Publications by authors named "Stefano Kim"

45 Publications

[Squamous cell anal carcinoma. What's next ?]

Bull Cancer 2021 Jan 8;108(1):80-89. Epub 2021 Jan 8.

University of Bourgogne Franche-Comté, Inserm, EFS BFC, UMR1098, RIGHT, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, 25000 Besançon, France; Department of Medical Oncology, University Hospital of Besançon, 25000 Besançon, France; Clinical Investigational Center, CIC-1431, 25000 Besançon, France; Oncology Multidisciplinary Group (GERCOR), 75011 Paris, France; French Federation of Digestive Cancerology (FFCD), 21000 Dijon, France.

Despite its status as a rare disease, the incidence of the squamous cell carcinoma of the anus (SCCA) is surging, especially in its metastatic form. In addition, the prognosis of initially localized diseases has not substantially changed since the 1970s with a recurrence rate of between 25-40 % after the chemoradiotherapy. The updated data from 115 patients included in the Epitopes-HPV01 and Epitopes-HPV02 trials, confirm the modified regimen of DCF (mDCF) as the treatment of choice for patients with advanced SCCA given the rate of sustained remissions and complete molecular responses observed. The carboplatin-paclitaxel regimen may be considered as an option for patients with contraindication to cisplatin or 5-FU. In chemo-refractory patients, the efficacy of anti-PD-1/PD-L1 in monotherapy is limited and only brings benefit to 10-20 % of patients, and its use cannot be generalized in the absence of an association potentiating its effectiveness. In order to better understand the immunological parameters associated with advanced SCCA, an analysis of peripheral immune responses was carried out in the Epitopes-HPV01 and 02 trials. It demonstrated the key role of CD4 Th1 specific responses of telomerase and M-MDSC as main prognostic factors for the therapeutic efficacy of DCF. Numerous combination trials are currently underway or will soon begin in localized SCCA, as well as in the first and second-line in the advanced stage. Finally, the detection of circulating tumor DNA of HPV oncoprotein E6 and E7 (HPVtc), especially by the "digital droplet PCR" technique, is highly sensitive and specific, and can be used in daily practice.
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http://dx.doi.org/10.1016/j.bulcan.2020.12.001DOI Listing
January 2021

Feasibility of health-related quality of life (HRQoL) assessment for cancer patients using electronic patient-reported outcome (ePRO) in daily clinical practice.

Qual Life Res 2021 Jan 2. Epub 2021 Jan 2.

Methodological and Quality of Life Unit in Oncology, University Hospital of Besançon, 25000, Besançon, France.

Introduction: Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance patient-centered care. We evaluated the feasibility of REMOQOL in the French context in the QOLIBRY study. The primary objective was to assess the patients' compliance with REMOQOL.

Methods: The QOLIBRY study was a single-center, prospective study conducted in the University Hospital of Besançon (France). Eligible patients were those treated with systemic therapies for breast, lung or colorectal cancer at any stage. Patients were invited to complete the EORTC QLQ-C30 questionnaire and cancer-site-specific modules before each visit on tablets and/or computers in the hospital or at home. During the consultation, physicians had real-time access to visual summaries of HRQoL scores. Compliance was assessed as adequate if at least 66% of HRQoL assessments were completed during the 4 months of follow-up.

Results: Between March 2016 and October 2018, 177 patients were included in the QOLIBRY study. Median age was 64 years (IQR 54-71). The proportion of patients with an adequate compliance rate was 95.5% (n = 63) in the breast cancer cohort, 98.2% (n = 55) in the colorectal cancer cohort, and 90.9% (n = 50) in the lung cancer cohort. The physicians checked the HRQoL results in 73.1% of visits and prescribed supportive care and adapted patient management in 8.3% and 5.2% of visits, respectively.

Conclusion & Perspectives: The results of QOLIBRY study suggest that REMOQOL is feasible in the French context. However, information about HRQoL monitoring, training of the physicians in the use of the software, and recommendations for using HRQoL results to guide care are essential and must be improved.
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http://dx.doi.org/10.1007/s11136-020-02721-0DOI Listing
January 2021

Avelumab versus standard second line treatment chemotherapy in metastatic colorectal cancer patients with microsatellite instability: The SAMCO-PRODIGE 54 randomised phase II trial.

Dig Liver Dis 2021 Mar 25;53(3):318-323. Epub 2020 Dec 25.

Gastroenterology Department and Medical Oncology Department, Poitiers University Hospital, Poitiers, France.

Immune checkpoint inhibitors have failed in treating metastatic colorectal cancer (mCRC) patients except those with dMMR/MSI tumors. However, until very recently we had only non-comparative promising data in this population with anti-programmed cell death 1/ programmed cell death ligand 1 (PD1/PD-L1) antibodies alone or combined with anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) antibodies. This comparative phase II trial (NCT03186326), conducted in more than 100 centers in France, will include dMMR/MSI mCRC patients with progression after a first-line treatment with chemotherapy ± targeted therapies, to evaluate efficacy and safety of the anti-PDL1 Avelumab versus a standard second-line treatment. Main inclusion criteria were patients aged 18 to 75 years, ECOG performance status ≤2, dMMR/MSI mCRC and failure of a standard first-line regimen. Patient will be randomised to receive Avelumab 10 mg/kg versus standard second-line doublet chemotherapy plus a targeted agent according to tumor RAS status. Patients will be followed for 4 years. A gain of 5 months in median PFS is expected in favour of the Avelumab arm (12 vs 7 months; HR=0.58). Secondary endpoints include objective response rate, overall survival, quality of life and toxicity. In addition, circulating tumour DNA and microbiota will be explored to test their potential prognostic and predictive values. The study was opened in March 2018.
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http://dx.doi.org/10.1016/j.dld.2020.11.031DOI Listing
March 2021

PRODIGE 59-DURIGAST trial: A randomised phase II study evaluating FOLFIRI + Durvalumab ± Tremelimumab in second-line of patients with advanced gastric cancer.

Dig Liver Dis 2021 Apr 6;53(4):420-426. Epub 2021 Jan 6.

Service d'Oncologie Médicale, CHU de Poitiers, Poitiers, France; Service d'Hépato-gastroentérologie, CHU de Poitiers et Université de Poitiers, 2 rue de la Milétrie, Poitiers 86021, France. Electronic address:

Gastric or gastro-oesophageal junction (GEJ) adenocarcinomas present poor overall survival (OS). First-line chemotherapy regimen for patients with HER2-negative tumours is based on a doublet or triplet of fluoropyrimidine plus platinum salt ± taxane. Second-line chemotherapy (Docetaxel or Irinotecan) improves OS which nonetheless remains poor (around 5 months). The first results of immune checkpoint inhibitors (anti-PD-1) combined with chemotherapy in metastatic gastric and GEJ cancers were discordant in recent phase III trials. Data on dual-blockade (anti-PD-L1 or anti-PD-1 plus anti-CTLA-4) plus chemotherapy are lacking. DURIGAST is a randomised, multicenter, non-comparative, phase II study, evaluating safety and efficacy of FOLFIRI plus Durvalumab (anti-PD-L1) versus FOLFIRI plus Durvalumab and Tremelimumab (anti-CTLA-4) as second-line treatment of advanced gastric and GEJ adenocarcinoma. The primary objective is the rate of patients alive and without progression at 4 months. The main inclusion criteria are: patients with advanced gastric or GEJ adenocarcinoma, pre-treated with fluoropyrimidine + platinum salt ± taxane. Due to a lack of data on FOLFIRI, Durvalumab and Tremelimumab combination, a 2-step safety run-in phase has been performed before the randomised phase II. The safety run-in phase did not show any safety issue and the randomised phase II starts in September 2020.
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http://dx.doi.org/10.1016/j.dld.2020.11.036DOI Listing
April 2021

Pooled analysis of 115 patients from updated data of Epitopes-HPV01 and Epitopes-HPV02 studies in first-line advanced anal squamous cell carcinoma.

Ther Adv Med Oncol 2020 4;12:1758835920975356. Epub 2020 Dec 4.

Centre Hospitalier Universitaire de Besançon, Besançon, France.

Aims: The addition of docetaxel to cisplatin and 5-fluorouracil (DCF) has shown promising efficacy in advanced squamous cell carcinoma of the anus (SCCA). Preliminary results of Epitopes-HPV01 study showed a high rate of long-lasting complete response to DCF. The prospective, multicenter, Epitopes-HPV02 trial then confirmed the high efficacy of the modified DCF (mDCF) regimen in terms of complete response rate and long-term survival in metastatic or non-resectable locally advanced recurrent SCCA. Here, we present updated results of the Epitopes-HPV01 and Epitopes-HPV02 studies.

Patients & Methods: Epitopes-HPV01 is a prospective study performed by the regional cancer network of Franche-Comté, France. Epitopes-HPV02 is a phase II study supported by two French collaborative oncological groups, performed in 25 centers. Both studies included patients with metastatic, or with unresectable local recurrent SCCA, treated with DCF regimen.

Results: In Epitopes-HPV01, 51 patients were enrolled between September 2012 and January 2019, and 49 patients were included for analysis; while 69 patients were included between September 2014 and December 2016 in Epitopes-HPV02, and 66 patients for analysis. Pooled analysis of 115 patients showed a median progression-free survival of 12.2 months [95% confidence interval (CI) 10.6-16.1] [11.0 months (9.3-16.0) in -HPV02, and 15.6 months (11.2-34.5) in -HPV01, ( = 0.06)]. The median overall survival was 39.2 months (26.0-109.1) [36.3 in -HPV02 (25.2-NR), and 61.1 months (21.4-120.0) in -HPV01 ( = 0.62)]. Objective response rate was 87.7% (90.9% in -HPV02 and 83.3% in -HPV01) with 40.3% of complete response (45.5% in -HPV02 and 33.3% in -HPV01). No differences were observed between standard DCF ( = 54) and mDCF ( = 58) in terms of OS ( = 0.57) and PFS ( = 0.99). 5-years PFS and OS rates were 24.5% and 44.4%, respectively, in the whole population. No treatment-related death was observed.

Conclusion: Updated results of Epitopes-HPV01 and 02 studies, as well as the pooled analysis, confirm mDCF as a standard treatment in patients with advanced SCCA.
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http://dx.doi.org/10.1177/1758835920975356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720302PMC
December 2020

How to Choose the Right Treatment for Patients With Advanced Squamous Cell Carcinoma in the Absence of a Comparative Randomized Clinical Trial.

J Clin Oncol 2020 11 7;38(33):3973-3974. Epub 2020 Oct 7.

Stefano Kim, MD, Centre Hospitalier Universitaire de Besançon, Besançon; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon; and INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Dewi Vernerey, PhD, INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, and Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France; and Christophe Borg, MD, Centre Hospitalier Universitaire de Besançon, Besançon; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon; and INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France.

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http://dx.doi.org/10.1200/JCO.20.02137DOI Listing
November 2020

Anti-Telomerase CD4 Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials.

Int J Mol Sci 2020 Sep 17;21(18). Epub 2020 Sep 17.

INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, F-25000 Besançon, France.

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients' clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients' survival.
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http://dx.doi.org/10.3390/ijms21186838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554943PMC
September 2020

Exposure-response analysis of Raltitrexed assessing liver toxicity.

Br J Clin Pharmacol 2021 Mar 4;87(3):1327-1337. Epub 2020 Sep 4.

INSERM, EFS BFC, Université Bourgogne Franche-Comté, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, F-25000, France.

Aim: Raltitrexed (RTX) is a thymidylate synthase inhibitor with large pharmacokinetics (PK) variability that can be administered in case of 5-fluorouracil (5FU) intolerance or dihydropyrimidine dehydrogenase deficiency. While it is a more potent thymidylate synthase inhibitor than 5FU, RTX failed to replace this drug for colorectal cancer patients, mainly due to its toxicity at the recommended dose of 3 mg/m every 3 weeks. However, every 2 weeks administration at 2 mg/m demonstrated a favourable toxicity profile.

Method: We performed a randomized crossover comparative population PK study between every 2 weeks TOMOX (RTX 2 mg/m ) and every 3 weeks TOMOX (RTX 3 mg/m ).

Results: A three-compartment model and a proportional error model best describe the data. Creatinine clearance and sex, but not body surface area (BSA), were covariates of RTX clearance leading to decrease of its interindividual variability of 28%. Weight and body surface area were covariates of central and peripheral volumes of distribution, respectively, leading to decreases of interindividual variability of 34.6% and 100%, respectively. In contrast to the dose, AUC was a good predictor of liver toxicity (P = 0.006, OR = 3.91, 95%CI = [1.48-10.34]). Using covariates to compute individual clearance and a threshold AUC (1.639, determined in this study), a covariates-based dose was calculated, leading to less variability in AUC than observed with the actual BSA-based or fixed doses.

Conclusion: These results advocate for the use of creatinine clearance and sex to determine the RTX dose instead of BSA.
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http://dx.doi.org/10.1111/bcp.14519DOI Listing
March 2021

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

Molecular description of ANGPT2 associated colorectal carcinoma.

Int J Cancer 2020 10 22;147(7):2007-2018. Epub 2020 May 22.

INSERM, EFS BFC, UMR1098, RIGHT, University of Bourgogne Franche-Comté, Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaireet Génique, Besançon, France.

Angiopoietin-2 (ANGPT2) is a prognostic factor in metastatic colorectal cancer (CRC). Nevertheless, it remains to be elucidated which molecular characteristics make up the ANGPT2-related poor-prognosis CRC subset. Public transcriptomic datasets were collected from Gene Expression Omnibus GEO and with the TCGAbiolinks R-package for the TCGA. After appropriate normalization, differential expression analysis was performed using Benjamini and Hochberg method for false discovery rate. Plasma from two prospective clinical trials were used to investigate the clinical impact of ANGPT2-related biomarkers. In the 935 samples included in four annotated platforms (GPL) and derived from localized CRC, ANGPT2 expression conferred a worst overall survival (HR = 1.20; p = 0.02). CRC stage, ANGPT2 expression but not Consortium Molecular Subtype (CMS) predict overall survival in multivariate analysis. ANGPT2 expression was not correlated with a specific CMS nor to RAS, RAF, MSI, p53, CIN, CIMP genomic alterations. Gene expression analysis revealed that ANGPT2 CRC subset is characterized by angiogenesis-related gene expression, presence of myeloid cells, stromal organization and resistance to chemotherapy. A prognostic model was proposed using seric levels of ANGPT2, STC1 and CD138 in 97 mCRC patients. Our results provide evidence that ANGPT2 is a prognostic factor in localized CRC and defined a specific CRC subset with potential clinical implementation.
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http://dx.doi.org/10.1002/ijc.32993DOI Listing
October 2020

FOLFOXIRI FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study.

World J Gastrointest Oncol 2020 Mar;12(3):332-346

University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon F-25000, France.

Background: FOLFIRINOX regimen is the first-line reference chemotherapy (L1) in advanced pancreatic ductal adenocarcinoma (aPDAC). FOLFOXIRI, a schedule with a lower dose of irinotecan and no bolus 5-fluorouracil, has demonstrated efficacy and feasibility in colorectal cancer.

Aim: To investigate the potential clinical value of FOLFOXIRI in patients with aPDAC in routine clinical practice.

Methods: Analyses were derived from all consecutive aPDAC patients treated in L1 between January 2011 and December 2017 in two French institutions, with either FOLFOXIRI ( = 165) or FOLFIRINOX ( = 124) regimens. FOLFOXIRI consisted of irinotecan (165 mg/m), oxaliplatin (85 mg/m), leucovorin (200 mg/m) and 5-fluorouracil (3200 mg/m as a 48-h continuous infusion) every 2 wk. Ninety-six pairs of patients were selected through propensity score matching, and clinical outcomes of the two treatment regimens were compared.

Results: Median overall survival was 11.1 mo in the FOLFOXIRI and 11.6 mo in the FOLFIRINOX cohorts, respectively. After propensity score matching, survival rates remained similar between the two regimens in terms of overall survival (hazard ratio = 1.22; = 0.219) and progression-free survival (hazard ratio = 1.27; = 0.120). The objective response rate was 37.1% in the FOLFOXIRI group 47.8% in the FOLFIRINOX group ( = 0.187). Grade 3/4 toxicities occurred in 28.7% of patients in the FOLFOXIRI cohort 19.5% in the FOLFIRINOX cohort ( = 0.079). FOLFOXIRI was associated with a higher incidence of grade 3/4 digestive adverse events. Hematopoietic growth factors were used after each chemotherapy cycle and the low hematological toxicity rates were below 5% with both regimens.

Conclusion: FOLFOXIRI is feasible in L1 in patients with aPDAC but does not confer any therapeutic benefit as compared with FOLFIRINOX. The low hematological toxicity rates strengthened the relevance of primary prophylaxis with hematopoietic growth factors.
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http://dx.doi.org/10.4251/wjgo.v12.i3.332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081111PMC
March 2020

RECIST and CHOI criteria in the evaluation of tumor response in patients with metastatic colorectal cancer treated with regorafenib, a prospective multicenter study.

Cancer Imaging 2019 Dec 9;19(1):85. Epub 2019 Dec 9.

GERCOR (Groupe Cooperateur Multidisciplinaire en Oncologie), 151 rue du Faubourg Saint Antoine, 75011, Paris, France.

Background: To evaluate the objective response rate (ORR) at 2 months of treatment with regorafenib according to RECIST 1.1, Choi, and modified Choi (mChoi) criteria in patients with metastatic colorectal cancer (mCRC).

Methods: Baseline and 2-month contrast-enhanced computed-tomography (CECT) scans of 55 patients with mCRC, prospectively enrolled in phase II TEXCAN trial, were centrally assessed. The primary endpoint was 2-month ORR by RECIST 1.1, Choi, and mChoi criteria. Final outcome was overall survival (OS).

Results: Of 55 patients included in this study (Intention-to-treat [ITT1] population), 35 had CECT at 2 months (ITT2 population). According to RECIST 1.1 criteria, 20 (57%) patients were SD and 15 were PD (43%) in the ITT2 population. According to Choi criteria, 18 (51%) patients were responders and 17 (48%) were non-responders. Median OS was 5.3 months (95% CI 3.7-8.6) in the ITT1 population and 8.9 months (95% CI 5.1-12.6) in the ITT2 population. In the ITT2 population, median OS was 16 months (95% CI 6.6-17.5) in SD patients (n = 20) and 4.6 months (95% CI 3.3-5.8) in PD patients (n = 15), according to RECIST 1.1 criteria (HR = 6.48). Median OS was 7.9 months (95% CI 4.2-17.5) in responders (n = 18) and 9.9 months (95% CI 3.7-NA) in non-responders (n = 17) according to Choi criteria (HR = 1.06). All patients except one were classified as non-responders with mChoi criteria.

Conclusion: At 2 months, unlike RECIST 1.1, Choi and mChoi criteria could not identify mCRC patients with regorafenib survival benefit.

Trial Registration: ClinicalTrials.gov Identifier: NCT02699073.Registered March 4, 2016, Retrospectively registered.
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http://dx.doi.org/10.1186/s40644-019-0271-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902493PMC
December 2019

Comparison of Molecular and Histologic Ultrastaging Methods in Sentinel Lymph Node Analysis from Clinical Stage II Colon Cancers.

Appl Immunohistochem Mol Morphol 2019 08;27(7):e65-e70

Departments of Pathology.

Various studies have demonstrated that occult metastases may be present in patients with clinical stage II colon cancer. The objective of this prospective investigation was to compare the performance of molecular analysis and histologic ultrastaging in detecting occult metastases in sentinel lymph nodes (SLNs). SLNs were collected ex vivo during surgery in 29 patients. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays were constructed. The results were compared with histologic ultrastaging analysis by hemalum and eosin stain and immunohistochemistry on step serial sections. At least 1 SLN was identified in 76% of the cases. The first hemalum and eosin section identified metastases in 23% of the 22 SLNs. Immunohistochemistry identified isolated tumor cells in 24% of the remaining 17 cases. An overall 73% of the SLNs analyzed by qRT-PCR were positive. Four of them were negative for ultrastaging analysis. qRT-PCR is a powerful tool for the detection of occult metastases in colorectal SLN and seems to be more sensitive than histologic ultrastaging analysis. A larger prospective cohort study is necessary to provide further evidence.
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http://dx.doi.org/10.1097/PAI.0000000000000624DOI Listing
August 2019

Clinical Validity of HPV Circulating Tumor DNA in Advanced Anal Carcinoma: An Ancillary Study to the Epitopes-HPV02 Trial.

Clin Cancer Res 2019 Apr 30;25(7):2109-2115. Epub 2018 Nov 30.

Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France.

Purpose: Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.

Experimental Design: According to the protocol, serum samples were collected before chemotherapy and on completion of chemotherapy. HPV16 ctDNA was quantified by droplet digital PCR (ddPCR) and correlated with prospectively registered patient characteristics and outcomes. A landmark was set at the time of chemotherapy completion for postchemotherapy progression-free survival (PFS) analyses.

Results: Among 57 patients with HPV16-related advanced SCCA, HPV ctDNA was detected in 91.1% (95% confidence interval, 81.1-96.2) of baseline samples. Baseline HPV ctDNA levels were not associated with any patient characteristics; baseline ctDNA level below the cutoff obtained by AUC (area under the curve) was associated with a longer PFS (HR = 2.1; = 0.04). Among the 36 patients who completed 5 months of chemotherapy, residual HPV ctDNA was detected after chemotherapy in 38.9% of patients. Residual HPV ctDNA detected at chemotherapy completion was associated with shorter postchemotherapy PFS (median PFS 3.4 months vs. not reached; HR = 5.5; < 0.001) and a reduction of 1-year overall survival rate (OR = 7.0; = 0.02).

Conclusions: This prospective study in advanced SCCA demonstrated a significant prognostic impact of HPV ctDNA level before first-line chemotherapy and HPV ctDNA negativity after chemotherapy completion. With a limited cost and short turnaround, this assay is a promising tool to optimize the therapeutic management of SCCA..
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2984DOI Listing
April 2019

Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment.

Oncotarget 2018 Oct 23;9(83):35394-35407. Epub 2018 Oct 23.

University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon F-25000, France.

Sorafenib, a multi-targeted kinase inhibitor, is the current standard systemic treatment for advanced hepatocellular carcinoma. Sorafenib has anti-angiogenic and anti-proliferative properties and is also known to favor anti-tumor T cell responses by reducing the population of immunosuppressive cells such as Treg and MDSC. Anti-tumor immune responses, especially mediated by CD4+ T-cells, are critical for tumor cells eradication and therapies modulating those responses are appealing in a growing number of cancers. Here, we report and investigate the case of a patient diagnosed with an advanced HCC treated by sorafenib who experienced a complete histological response. We aimed to identify immunogenic peptides derived from tumor mutated proteins that stimulated CD4+ T cells responses thus favoring the exceptional recovery process of this patient. Tumor neoantigens were identified using whole exome sequencing of normal and tumor tissue and peptide MHC binding prediction algorithms. Among 442 tumor-specific somatic variants, 50 missense mutations and 20 neoepitopes predicted to bind MHC-II were identified. Candidate neoepitopes immunogenicity was assessed by IFN-γ ELISpot after culture of patient's PBMCs in presence of synthetic neopeptides. CD4+ memory T cell responses were detected against a mutated IL-1β peptide and two additional neoepitopes from HELZ2 and MLL2 suggesting that efficient anti-tumor immune response occurred in this patient. These results showed that T cells can recognize neoantigens and may lead to the cancer elimination after immunomodulation in the tumor-microenvironment induced by sorafenib. This observation indicates that other immunotherapies in combination with sorafenib could potentially increase the response rate in HCC at advanced stage.
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http://dx.doi.org/10.18632/oncotarget.26247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226040PMC
October 2018

FOLFIRI3-aflibercept in previously treated patients with metastatic colorectal cancer.

World J Clin Oncol 2018 Sep;9(5):110-118

Department of Medical Oncology, Franco-British Institute, Levallois-Perret 92300, France.

Aim: To evaluate the efficacy and safety of the modified FOLFIRI3-aflibercept as second-line therapy in patients with metastatic colorectal cancer.

Methods: This is a retrospective multicenter cohort, evaluating the efficacy and safety of the association of aflibercept with FOLFIRI3 (day 1: aflibercept 4 mg/kg, folinic acid 400 mg/m, irinotecan 90 mg/m, 5-fluorouracil infusion 2400 mg/m per 46 h; day 3: irinotecan 90 mg/m) in patients with previously treated metastatic colorectal cancer. The primary endpoint was overall response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.

Results: Among 74 patients treated in four French centers, nine were excluded due to prior use of aflibercept ( = 3), more than one prior treatment line in irinotecan-naïve patients ( = 3), and inadequate liver function ( = 3). In the "irinotecan-naïve" patients ( = 30), ORR was 43.3% and DCR was 76.7%. Median PFS and OS were 11.3 mo (95%CI: 6.1-29.0) and 17.0 mo (95%CI: 13.0-17.3), respectively. The most common (> 5%) grade 3-4 adverse events were diarrhea (37.9%), neutropenia (14.3%), stomatitis and anemia (10.4%), and hypertension (6.7%). In the "pre-exposed irinotecan" patients ( = 35), 20 (57.1%) received ≥ 2 prior lines of treatment. ORR was 34.3% and DCR was 60.0%. Median PFS and OS were 5.7 mo (95%CI: 3.9-10.4) and 14.3 mo (95%CI: 12.8-19.5), respectively.

Conclusion: Minimally modified FOLFIRI has improvement dramatically the FOLFIRI3-aflibercept efficacy, whatever prior use of irinotecan. A prospective randomized trial is warranted to compare FOLFIRI-aflibercept to FOLFIRI3-aflibercept.
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http://dx.doi.org/10.5306/wjco.v9.i5.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153125PMC
September 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

SALL4 oncogene is an immunogenic antigen presented in various HLA-DR contexts.

Oncoimmunology 2018;7(4):e1412030. Epub 2018 Jan 17.

University of Bourgogne Franche-Comté (UBFC), INSERM, EFS BFC, UMR1098, Interactions hôte-greffon-tumeur - Ingénierie Cellulaire et Génique, Besançon, France.

: To investigate the immunoprevalence of SALL4-derived peptides in healthy volunteers and cancer patients. : A multistep approach including prediction algorithms was used to design SALL4-derived peptides theoretically able to bind on common HLA-DR and HLA-A/B molecules. The presence of T-cell responses after a long term T-cell assay (28 days) against SALL4 was monitored in 14 healthy donors and the presence of T-cell responses after a short term T-cell assay (10 days) was monitored in 67 cancer patients using IFN-γ ELISPOT assay. A T-cell clone specific for the immunoprevalent A18 K-derived peptide was isolated, characterized and used as a tool to characterize the natural processing of A18 K. : A SALL4 specific T-cell repertoire was present in healthy donors (8/14) and cancer patients (29/67) after short term T-cell assay. We further identified two immunoprevalant SALL4-derived peptides, R18 A and A18 K, which bind MHC-class II. In parallel, an A18 K specific Th1 clone recognized monocyte derived Dendritic Cell (moDC) loaded with SALL4 containing cell lysate. The level of IFN-γ secreted by specific T-cell clone was greater in presence of moDC loaded with SALL4 containing cell lysate (49.23 ± 14.02%) than with moDC alone (18.03 ± 3.072%) (p = 0.0477) : These results show for the first time immunogenicity of SALL4 oncogenic protein-derived peptides, especially A18 K and R18 A peptides and make them potential targets for personalized medicine. Thus, SALL4 possess major characteristics of a tumor antigen.
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http://dx.doi.org/10.1080/2162402X.2017.1412030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889287PMC
January 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

A simple and fast LC-MS/MS method with a very high sensitivity for the measurement of raltitrexed in human plasma.

J Chromatogr B Analyt Technol Biomed Life Sci 2017 Aug 13;1060:240-246. Epub 2017 Jun 13.

INSERM, Unit 1098, University of Bourgogne Franche-Comté, F-25020 Besançon, France; CHU Besançon, Department of Pharmacology and Toxicology, F-25030 Besançon Cedex, France. Electronic address:

Raltitrexed is a thymidylate synthase inhibitor that can be administered safely to patients with cardiovascular disease or dihydropyrimidine dehydrogenase deficiency, as opposed to 5FU. The recommended dose of 3mg/m every 3 weeks often leads to toxicity. Interestingly, the 2mg/m every 2 weeks dose appears to be less toxic. A pharmacokinetic trial was then performed by our team to investigate such phenomenon. However, there are currently, two main methods for RTX measurement described in the literature: a radioimmunoassay (RIA) and chromatographic-based methods with either UV or mass spectrometry detections. The RIA methods: display a low limit of quantification (below 1μg/L), but also a low extent of linearity for the calibration curve. The chromatographic-based methods: include high level of calibrators, but have poor sensitivity (>2μg/mL). If a high sensitivity is essential to satisfactorily describe the elimination of RTX, high concentrations in the calibration curve are also needed to avoid bias linked to the dilutions of the samples. A new LC-MS/MS method was then developed that allows to simultaneously measure very low (0.1μg/L) and very high (3000μg/L) concentrations in the same run. Moreover, the extraction steps are very simple and fast with mainly a precipitation and a filtration steps. This method was validated following the EMA recommendations. In view of the extent of the calibration curve, the carry-over effect was more deeply investigated. With this method, it was possible to measure RTX in samples taken 3 weeks after the administration. Taken together, this method allows to simply and quickly measure RTX in plasma of patients.
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http://dx.doi.org/10.1016/j.jchromb.2017.06.021DOI Listing
August 2017

A new anti-mesothelin antibody targets selectively the membrane-associated form.

MAbs 2017 04;9(3):567-577

a University of Bourgogne-Franche-Comte , Besançon Cedex , France.

Mesothelin is a glycosylphosphatidylinositol (GPI)-anchored membrane protein that shows promise as a target for antibody-directed cancer therapy. High levels of soluble forms of the antigen represent a barrier to directing therapy to cellular targets. The ability to develop antibodies that can selectively discriminate between membrane-bound and soluble conformations of a specific protein, and thus target only the membrane-associated antigen, is a substantive issue. We show that use of a tolerance protocol provides a route to such discrimination. Mice were tolerized with soluble mesothelin and a second round of immunizations was performed using mesothelin transfected P815 cells. RNA extracted from splenocytes was used in phage display to obtain mesothelin-specific antigen-binding fragments (Fabs) that were subsequently screened by flow cytometry and ELISA. This approach generated 147 different Fabs in 34 VH-CDR3 families. Utilizing competition assays with soluble protein and mesothelin-containing serum obtained from metastatic cancer patients, 10 of these 34 VH-CDR3 families were found to bind exclusively to the membrane-associated form of mesothelin. Epitope mapping performed for the 1H7 clone showed that it does not recognize GPI anchor. VH-CDR3 sequence analysis of all Fabs showed significant differences between Fabs selective for the membrane-associated form of the antigen and those that recognize both membrane bound and soluble forms. This work demonstrates the potential to generate an antibody specific to the membrane-bound form of mesothelin. 1H7 offers potential for therapeutic application against mesothelin-bearing tumors, which would be largely unaffected by the presence of the soluble antigen.
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http://dx.doi.org/10.1080/19420862.2017.1288770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384705PMC
April 2017

Additive value of pre-operative and one-month post-operative lymphocyte count for death-risk stratification in patients with resectable pancreatic cancer: a multicentric study.

BMC Cancer 2016 10 26;16(1):823. Epub 2016 Oct 26.

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

Background: Pancreatic adenocarcinoma (PDAC) incidence is increasing worldwide. Several studies have shown that lymphopenia was correlated with a poor prognosis but the potential interest to measure lymphopenia in the pre and post-operative setting as well as its added value among conventional prognostic factors was never investigated.

Methods: Data from two independent cohorts in whom patients underwent resection for pancreatic carcinoma were retrospectively recorded. We examined the association between perioperative findings, pre and post-operative lymphocyte counts and overall survival (OS) in univariate and multivariate analyses. Performance assessment and internal validation of the final model were evaluated with Harrell's C-index, calibration plot and bootstrap sample procedures.

Results: Three hundred ninety patients were included in the analysis between 2000 and 2011. Pre and post-operative lymphocyte counts were independent prognostic factors associated with OS in multivariate analysis (p = 0.0128 and p = 0.0764, respectively). The addition of lymphocyte count variable to the conventional parameters identified in multivariate analysis (metastatic lymph node ratio, veinous emboli and adjuvant chemotherapy) significantly improved the model discrimination capacity (bootstrap mean difference = 0.04; 95 % CI, 0.01-0.06). The use of a threshold and combining the categorical (≥1000; <1000) information in pre and post lymphocyte counts permitted the identification of 4 subgroups of patients with different prognosis (p < 0.0001). Finally, the description of patients in long-term remission showed that only 3 of 65 (4.6 %) patients with post-operative lymphocyte count under 1000/mm were alive 4 years after surgery contrary to 54 of 236 (22.8 %) patients with a post-operative lymphocyte count above 1000/mm.

Conclusion: Pre and post-operative lymphopenia are independent prognostic factors for OS and they have an additive value regarding conventional prognostic factors for death-risk stratification and to predict long-term survival. Lymphopenia should be included as stratification factors in future clinical trial assessing overall survival in pancreatic cancer patients.
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http://dx.doi.org/10.1186/s12885-016-2860-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080693PMC
October 2016

Docetaxel, Cisplatin, and 5-Fluorouracil as perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma.

Cancer Med 2016 11 11;5(11):3085-3093. Epub 2016 Oct 11.

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

Docetaxel, cisplatin, and 5-fluorouracil (DCF) significantly improved overall survival in metastatic gastroesophageal adenocarcinoma (GEA). The aim of this study was to assess efficacy of DCF regimen as perioperative chemotherapy compared with surgery alone in patients with resectable GEA. We identified 789 patients who underwent surgery alone and 62 patients who received at least one cycle of DCF regimen consisting of docetaxel (75 mg/m on day 1), cisplatin (75 mg/m on day 1), and 5-fluorouracil (750 mg/m /day on continuous perfusion on days 1 to 5), every 3 weeks. Overall survival was compared using Cox proportional hazards regression model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis. In Cox multivariate analysis weighted by IPTW, DCF group was associated with favorable overall survival (OS) compared with the surgery group (HR = 0.59; 95% CI, 0.45-0.78; P = 0.0003). For the matched-pair analysis (comparing 41 patients for each group with the same baseline characteristics), median OS was 22 months and 57 months for the surgery group and DCF group, respectively (log-rank P = 0.0011). In Cox multivariate analysis, DCF group was associated with favorable OS compared with the surgery group (HR = 0.29; 95% IC, 0.14-0.64; P = 0.0019). In the matched-pair population, major complications (Dindo-Clavien grade 3-5) arose in six patients (14.63%) in the DCF group and seven patients (17.07%) in the surgery group (P = 1). Perioperative DCF chemotherapy is superior to surgery alone in terms of OS. A randomized phase III trial should compare DCF to standard perioperative regimens.
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http://dx.doi.org/10.1002/cam4.885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5119963PMC
November 2016

Complete Response to Aflibercept-FOLFIRI in One Patient With Colorectal Cancer Refractory to Bevacizumab-FOLFOX: A Possible Autocrine Vascular Endothelial Growth Factor Receptor 2-Related Mechanism.

Clin Colorectal Cancer 2016 12 9;15(4):e229-e234. Epub 2016 Aug 9.

Department of Medical Oncology, University Hospital of Besançon, Besançon, France; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France.

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http://dx.doi.org/10.1016/j.clcc.2016.07.015DOI Listing
December 2016

Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score.

Int J Cancer 2016 11 13;139(10):2325-35. Epub 2016 Aug 13.

INSERM, Unit 1098, University of Bourgogne- Franche Comté, Besançon, France.

In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values.
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http://dx.doi.org/10.1002/ijc.30367DOI Listing
November 2016

Efficacy, Safety and Cost of Regorafenib in Patients with Metastatic Colorectal Cancer in French Clinical Practice.

Clin Med Insights Oncol 2016 4;10:59-66. Epub 2016 Jul 4.

INSERM, UMR 1098, Besançon, France.; University of Bourgogne-Franche-Comté, UMR 1098, SFR IBCT, Besançon, France.; Pharmacy Department, Besançon University Hospital, Besançon, France.

Background: Regorafenib is an orally administered multikinase inhibitor that has been approved for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Even though regorafenib significantly improved survival in two international phase 3 trials (CORRECT and CONCUR), a high rate of treatment-related toxic effects and dose modifications were observed with a modest benefit. The aim of this study was to provide information concerning the efficacy, safety, and cost of regorafenib in patients with mCRC in clinical practice.

Material And Methods: We retrospectively reviewed patients treated with regorafenib monotherapy for unresectable mCRC in five Franche-Comté cancer hospitals (France). The primary end point was overall survival. Secondary end points were safety and descriptive cost analyses of patients treated with regorafenib in clinical practice. Another aim of this study was to assess the impact of regorafenib prescription on the risk of hospitalization in real-life practice.

Results: From January 2014 to August 2014, 29 consecutive patients were enrolled. Patients were heavily pretreated and were refractory to standard chemotherapies. The primary tumor sites were the colon and the rectum for 55% and 45% of patients, respectively. Fifteen patients (51%) harbored an RAS mutation. Eastern Cooperative Oncology Group - Performance Status (PS) was 0-1 for 86% of patients and 2 for 14% of patients. Nineteen patients (66%) initially received reduced doses of 120 or 80 mg/day. The median duration of treatment was 2.5 months (range, 0.13-11.4 months). Treatment-related adverse events occurred in 86% of patients. The most frequent adverse events of any grade were fatigue (35%), diarrhea (20%), and hand-foot skin reaction (20%). Grade 3 or 4 treatment-related adverse events occurred in 10 patients (35%). Three patients (10%) were admitted to hospital due to drug-related severe adverse events. The mean cost of patient management with regorafenib for the duration of treatment was 9908 ± 8191€, and median cost was 7917€ (Interquartile range (IQR) 4469-13,042). The median overall survival was six months (95% confidence interval, five to eight months).

Conclusions: The safety and efficacy of regorafenib in heavily pretreated mCRC patients was comparable, in our study, to prospective and retrospective trials. Toxic effects were mostly manageable in an outpatient setting. Regorafenib itself represented the most important (93%) part of supported costs. Even though most side effects were manageable in an outpatient setting, severe adverse events occurred from hospitalization in 10% of patients. These data should be confirmed in a larger real-life-based cohort. Identification of predictive biomarkers is needed for mCRC patient selection for regorafenib treatment.
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http://dx.doi.org/10.4137/CMO.S38335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933532PMC
July 2016

Gemcitabine-Induced Pulmonary Toxicity: A Case Report of Pulmonary Veno-Occlusive Disease.

Clin Med Insights Oncol 2015 1;9:75-9. Epub 2015 Sep 1.

Department of Medical Oncology, University Hospital of Besançon, Besançon, France. ; INSERM, Unit 1098, University of Franche-Comté, Besançon, France.

Introduction: Gemcitabine is a chemotherapeutic agent frequently used by for the treatment of several malignancies both in the adjuvant and metastatic setting. Although myelosuppression is the most adverse event of this therapy, gemcitabine might induce severe pulmonary toxicities. We describe a case of pulmonary veno-occlusive disease (PVOD) related to gemcitabine.

Case Presentation: The patient was an 83-year-old man with a metastatic pancreatic cancer who was treated by gemcitabine as first-line therapy. He was in good health and received no other chemotherapy. A dose of 1000 mg/m(2) of gemcitabine was administered over a 30-minute intravenous infusion on days 1, 8, and 15 of a 28-day cycle. After a period of 6 months, a complete response was observed. Nevertheless, the patient developed a severe dyspnea, with arterial hypoxemia and very low lung diffusion for carbon monoxide. A CT scan showed diffuse ground glass opacities with septal lines, bilateral pleural effusion, and lymph node enlargement. On echocardiography, there was a suspicion of pulmonary hypertension with elevated systolic pulmonary artery pressure and normal left ventricular pressures. Right heart catheterization confirmed pulmonary hypertension and normal pulmonary artery occlusion pressure. Diagnosis of PVOD was made, and a gemcitabine-induced toxicity was suspected. A symptomatic treatment was started. At last follow-up, patient was in functional class I with near-normal of CT scan, arterial blood gases, and echocardiography. A gemcitabine-induced PVOD is the more likely diagnosis.
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http://dx.doi.org/10.4137/CMO.S26537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559186PMC
September 2015

Primary Linitis Plastica of the Rectum: Focus on Magnetic Resonance Imaging Patterns and Treatment Options.

Am J Case Rep 2015 Aug 31;16:581-5. Epub 2015 Aug 31.

Department of Radiotherapy, University Hospital of Besançon, Besançon, France.

Background: Rectal linitis plastica (RLP) is a rare disease with poor outcome. It is often accompanied by a delayed histopathological diagnosis, primarily due to submucosal disease. A concentric ring pattern or "target sign" on T2-weighted magnetic resonance imaging (MRI) has been proposed as being characteristic for early suspicion. Even though RLP is more aggressive and has poorer survival than other rectal adenocarcinomas, no specific treatment is recommended. In this case report of 3 patients, we challenge the sensitivity of the characteristic radiological pattern, and we review the existing data for a treatment strategy.

Case Report: One patient presented classic clinical characteristics of RLP with young age and advanced stage at diagnosis, with chemo-refractory disease and rapid fatal evolution. Biopsies confirmed the RLP with the presence of signet-ring cells (SRC) in a strong desmoplastic stromal reaction. However, the characteristic concentric ring pattern was absent. Instead, he had a large vegetative lesion with important tumor infiltration in mesorectum and pelvic organs, with major lymph node involvement. The 2 other patients presented resectable locally advanced disease with characteristic concentric ring pattern. No clinical and radiological responses were observed to neo-adjuvant chemoradiotherapy (CRT), including 1 patient with non-resectable disease at surgery and another with upstaged disease at pathological specimen after resection. However, data suggest 2 types of RLP: about half of patients are extremely sensitive to CRT with pathological complete response, and the other half are highly resistant with no response to CRT. Current data are insufficient to distinguish between these 2 populations.

Conclusions: The absence of a concentric ring pattern should not eliminate the suspicion of RLP, especially in young patients with aggressive clinical presentation. There are probably 2 types of RLP in terms of chemoradiosensitivity, and neoadjuvant CRT could delay the curative-intent surgery in refractory patients. Future molecular analysis of the tumor and its environment are required to characterize the 2 different forms of RLP to develop more personalized treatment strategies.
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http://dx.doi.org/10.12659/AJCR.893830DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559009PMC
August 2015

Evaluation of a 36 Gy elective node irradiation dose in anal cancer.

Radiother Oncol 2015 Aug 12;116(2):197-201. Epub 2015 Aug 12.

Department of Radiation Oncology, University Hospital of Besançon, Besançon, France.

Purpose: To retrospectively analyze the efficacy of 36 Gy of elective node irradiation and report patterns of recurrence in patients with anal cancer treated by chemoradiation with the same radiotherapy (RT) treatment scheme.

Methods And Materials: Between January 1996 and December 2013, 142 patients with anal squamous cell cancer were scheduled to receive a dose of 36 Gy of elective node irradiation (ENI) to the inguinal area and whole pelvis over 4 weeks followed after a 2-week gap by a boost dose of 23.4 Gy over 17 days to the macroscopic disease. Mitomycin C combined with fluorouracil, capecitabin or cisplatin was given at day 1 of each sequence of RT.

Results: Disease stages were I: 3, II: 78, IIIA: 23, IIIB: 38. Compliance rates were 97.2% with RT and 87.9% with chemotherapy. After a median follow up of 48 months [3.6-192], estimated 5-year overall survival and colostomy-free survival were 75.4% and 85.3% respectively. Eleven patients (7.7%) never achieved a complete response, 15 had a local component of recurrence and 5 a regional one. One patient had failure in the common iliac node area outside the treatment fields. The inguinal control rate was 98.5%. The 5-year tumor and nodal control rates were 81.5% and 96.0%, respectively.

Conclusion: Chemoradiation with a dose of 36 Gy ENI achieved excellent nodal control. However, it is necessary to improve the 5-year control rate of the primary tumor. Omitting the gap and using additional doses per fraction or hyper-fractionation are to be explored.
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http://dx.doi.org/10.1016/j.radonc.2015.07.050DOI Listing
August 2015