC Cancer 2017 Aug 25;17(1):574. Epub 2017 Aug 25.

Centre Hospitalier Universitaire de Besançon, Besançon, France.

Background: The squamous cell carcinoma of the anus (SCCA) is a rare disease, but its incidence is markedly increasing. About 15% of patients are diagnosed at metastatic stage, and more than 20% with a localized disease treated by chemoradiotherapy (CRT) will recur. In advanced SCCA, cisplatin and 5-fluorouracil (CF) combination is the standard option but complete response is a rare event and the prognosis remains poor with most disease progression occurring within the first 12 months. We have previously published the potential role of the addition of docetaxel (D). Among 8 consecutive patients with advanced recurrent SCCA after CRT, the DCF regimen induced a complete response in 4 patients, including 3 pathological complete responses. Then, the Epitopes-HPV02 study was designed to confirm the interest of DCF regimen in SCCA patients.

Methods: This multicentre phase II trial assesses the DCF regimen in advanced SCCA patients. Main eligibility criteria are: histologically proven SCCA, unresectable locally advanced recurrent or metastatic disease, Eastern Cooperative Oncology Group-performance status (ECOG-PS) <2, and being eligible for DCF. Patients receive either 6 cycles of standard DCF or 8 cycles of modified DCF depending on age (> vs. ≤ 75 years-old) and ECOG-PS (0 vs. 1). The trial was set up based on a Simon's optimal two-stage design for phase II trials, allowing an early futility interim analysis. The primary endpoint is the observed progression-free survival (PFS) rate at 12 months from the first DCF cycle. A PFS rate below 10% is considered uninteresting, while a PFS rate above 25% is expected. With a unilateral alpha error of 5% and a statistical power of 90%, 66 evaluable patients should be included. Main secondary endpoints are overall survival, PFS, response rate, safety, health-related quality of life, and the correlation of biomarkers with treatment efficacy.

Discussion: Since the recommended CF regimen is based in a small retrospective analysis and generates a low rate of complete responses, the Epitopes-HPV02 study will establish a new standard in case of a positive result. Associated biomarker studies will contribute to understand the underlying mechanism of resistance and the role of immunity in SCCA.

Trial Registration: NCT02402842 , EudraCT: 2014-001789-81.
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http://dx.doi.org/10.1186/s12885-017-3566-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574110PMC
August 2017

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

Br J Cancer 2017 Sep 17;117(7):965-973. Epub 2017 Aug 17.

INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.

Background: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes.

Methods: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1).

Results: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763).

Conclusion: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.
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http://dx.doi.org/10.1038/bjc.2017.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625679PMC
September 2017

Evaluating lanreotide as maintenance therapy after first-line treatment in patients with non-resectable duodeno-pancreatic neuroendocrine tumours.

Dig Liver Dis 2017 May 11;49(5):568-571. Epub 2017 Mar 11.

Edouard Herriot Hospital, Department of Gastroenterology, Hospices Civils de Lyon, Lyon, France.

Introduction: Patients with metastatic or locally advanced, non-resectable, grade 1 or 2 well-differentiated duodeno-pancreatic (WDDP) NETs are treated following European guidelines. Patients (Pts) with aggressive disease, i.e. progressive and/or symptomatic metastases and/or with significant hepatic invasion (>30-50%), and/or bone metastases, anti-tumour therapy should receive systemic combination of chemotherapy once disease control is obtained.

Aim(s): The aim is to stop chemotherapy until progression. REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study designed to evaluate lanreotide (LAN) as maintenance treatment after L1 chemotherapy in G1-G2 WDDP NET.

Materials And Methods: Main eligibility criteria: adults pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs and documented control disease after L1 therapy at least 4 weeks prior to randomization.

Results: 222 patients will be randomly assigned in a 1:1 ratio to receive 120mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. The aim of the phase II part is to demonstrate a 6-months PFS >45% in LAN arm. Secondary endpoints are PFS according to central review, overall survival, safety and quality of life. A bio-bank of frozen blood will be constituted.

Conclusion: The study is currently open in France, Germany, Belgium, United Kingdom and Ireland. A total of 25 patients are randomized (NCT02288377).
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http://dx.doi.org/10.1016/j.dld.2017.02.004DOI Listing
May 2017

Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer.

Eur J Cancer 2016 11 18;68:163-172. Epub 2016 Oct 18.

AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom. Electronic address:

Background: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m) and triplet hepatic artery infusion (HAI) within European trial OPTILIV.

Methods: Irinotecan (180 mg/m), 5-fluorouracil (2800 mg/m) and oxaliplatin (85 mg/m) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models.

Results: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses.

Conclusions: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.
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http://dx.doi.org/10.1016/j.ejca.2016.09.011DOI Listing
November 2016