PubMed | University of Hamburg, University of Lleida, University of Helsinki, ICM Val dAurelle and 2 more.
Type: Journal Article | Journal: Targeted oncology | Year: 2016
Colorectal cancer is the third most common cancer worldwide. A significant proportion of patients presents with unresectable metastatic disease or develops metachronous metastases following surgical resection of the primary tumor. The prognosis of the disease has improved over the past two decades, with extended multimodality treatment options and the development of increasingly intensified chemotherapy regimens that now typically include targeted biologics. A recent advance in therapy is a treatment regimen composed of three chemotherapeutic agents (i.e., triplet chemotherapy: 5-fluorouracil [5-FU]/leucovorin [LV], oxaliplatin, and irinotecan; FOLFOXIRI) in combination with the vascular endothelial growth factor inhibitor bevacizumab. This regimen has been shown to elicit significantly improved objective response rates and median progression-free survival compared with 5-FU/LV and irinotecan in combination with bevacizumab. However, triplet chemotherapy has been associated with increased rates of chemotherapy-related adverse events, and treatment-emergent adverse events should be properly managed to minimize treatment interruption or discontinuation. We present herein a review of clinical studies evaluating the safety and efficacy of FOLFOXIRI with bevacizumab in metastatic colorectal cancer, and propose a practical guide for the management of adverse events associated with the regimen.
PubMed | Center Francois Baclesse, Hopital Jean Minjoz, Icl Institute Of Cancerologie Of Lorraine, Hoffmann-La Roche and 15 more.
Type: | Journal: British journal of cancer | Year: 2017
Backround:Patients with metastatic endometrial carcinoma have a poor prognosis and PIK3CA mutations and amplifications are common in these cancers. This study evaluated the efficacy and safety of the pure PI3K inhibitor BKM120 in advanced or recurrent endometrial carcinoma.This phase II, multicentre, single-arm, double strata (histological low grade (LG) or high grade (HG)) open-label study enrolled patients with histologically confirmed advanced or recurrent endometrial carcinoma who had received not more than one prior chemotherapy regimen. Patients received initially BKM120 100mg tablets once daily. Primary end points were proportion of patients free of progression at 2 months (HG strata) or at 3 months (LG strata), objective response rate (ORR), and safety.A total of 40 patients were enrolled, of whom 16 patients had received BKM120 at 100mg. Because of high toxicities (cutaneous rash (54%), depressive events (47%), and anxiety (40%), the IDMC has proposed to stop recruitment at 100mg and to continue the clinical trial with a lower dose of 60mg per day. In addition, 24 patients (median age 67 years old) were newly enrolled (14 in the LG strata and 10 in the HG strata). Rate of nonprogression at 2 months in the HG strata was 70% and at 3 months was 60% in the LG strata. Median progression-free survival (PFS) for all patients is 4.5 months (CI 95% 2.8-6.1), and the median PFS for LG strata is 8.3 months compared with 3.8 months for the HG strata. No response was reported. At 60mg per day, the most commonly reported treatment-related adverse events (AEs) were hyperglycaemia (58%), cognitive (31%), digestive (28%), hepatic liver functions (26%), and rash (23%). The most commonly reported treatment-related grade 3 AEs were HTA (17%), hyperglycaemia (17%), and increased alanine aminotransferase (24%). Five patients (21%) stopped BKM120 for toxicity.The BKM120 was associated with an unfavourable safety profile and minimal antitumour activity in monotherapy in advanced or recurrent endometrial carcinoma. The clinical trial was stopped before end of recruitment for toxicity.British Journal of Cancer advance online publication 10 January 2017; doi:10.1038/bjc.2016.430 www.bjcancer.com.
Zhu A.X.,Harvard University |
Kudo M.,Kinki University |
Assenat E.,ICM Val dAurelle |
Cattan S.,University of Lille Nord de France |
And 18 more authors.
JAMA - Journal of the American Medical Association | Year: 2014
IMPORTANCE: Aside from the multikinase inhibitor sorafenib, there are no effective systemic therapies for the treatment of advanced hepatocellular carcinoma. OBJECTIVE: To assess the efficacy of everolimus in patients with advanced hepatocellular carcinoma for whom sorafenib treatment failed. DESIGN, SETTING, AND PARTICIPANTS: EVOLVE-1was a randomized, double-blind, phase 3 study conducted among 546 adults with Barcelona Clinic Liver Cancer stage B or C hepatocellular carcinoma and Child-Pugh A liver function whose disease progressed during or after sorafenib or who were intolerant of sorafenib. Patients were enrolled from 17 countries between May 2010 and March 2012. Randomization was stratified by region (Asia vs rest of world) and macrovascular invasion (present vs absent). INTERVENTIONS: Everolimus, 7.5mg/d, or matching placebo, both given in combination with best supportive care and continued until disease progression or intolerable toxicity. Per the 2:1 randomization scheme, 362 patients were randomized to the everolimus group and 184 patients to the placebo group. MAIN OUTCOMES AND MEASURES: The primary end pointwas overall survival. Secondary end points included time to progression and the disease control rate (the percentage of patients with a best overall response of complete or partial response or stable disease). RESULTS: No significant difference in overall survival was seen between treatment groups, with 303 deaths (83.7%) in the everolimus group and 151 deaths (82.1%) in the placebo group (hazard ratio [HR], 1.05; 95% CI, 0.86-1.27; P = .68; median overall survival, 7.6 months with everolimus, 7.3 months with placebo). Median time to progression with everolimus and placebo was 3.0 months and 2.6 months, respectively (HR, 0.93; 95%CI, 0.75-1.15), and disease control rate was 56.1% and 45.1%, respectively (P = .01). The most common grade 3/4 adverse events for everolimus vs placebo were anemia (7.8%vs 3.3%, respectively), asthenia (7.8%vs 5.5%, respectively), and decreased appetite (6.1%vs 0.5%, respectively). No patients experienced hepatitis C viral flare. Based on central laboratory results, hepatitis B viral reactivation was experienced by 39 patients (29 everolimus, 10 placebo); all cases were asymptomatic, but 3 everolimus recipients discontinued therapy. CONCLUSIONS AND RELEVANCE: Everolimus did not improve overall survival in patients with advanced hepatocellular carcinoma whose disease progressed during or after receiving sorafenib or who were intolerant of sorafenib. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01035229 Copyright 2014 American Medical Association. All rights reserved.
Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: A retrospective, exploratory analysis of the CORRECT trial
Tabernero J.,Autonomous University of Barcelona |
Lenz H.-J.,University of Southern California |
Siena S.,Niguarda Cancer Center |
Siena S.,University of Milan |
And 17 more authors.
The Lancet Oncology | Year: 2015
Background: Tumour mutational status is an important determinant of the response of metastatic colorectal cancer to targeted treatments. However, the genotype of the tissue obtained at the time of diagnosis might not accurately represent tumour genotype after multiple lines of treatment. This retrospective exploratory analysis investigated the clinical activity of regorafenib in biomarker subgroups of the CORRECT study population defined by tumour mutational status or plasma protein levels. Methods: We used BEAMing technology to identify KRAS, PIK3CA, and BRAF mutations in DNA obtained from the plasma of 503 patients with metastatic colorectal cancer who enrolled in the CORRECT trial. We quantified total human genomic DNA isolated from plasma samples for 503 patients using a modified version of human long interspersed nuclear element-1 (LINE-1) quantitive real-time PCR. We also measured the concentration of 15 proteins of interest-angiopoietin 2, interleukin 6, interleukin 8, placental growth factor, soluble TIE-1, soluble VEGFR1, VEGF-A, VEGF-C, VEGF-D, VEGF-A isoform 121, bone morphogenetic protein 7, macrophage colony-stimulating factor, stromal cell-derived factor-1, tissue inhibitor of metalloproteinase 2, and von Willebrand factor-in plasma samples from 611 patients. We did correlative analyses of overall survival and progression-free survival in patient subgroups based on mutational status, circulating DNA concentration, and protein concentrations. The CORRECT trial was registered with ClinicalTrials.gov, number NCT01103323. Findings: Tumour-associated mutations were readily detected with BEAMing of plasma DNA, with KRAS mutations identified in 349 (69%) of 503 patients, PIK3CA mutations in 84 (17%) of 503 patients, and BRAF mutations in 17 (3%) of 502 patients. We did not do correlative analysis based on BRAF genotype because of the low mutational frequency detected for this gene. Some of the most prevalent individual hot-spot mutations we identified included: KRAS (KRAS G12D, 116 [28%] of 413 mutations; G12V, 72 [17%]; and G13D, 67 [16%]) and PIK3CA (PIK3CA E542K, 27 [30%] of 89 mutations; E545K, 37 [42%]; and H1047R, 12 [14%]). 41 (48%) of 86 patients who had received anti-EGFR therapy and whose archival tumour tissue DNA was KRAS wild-type in BEAMing analysis were identified as having KRAS mutations in BEAMing analysis of fresh plasma DNA. Correlative analyses suggest a clinical benefit favouring regorafenib across patient subgroups defined by KRAS and PIK3CA mutational status (progression-free survival with regorafenib vs placebo: hazard ratio [HR] 0·52, 95% CI 0·35-0·76 for KRAS wild-type; HR 0·51, 95% CI 0·40-0·65 for KRAS mutant [KRAS wild type vs mutant, pinteraction=0·74]; HR 0·50, 95% CI 0·40-0·63 for PIK3CA wild-type; HR 0·54, 95% CI 0·32-0·89 for PIK3CA mutant [PIK3CA wild-type vs mutant, pinteraction=0·85]) or circulating DNA concentration (progression-free survival with regorafenib vs placebo: HR 0·53, 95% CI 0·40-0·71, for low circulating DNA concentrations; HR 0·52, 95% CI 0·40-0·70, for high circulating DNA concentrations; low vs high circulating DNA, pinteraction=0·601). With the exception of von Willebrand factor, assessed with the median cutoff method, plasma protein concentrations were also not associated with regorafenib activity in terms of progression-free survival. In univariable analyses, the only plasma protein that was associated with overall survival was TIE-1, high concentrations of which were associated with longer overall survival compared with low TIE-1 concentrations. This association was not significant in multivariable analyses. Interpretation: BEAMing of circulating DNA could be a viable approach for non-invasive analysis of tumour genotype in real time and for the identification of potentially clinically relevant mutations that are not detected in archival tissue. Additionally, the results show that regorafenib seems to be consistently associated with a clinical benefit in a range of patient subgroups based on mutational status and protein biomarker concentrations. Funding: Bayer HealthCare Pharmaceuticals. © 2015 Elsevier Ltd.
PubMed | ICM Val dAurelle, Service Route, Institute Sainte Catherine and University Paris Est Creteil
Type: | Journal: Cancer radiotherapie : journal de la Societe francaise de radiotherapie oncologique | Year: 2016
Surgery (radical cystectomy) is the standard treatment of muscle-invasive bladder cancer. Radiochemotherapy has risen as an alternative treatment option to surgery as part as organ-sparing combined modality treatment or for patients unfit for surgery. Radiochemotherapy achieves 5-year bladder intact survival of 40 to 65% and 5-year overall survival of 40 to 50% with excellent quality of life. This article introduces the French recommendations for radiotherapy of bladder cancer: indications, exams, technique, dosimetry, delivery and image guidance.
Bertrand M.M.,ICM Val DAurelle |
Colombo P.E.,ICM Val DAurelle |
Alsaid B.,Damascus University |
Prudhomme M.,Nimes University Hospital Center |
Rouanet P.,ICM Val DAurelle
Diseases of the Colon and Rectum | Year: 2014
The transanal approach for rectal resection is a promising approach, because it increases the circumferential radial margin, especially for difficult cases. Meanwhile, functional sequelae are frequent after rectal cancer surgery and are often due to neurological lesions. There is little literature describing surgical anatomy from bottom to top. We combined our surgical experience with our fetal and adult anatomical research to provide a bottom-up surgical description focusing on neurological anatomy (see Video, Supplemental Digital Content 1, http://links.lww.com/DCR/A148). © The ASCRS 2014.
PubMed | University of Lyon, Michallon University Hospital, Center Oscar Lambret, ICM Val DAurelle and 3 more.
Type: Journal Article | Journal: European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology | Year: 2015
There is a significant worldwide variation in practice regarding the criteria for operative intervention and overall management in patients with locally recurrent rectal cancer (LRRC). A survival benefit has been described for patients with clear resection margins in patients undergoing surgery for LRRC which is seen as an important surgical quality indicator.A prospective French national database was established in 2008 which recorded procedures undertaken for locally recurrent rectal cancer (LRRC). Overall and Disease-Free Survival (OS, DFS) were assessed retrospectively. We report the variability and the heterogeneity of LRRC management in France as well as 5-year oncological outcomes.In this national report, 104 questionnaires were completed at 29 French surgical centres with a high variability of cases-loaded. Patients had preoperative treatment in 86% of cases. Surgical procedures included APER (36%), LAR (25%), Hartmanns procedure (21%) and pelvic exenterations (15.5%). Four patients had a low sacrectomy (S4/S5). There were no postoperative deaths and overall morbidity was 41%. R0 was achieved in 60%, R1 and R2 in 29% and 11%, respectively. R0 resection resulted in a 5-year OS of 35% compared to 12% and 0% for respectively R1 and R2 (OR = 2.04; 95% CI: 1.4-2.98; p < 0.001). OS was similar between R2 and non-resected patients (OR = 1.47; 95% CI: 0.58-3.76; p = 0.418).Our data is in accordance with the literature except the rate of extended resection procedures. This underlines the selective character of operative indications for LRRC in France as well as the care variability and the absence of optimal clinical pathway regarding these patients.
PubMed | Humanitas Clinical and Research Center, ICM Val dAurelle and Oncology Institute of Southern Switzerland
Type: Journal Article | Journal: PloS one | Year: 2015
To evaluate the performance of a model-based optimisation process for volumetric modulated arc therapy, VMAT, applied to whole breast irradiation.A set of 150 VMAT dose plans with simultaneous integrated boost were selected to train a model for the prediction of dose-volume constraints. The dosimetric validation was done on different groups of patients from three institutes for single (50 cases) and bilateral breast (20 cases).Quantitative improvements were observed between the model-based and the reference plans, particularly for heart dose. Of 460 analysed dose-volume objectives, 13% of the clinical plans failed to meet the constraints while the respective model-based plans succeeded. Only in 5 cases did the reference plans pass while the respective model-based failed the criteria. For the bilateral breast analysis, the model-based plans resulted in superior or equivalent dose distributions to the reference plans in 96% of the cases.Plans optimised using a knowledge-based model to determine the dose-volume constraints showed dosimetric improvements when compared to earlier approved clinical plans. The model was applicable to patients from different centres for both single and bilateral breast irradiation. The data suggests that the dose-volume constraint optimisation can be effectively automated with the new engine and could encourage its application to clinical practice.