SIRIC OncoLille

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SIRIC OncoLille

France
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Markar S.R.,Imperial College London | Gronnier C.,Lille University Hospital Center | Gronnier C.,North of France University | Gronnier C.,French Institute of Health and Medical Research | And 11 more authors.
Annals of Surgery | Year: 2016

Objective: The objectives of this study were to establish if R1 resection margin after esophagectomy was (i) a poor prognostic factor independent of patient and tumor characteristics, (ii) a marker of tumor aggressiveness and (iii) to look at the impact of adjuvant treatment in this subpopulation. Methods: Data were collected from 30 European centers from 2000 to 2010. Patients with an R1 resection margin (n = 242) were compared with those with an R0 margin (n = 2573) in terms of short-and long-term outcomes. Propensity score matching and multivariable analyses were used to compensate for differences in baseline characteristics. Results: Independent factors significantly associated with an R1 resection margin included an upper third esophageal tumor location, preoperative malnutrition, and pathological stage III. There were significant differences between the groups in postoperative histology, with an increase in pathological stage III and TRG 4-5 in the R1 group. Total average lymph node harvests were similar between the groups; however, there was an increase in the number of positive lymph nodes seen in the R1 group. Propensity matched analysis confirmed that R1 resection margin was significantly associated with reduced overall survival and increased overall, locoregional, and mixed tumor recurrence. Similar observations were seen in the subgroup that received neoadjuvant chemoradiation. In R1 patients adjuvant therapy improved survival and reduced distant recurrence however failed to affect locoregional recurrence. Conclusions: This large multicenter European study provides evidence to support the notion that R1 resection margin is a prognostic indication of aggressive tumor biology with a poor long-term prognosis. © 2015 Wolters Kluwer Health, Inc. All rights reserved.


Pasquer A.,University of Lyon | Gronnier C.,Lille University Hospital Center | Gronnier C.,North of France University | Gronnier C.,French Institute of Health and Medical Research | And 12 more authors.
Annals of Surgical Oncology | Year: 2015

Background: Whereas the optimal therapeutic strategy in node positive esophageal cancer primarily treated by surgery remains unknown, the study was designed to evaluate the impact of adjuvant chemotherapy on survival in such population. Methods: Among 2944 consecutive patients operated on for esophageal cancer between 2000 and 2010 in 30 European centers, patients with lymph node metastasis treated by adjuvant treatment (n = 178) were compared to patients who did not received adjuvant treatment (n = 378). Multivariable analyses and propensity score matching were used to compensate for differences in baseline characteristics. Results: After matching, patients were comparable between the two groups. When comparing adjuvant treatment and nonadjuvant treatment groups, there was no significant differences in 3-year overall (40.9 vs. 35.8 %, P = 0.560) and disease-free (33.9 vs. 28.5 %, P = 0.190) survivals. Locoregional recurrence was lower in the adjuvant treatment group (14.4 vs. 30.9 %, P = 0.012). In the adjuvant treatment group, 94 patients received chemotherapy and 84 chemoradiotherapy, without significant survival benefit over chemoradiotherapy compared with chemotherapy alone (P = 0.280). Predictive factors of overall survival were age ≥60 years, ASA III–IV score, and pN+ classification. No survival benefit was observed according to histological subtype or occurrence of postoperative complications. Conclusions: Adjuvant chemo(radio)therapy did not offer survival benefit in lymph node-positive esophageal cancer patients primarily treated with surgery. © 2015, Society of Surgical Oncology.


Markar S.,Imperial College London | Gronnier C.,Lille University Hospital Center | Gronnier C.,North of France University | Gronnier C.,French Institute of Health and Medical Research | And 11 more authors.
Annals of Surgical Oncology | Year: 2015

Background: High center procedural volume has been shown to reduce postoperative mortality (POM); however, the cause of POM has been poorly studied previously. The aim of this study was to define the pattern of POM and major morbidity in relation to center procedural volume. Methods: Data from 2,944 consecutive adult patients undergoing esophagectomy for esophageal cancer in 30 centers between 2000 and 2010 were retrospectively collected. Data between patients who suffered 30-day POM were compared with those who did not. Factors associated with POM were identified using binary logistic regression, with propensity matching to compare low- (LV) and high-volume (HV) centers. Results: The 30-day and in-hospital POM rates were 5.0 and 7.3 %, respectively. Pulmonary complications were the most common, affecting 38.1 % of patients, followed by surgical site infection (15.5 %), cardiovascular complications (11.2 %), and anastomotic leak (10.2 %). Factors that were independently associated with 30-day POM included American Society of Anesthesiologists grade IV, LV center, anastomotic leak, pulmonary, cardiovascular and neurological complications, and R2 resection margin status. Surgical complications preceded POM in approximately 30 % of patients compared to medically-related causes in 68 %. Propensity-matched analysis demonstrated LV centers were significantly associated with increased 30-day POM, and POM secondary to anastomotic leak, and pulmonary- and cardiac-related causes. Conclusions: The results of this large, multicenter study provide further evidence to support the centralization of esophagectomy to HV centers, with a lower rate of morbidity and better infrastructure to deal with complications following major surgery preventing further mortality. © 2015, Society of Surgical Oncology.


Piessen G.,Lille University Hospital Center | Piessen G.,University of Lille Nord de France | Piessen G.,French Institute of Health and Medical Research | Lefevre J.H.,University Pierre and Marie Curie | And 27 more authors.
Annals of Surgery | Year: 2015

Objectives: The aim of the study was to compare the postoperative and oncologic outcomes of laparoscopic versus open surgery for gastric gastrointestinal stromal tumors (gGISTs). Background: The feasibility of the laparoscopic approach for gGIST resection has been demonstrated; however, its impact on outcomes, particularly its oncologic safety for tumors greater than 5cm, remains unknown. Methods: Among 1413 patients treated for a GIST in 61 European centers between 2001 and 2013, patients who underwent primary resection for a gGIST smaller than 20cm (N=666), by either laparoscopy (group L, n=282) or open surgery (group O, n=384), were compared. Multivariable analyses and propensity score matching were used to compensate for differences in baseline characteristics. Results: In-hospital mortality and morbidity rates in groups L and O were 0.4% versus 2.1% (P=0.086) and 11.3% vs 19.5% (P=0.004), respectively. Laparoscopic resection was independently protective against in-hospital morbidity (odds ratio 0.54, P=0.014). The rate of R0 resection was 95.7% in group L and 92.7% in group O (P=0.103). After 1:1 propensity score matching (n=224), the groups were comparable according to age, sex, tumor location and size, mitotic index, American Society of Anesthesiology score, and the extent of surgical resection. After adjustment for BMI, overall morbidity (10.3% vs 19.6%; P=0.005), surgical morbidity (4.9% vs 9.8%; P=0.048), and medical morbidity (6.2% vs 13.4%; P=0.01) were significantly lower in group L. Five-year recurrence-free survival was significantly better in group L (91.7% vs 85.2%; P=0.011). In tumors greater than 5cm, in-hospital morbidity and 5-year recurrence-free survival were similar between the groups (P=0.255 and P=0.423, respectively). Conclusions: Laparoscopic resection for gGISTs is associated with favorable short-term outcomes without compromising oncologic results. © 2015 Wolters Kluwer Health, Inc.


PubMed | Brest University Hospital Center, University of Lyon, Haut Leveque University Hospital, Lille University Hospital Center and 4 more.
Type: | Journal: Annals of surgical oncology | Year: 2015

Whereas the optimal therapeutic strategy in node positive esophageal cancer primarily treated by surgery remains unknown, the study was designed to evaluate the impact of adjuvant chemotherapy on survival in such population.Among 2944 consecutive patients operated on for esophageal cancer between 2000 and 2010 in 30 European centers, patients with lymph node metastasis treated by adjuvant treatment (n = 178) were compared to patients who did not received adjuvant treatment (n = 378). Multivariable analyses and propensity score matching were used to compensate for differences in baseline characteristics.After matching, patients were comparable between the two groups. When comparing adjuvant treatment and nonadjuvant treatment groups, there was no significant differences in 3-year overall (40.9 vs. 35.8 %, P = 0.560) and disease-free (33.9 vs. 28.5 %, P = 0.190) survivals. Locoregional recurrence was lower in the adjuvant treatment group (14.4 vs. 30.9 %, P = 0.012). In the adjuvant treatment group, 94 patients received chemotherapy and 84 chemoradiotherapy, without significant survival benefit over chemoradiotherapy compared with chemotherapy alone (P = 0.280). Predictive factors of overall survival were age 60 years, ASA III-IV score, and pN+ classification. No survival benefit was observed according to histological subtype or occurrence of postoperative complications.Adjuvant chemo(radio)therapy did not offer survival benefit in lymph node-positive esophageal cancer patients primarily treated with surgery.


PubMed | Biostatistics Unit, Medical Oncology, Medical University of Graz, Center Leon Berard and 5 more.
Type: | Journal: BMC cancer | Year: 2015

Angiogenesis, among other signaling pathways, plays a key-role in sarcoma biology. Regorafenib (RE) has recently been shown to be effective in imatinib and sunitinib-refractory GIST in a phase III trial.We are conducting an international trial (France, Austria and Germany) consisting in 4 parallel double-blind placebo-controlled randomized (1/1) phase II trials to assess the activity and safety of RE in doxorubicin-refractory STS (ClinicalTrials.gov: NCT01900743). Each phase II trial is dedicated to one of the 4 following histological subgroups: liposarcoma, leiomyosarcoma, synovial sarcoma and other sarcoma. Within each randomized trial the following stratification factors will be applied: countries and prior exposure to pazopanib. Key-eligibility criteria are: measurable disease, age 18, not>3 previous systemic treatment lines for metastatic disease, metastatic disease not amenable to surgical resection. The primary endpoint is progression-free survival (PFS) according to central radiological review. Secondary endpoints are: Toxicity (NCI-CTC AE V4.0); time to progression; Growth modulation index in pts receiving RE after randomization; 3 and 6 months PFS-Rates, best response rate and overall survival. Each phase II trial will be separately analyzed. In 3 trials, statistical assumptions are: PFS0=1.6 & PFS1=4.6 months; 1-sided =0.1; =0.05 with a total sample size of 192 pts. To take into account the rarity of synovial sarcoma, the statistical assumptions are: PFS0=1.6 & PFS1=4.6 months; 1-sided =0.1; =0.2 Tumor assessment is done monthly during the 4 first months, and every 3 months thereafter. After central radiological confirmation of tumor progression, an optional open-label option is offered to eligible patients.The design of this trial allows an assessment of regorafenib activity over placebo in four sarcoma strata and might provide evidence for launching a phase III trial. This study includes both integrative and exploratory translational research program. The study is enrolling since June 2013 (TRIAL REGISTRATION NUMBER: EudraCT N: 2012-005743-24, on the 15(th) February 2012).


Ligier K.,Registre general des cancers de Lille et de sa region | Maynou C.,Hopital Roger Salengro | Leroy X.,CHRU de Lille | Robin Y.-M.,Center Oscar Lambret | And 7 more authors.
BMC Cancer | Year: 2015

Background: Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study. Methods: We conducted a before-after population-based study (before: 2005 with 63 cases, after: 2008-2009 with 86 cases) in the Lille area (Northern France urban/sub-urban area with 800,000 inhabitants). The following were the key-indicators of adult sarcoma management: pre-therapeutic biopsy, appropriate tumour and chest imaging, expert interdisciplinary discussion, expert interdisciplinary discussion before the first treatment and in operated cases, the rate of R0 resection. Results: There was no statistically significant difference in patient and tumour characteristics for the two time periods in terms of gender, prior cancer, primary location, histological subtype, grade, size, metastasis and lymph node involvement. There was no statistically significant improvement in primary tumour imaging (83 versus 87%), chest imaging (67 vs 71%), pre-therapeutic biopsy (57 vs 58%). There was an improvement in expert multidisciplinary discussion (37 vs 45%) or discussion before the first treatment (26 vs 44%) but no statistically significant. However, when soft tissue and bone sarcomas were analysed separately, we observed statistically significant improvements in expert multidisciplinary discussion (50 vs 74%, p = 0.02) and R0 resection rate (58 vs 91%, p = 0.002). In contrast, in cases of visceral sarcoma, there was no improvement in expert multidisciplinary discussion (10 vs 16%, p = 0.7) or in R0 resection (88 vs 81%, p = 0.7). Conclusions: The dissemination of EBG was associated with a limited improvement in sarcoma management when measured in this before-after population-based study, and this improvement was dependent on the primary location of the tumour. Efforts to implement these guidelines by all surgical teams that could treat sarcoma, including visceral sarcoma, need to be made. © 2015 Ligier et al.


PubMed | Service de Cancerologie, CHRU de Lille, Hopital Roger Salengro, Center Oscar Lambret and 2 more.
Type: | Journal: BMC cancer | Year: 2015

Improvement of the initial management of sarcomas after the dissemination of evidence-based guidelines depends on the primary sarcoma location: a population-based study. To improve the initial management of adult sarcomas, a regional expert team in Northern France performed two actions: dissemination of evidence-based guidelines (EBG) for the management of soft tissue/visceral sarcoma and yearly educational symposia. The aim of this study was to measure the impact of the dissemination of EBG on the key-indicators of adult sarcoma management.We conducted a before-after population-based study (before: 2005 with 63 cases, after: 2008-2009 with 86 cases) in the Lille area (Northern France urban/sub-urban area with 800,000 inhabitants). The following were the key-indicators of adult sarcoma management: pre-therapeutic biopsy, appropriate tumour and chest imaging, expert interdisciplinary discussion, expert interdisciplinary discussion before the first treatment and in operated cases, the rate of R0 resection.There was no statistically significant difference in patient and tumour characteristics for the two time periods in terms of gender, prior cancer, primary location, histological subtype, grade, size, metastasis and lymph node involvement. There was no statistically significant improvement in primary tumour imaging (83 versus 87%), chest imaging (67 vs 71%), pre-therapeutic biopsy (57 vs 58%). There was an improvement in expert multidisciplinary discussion (37 vs 45%) or discussion before the first treatment (26 vs 44%) but no statistically significant. However, when soft tissue and bone sarcomas were analysed separately, we observed statistically significant improvements in expert multidisciplinary discussion (50 vs 74%, p=0.02) and R0 resection rate (58 vs 91%, p=0.002). In contrast, in cases of visceral sarcoma, there was no improvement in expert multidisciplinary discussion (10 vs 16%, p=0.7) or in R0 resection (88 vs 81%, p=0.7).The dissemination of EBG was associated with a limited improvement in sarcoma management when measured in this before-after population-based study, and this improvement was dependent on the primary location of the tumour. Efforts to implement these guidelines by all surgical teams that could treat sarcoma, including visceral sarcoma, need to be made.


Simonneau C.,Lille University of Science and Technology | Leclercq B.,Lille University of Science and Technology | Mougel A.,Lille University of Science and Technology | Adriaenssens E.,Lille University of Science and Technology | And 10 more authors.
Chemical Science | Year: 2015

The development of MET receptor agonists is an important goal in regenerative medicine, but is limited by the complexity and incomplete understanding of its interaction with HGF/SF (Hepatocyte Growth Factor/Scatter Factor). NK1 is a natural occurring agonist comprising the N-terminal (N) and the first kringle (K1) domains of HGF/SF. In the presence of heparin, NK1 can self-associate into a "head to tail" dimer which is considered as the minimal structural module able to trigger MET dimerization and activation whereas isolated K1 and N domains showed a weak or a complete lack of agonistic activity respectively. Starting from these structural and biological observations, we investigated whether it was possible to recapitulate the biological properties of NK1 using a new molecular architecture of isolated N or K1 domains. Therefore, we engineered multivalent N or K1 scaffolds by combining synthetic and homogeneous site-specifically biotinylated N and K1 domains (NB and K1B) and streptavidin (S). NB alone or in complex failed to activate MET signaling and to trigger cellular phenotypes. Importantly and to the contrary of K1B alone, the semi-synthetic K1B/S complex mimicked NK1 MET agonist activity in cell scattering, morphogenesis and survival phenotypic assays. Impressively, K1B/S complex stimulated in vivo angiogenesis and, when injected in mice, protected the liver against fulminant hepatitis in a MET dependent manner whereas NK1 and HGF were substantially less potent. These data reveal that without N domain, proper multimerization of K1 domain is a promising strategy for the rational design of powerful MET agonists. © The Royal Society of Chemistry 2015.


PubMed | SIRIC OncoLille, Center Francois Baclesse, Methodology and Biostatistics Unit, Institute Claudius Regaud and University of Nimes
Type: Review | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Time to progression (TTP) is often used as a primary end point in phase II clinical trials. Since the actual date of nadir and progression is never known, most calculated TTP are overestimated. This study evaluates the imprecision on the estimate of TTP under two hypothetical tumor kinetic settings and various assessment schedules.A two-component tumor growth model was used to account for treatment effect assuming exponential decay for tumor shrinkage and linear growth for progression. Evolution of tumor burden (TB) was modelized according to two scenarios using either a cytotoxic or a cytostatic agent and several assessment schedules. TB, nadir, progression and TTP were simulated for each visit schedule.For cytotoxic agents, our model predicted response at 1.5 weeks, a TB at nadir of 40.2 mm (starting from 100 mm) occurring at 6.7 weeks and true progression at 11.2 weeks with a TB of 48.2 mm. For cytostatic agents, our model predicted no response, a TB at nadir of 77 mm occurring at 9.2 weeks and true progression at 19.4 weeks with a TB of 92 mm. Depending on the assessment schedule, estimated TTP was increased from 0.8 to 36.8 weeks and from 0.6 to 28.6 weeks when compared with the true TTP and varied from 5.2% to 298% and from 1.66 to 109.58% when compared with the true TB at progression for cytotoxic and cytostatic agents, respectively. Our model further shows that for cytotoxic agents, evaluation of TB every 6 weeks is optimal to capture the true nadir, the time to nadir, the true progression and the true TTP, whereas for cytostatic agents, this evaluation is optimal every 10 weeks.Our results emphasize the importance to estimate the effects of tested drugs on tumor shrinkage before design any phase II clinical trials to choose optimal TB evaluations timing.

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