Publications by authors named "Marie-Christine Kaminsky"

25 Publications

  • Page 1 of 1

A phase II study of monalizumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck: The I1 cohort of the EORTC-HNCG-1559 UPSTREAM trial.

Eur J Cancer 2021 Oct 9;158:17-26. Epub 2021 Oct 9.

Service d'Oncologie Médicale, Institut Roi Albert II, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain (UCLouvain), Avenue Hippocrate 10, 1200 Brussels, Belgium. Electronic address:

Purpose: Monalizumab is a monoclonal antibody targeting the inhibitory natural killer group 2A (NKG2A) receptor localised on natural killer (NK) and T cells. Its ligand, the human leukocyte antigen E (HLA-E), is overexpressed in squamous cell carcinoma of the head and neck (SCCHN). By targeting the HLA-E-NKG2A pathway, monalizumab may enhance NK and T cell activity.

Experimental Design: The UPSTREAM trial is a biomarker-driven umbrella trial studying targeted therapies and immunotherapies in patients with recurrent/metastatic (R/M) SCCHN progressing after platinum therapy. The immunotherapy 1 (I1) cohort was a phase II, single-arm substudy evaluating monalizumab (10 mg/kg intravenously on day 1 of a 14-day cycle). The primary end-point was the objective response (OR) rate (Response Evaluation Criteria in Solid Tumours 1.1) over the first 16 weeks. A two-stage Simon design was used (H1 15%, H0 3%, α 8%, power 90%) with pre-planned interruption of accrual if no OR was observed after the first 25 patients.

Results: Twenty-six eligible patients were enrolled. Seventeen (65%) patients had received ≥2 previous lines of systemic treatment, and 15 (58%) patients were PD(-L)1 inhibitor pretreated. No OR was observed. Stable disease was observed in 6 patients (23%) with a median duration of 3.8 months (95% confidence interval [CI]: 2.7-NE). The median progression-free survival and overall survival were 1.7 months (95% CI: 1.5-1.8) and 6.7 months (95% CI: 3.0-9.6), respectively. The most frequent treatment-related adverse event was grade I/II fatigue (19%).

Conclusions: Monalizumab monotherapy has limited activity in R/M SCCHN. The I1 cohort did not meet its primary objective. Monalizumab combined with durvalumab is under investigation within UPSTREAM.
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http://dx.doi.org/10.1016/j.ejca.2021.09.003DOI Listing
October 2021

Real-World Experience of Bevacizumab as First-Line Treatment for Ovarian Cancer: The GINECO ENCOURAGE Cohort of 468 French Patients.

Front Pharmacol 2021 20;12:711813. Epub 2021 Sep 20.

Groupe Hospitalier Diaconesses Croix Saint Simon, Paris, France.

Bevacizumab-containing therapy is considered a standard-of-care front-line option for stage IIIB-IV ovarian cancer based on results of randomized phase 3 trials. The multicenter non-interventional ENCOURAGE prospective cohort study assessed treatment administration and outcomes in the French real-world setting. Eligible patients were aged ≥ 18 years with planned bevacizumab-containing therapy for newly diagnosed ovarian cancer. The primary objective was to assess the safety profile of front-line bevacizumab in routine clinical practice; secondary objectives were to describe patient characteristics, indications/contraindications for bevacizumab, treatment regimens and co-medications, follow-up and monitoring, progression-free survival, and treatment at recurrence. In this non-interventional study, treatment was administered as chosen by the investigator and participation in the trial had no influence on the management of the disease. Of 1,290 patients screened between April 2013 and February 2015, 468 were eligible. Most patients (86%) received bevacizumab 15 mg/kg every 3 weeks or equivalent, typically with carboplatin (99%) and paclitaxel (98%). The median duration of bevacizumab was 12.2 (range 0-28, interquartile range 6.9-14.9) months; 8% of patients discontinued bevacizumab because of toxicity. The most common adverse events were hypertension (38% of patients), fatigue (35%), and bleeding (32%). There were no treatment-related deaths. Most physicians (90%) reported blood pressure measurement immediately before each bevacizumab infusion and almost all (97%) reported monitoring for proteinuria before each bevacizumab infusion. Median progression-free survival was 17.4 (95% CI, 16.4-19.1) months. The 3-year overall survival rate was 62% (95% CI, 58-67%). The most commonly administered chemotherapies at recurrence were carboplatin and pegylated liposomal doxorubicin. Clinical outcomes and tolerability with bevacizumab in this real-life setting are consistent with randomized trial results, notwithstanding differences in the treated patient population and treatment schedule. ClinicalTrials.gov, Identifier NCT01832415.
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http://dx.doi.org/10.3389/fphar.2021.711813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489574PMC
September 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

A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX.

Am J Clin Nutr 2020 12;112(6):1523-1531

Clinical Nutrition and Gastroenterology Department, Montpellier Cancer Institute (ICM), University of Montpellier, Montpellier, France.

Background: In a previous phase II study an immunonutrient supplement was found to reduce severe acute toxicities for head and neck squamous cell cancer (HNSCC) patients treated with concomitant cisplatin and radiotherapy.

Objectives: The primary objective of the present study was to evaluate efficacy of the same immunonutrient supplement on severe mucositis. Secondary objectives included tolerance, compliance to oral supplementation, chemotherapy interruptions and delays, quality of life, and progression-free survival (PFS) and overall survival (OS) at 1, 2, and 3 y.

Methods: Between November 2009 and June 2013, 180 HNSCC patients eligible for adjuvant chemotherapy after surgery with curative intent were included in our double-blind phase III multicenter trial. They were assigned to receive oral supplementation (3 sachets/d) of either a formula enriched with l-arginine and omega-3 (n-3) fatty and ribonucleic acids (experimental arm), or an isocaloric isonitrogenous control (control arm), for 5 d before each of 3 cycles of cisplatin. Intention-to-treat (ITT) and per-protocol (PP) analyses were undertaken, along with subgroup analyses of ≥75% compliant patients, to compare the incidence of acute mucositis (Radiation Therapy Oncology Group and WHO scales) and 36-mo survival.

Results: At 1 mo after terminating chemoradiotherapy (CRT), no differences were observed in the incidence of grade 3-4 mucositis between treatment groups, in the ITT, PP (172 patients), and subgroup (≥75% compliance, n = 112) analyses. The immunomodulating supplement did not significantly improve survival in the ITT and PP analyses at 3 y after CRT. Among ≥75% compliant patients, however, OS at 3 y was significantly improved in the immunomodulating formula group (81%; 95% CI: 67%, 89%) compared with controls (61%; 95% CI: 46%, 73%; P = 0.034), as well as PFS (73%; 95% CI: 58%, 83% compared with 50%; 95% CI: 36%, 63%; P = 0.012).

Conclusions: Although this immunomodulating formula failed to reduce severe mucositis during CRT, the findings suggest that the long-term survival of compliant HNSCC patients was improved.This trial was registered at clinicaltrials.gov as NCT01149642.
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http://dx.doi.org/10.1093/ajcn/nqaa227DOI Listing
December 2020

Debio 1143 and high-dose cisplatin chemoradiotherapy in high-risk locoregionally advanced squamous cell carcinoma of the head and neck: a double-blind, multicentre, randomised, phase 2 study.

Lancet Oncol 2020 09 3;21(9):1173-1187. Epub 2020 Aug 3.

Debiopharm International, Lausanne, Switzerland.

Background: Debio 1143 is an orally available antagonist of inhibitor of apoptosis proteins with the potential to enhance the antitumour activity of cisplatin and radiotherapy. The radiosensitising effect of Debio 1143 is mediated through caspase activation and TNF, IFNγ, CD8 T cell-dependent pathways. We aimed to investigate the efficacy and safety of Debio 1143 in combination with standard chemoradiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck.

Methods: This double-blind, multicentre, randomised, phase 2 study by the French Head and Neck Radiotherapy Oncology Group (GORTEC) was run at 19 hospitals in France and Switzerland. Eligible patients were aged 18-75 years with locoregionally advanced, squamous cell carcinoma of the head and neck (characterised as non-metastatic, measurable stage III, IVa, or IVb [limited to T ≥2, N0-3, and M0] disease), Eastern Cooperative Oncology Group performance status of 0 or 1, a history of heavy tobacco smoking (>10 pack-years) with no previous or current treatment for invasive head and neck cancer, and no previous treatment with inhibitor of apoptosis protein antagonists. Patients were randomly assigned (1:1) to receive oral Debio 1143 (200 mg per day on days 1-14 of 21-day cycles, for three cycles) or oral placebo (20 mg/mL, administered at the same dosing schedule) using a stochastic minimisation technique according to node involvement and primary tumour site, and HPV-16 status in patients with an oropharyngeal primary tumour site. All patients received standard high-dose cisplatin chemoradiotherapy. The primary endpoint was the proportion of patients with locoregional control 18 months after chemoradiotherapy, analysed in the intention-to-treat population (primary analysis), and repeated in the per-protocol population. Responses were assessed according to Response Evaluation Criteria in Solid Tumors (version 1.1). This trial is registered with ClinicalTrials.gov, NCT02022098, and is still active but not recruiting.

Findings: Between Jan 25, 2016, and April 24, 2017, 48 patients were randomly assigned to the Debio 1143 group and 48 to the placebo group (one patient in the placebo group did not receive the study drug and was not included in the safety analysis). Median duration of follow-up was 25·0 months (IQR 19·6-29·4) in the Debio 1143 group and 24·2 months (6·6-26·8) in the placebo group. Locoregional control 18 months after chemoradiotherapy was achieved in 26 (54%; 95% CI 39-69) of 48 patients in the Debio 1143 group versus 16 (33%; 20-48) of 48 patients in the placebo group (odds ratio 2·69 [95% CI 1·13-6·42], p=0·026). Grade 3 or worse adverse events were reported in 41 (85%) of 48 patients in the Debio 1143 group and in 41 (87%) of 47 patients in the placebo group. The most common grade 3-4 adverse events were dysphagia (in 24 [50%] patients in the Debio 1143 group vs ten [21%] in the placebo group), mucositis (in 15 [31%] vs ten [21%]), and anaemia (in 17 [35%] vs 11 [23%]). Serious treatment-emergent adverse events were recorded in 30 (63%) of 48 patients in the Debio 1143 group and 28 (60%) of 47 in the placebo group. In the placebo group, two (4%) deaths were due to adverse events (one multiple organ failure and one asphyxia; neither was considered to be related to treatment). No deaths due to adverse events occurred in the Debio 1143 group.

Interpretation: To our knowledge, this is the first treatment regimen to achieve superior efficacy in this disease setting against a high-dose cisplatin chemoradiotherapy comparator in a randomised trial. These findings suggest that inhibition of inhibitor of apoptosis proteins is a novel and promising approach in this poor prognostic population and warrant confirmation in a phase 3 study with the aim of expanding the therapeutic options for these patients.

Funding: Debiopharm.
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http://dx.doi.org/10.1016/S1470-2045(20)30327-2DOI Listing
September 2020

Comparative analysis of predictive values of the kinetics of 11 circulating miRNAs and of CA125 in ovarian cancer during first line treatment (a GINECO study).

Gynecol Oncol 2020 10 22;159(1):256-263. Epub 2020 Jul 22.

EMR3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Maïeutique Lyon-Sud Charles Mérieux, Université Claude Bernard Lyon 1, Oullins, France, Université de Lyon, Lyon, France; Service d'Oncologie Médicale, CITOHL, Centre Hospitalo-Universitaire Lyon-Sud, Institut de Cancérologie des Hospices Civils de Lyon (IC-HCL), Pierre-Bénite, France, GINECO, Paris, France.

Objective: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS).

Methods: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data.

Results: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests.

Conclusions: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified.
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http://dx.doi.org/10.1016/j.ygyno.2020.07.021DOI Listing
October 2020

A prospective multicentre REFCOR study of 470 cases of head and neck Adenoid cystic carcinoma: epidemiology and prognostic factors.

Eur J Cancer 2020 05 11;130:241-249. Epub 2020 Mar 11.

Sorbonne University, APHP, Department of ENT-Head and Neck Surgery, Tenon Hospital, 4 Rue de La Chine, 75020, Paris, France. Electronic address:

Background: Adenoid cystic carcinoma (ACC) accounts for 1% of malignant head and neck tumours [1] and 10% of salivary glands malignant tumours. The main objective of our study is to investigate the prognostic factors influencing the event-free survival (EFS) of patients with ACC.

Patients And Methods: A multicentre prospective study was conducted from 2009 to 2018. All 470 patients with ACC whose survival data appear in the REFCOR database were included in the study. The main judgement criterion was EFS. Both a bivariate survival analysis using log-rank test and a multivariate using Cox model were performed using the R software.

Results: Average age was 55 years. Females accounted for 59.4% of the cohort. The body mass index (BMI) was normal in 86% of cases. Tumours were located in minor salivary glands in 60% of cases. T3/T4 stages represented 58%; 89% of patients were cN0. histological grade III was observed on 21% of patients. The EFS and overall 5-year survival rates were 50% and 85%, respectively. After adjustment, the most significant pejorative prognostic factors were age ≥65 years (hazard ratio [HR] = 1.67), BMI<16.5 (HR = 2.62), and lymph node invasion cN (HR = 2.08).

Conclusion: Age, BMI and N stage are the three main clinical prognostic factors determining EFS identified in this prospective series of patients with ACC. Such findings open new research perspectives on the influence of these components on initial patient care.
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http://dx.doi.org/10.1016/j.ejca.2020.01.023DOI Listing
May 2020

Predictive factors for early progression during induction chemotherapy and chemotherapy-free interval: analysis from PRODIGE 9 trial.

Br J Cancer 2020 03 4;122(7):957-962. Epub 2020 Feb 4.

Oncology Department, Centre Georges-François Leclerc, Dijon, France.

Background: Identifying patients with metastatic colorectal cancer who will have an early disease progression during induction chemotherapy (IC) and identifying patients who may have a chemotherapy-free interval (CFI) after IC are two major challenges.

Methods: A logistic model was used to identify factors associated with early progression during IC and with short duration of the first CFI in 488 patients enrolled in the PRODIGE 9 trial. Independent factors were defined with a threshold 0.10.

Results: In multivariate analysis, baseline leukocytes >10 × 10/L (OR = 1.98 [1.02-3.8], p = 0.04), and stable or increasing CEA at 2 months (OR = 3.61 [1.68-7.75], p = 0.01) were independent factors associated with progression during IC. Male gender (OR = 1.725 [0.92-3.325], p = 0.09) and no tumour response at first evaluation (OR = 1.90 [0.96-3.76], p = 0.07) were significantly associated with a short CFI. The presence of BRAF V600E mutation was also associated with short CFI (OR = 4.59 [0.95; 22.3], p = 0.058).

Conclusion: High baseline leukocyte count and the lack of CEA decrease level at first evaluation were associated with early progression, and could be in favour of early chemotherapy intensification. Male gender, no tumour response at first evaluation and BRAF mutation are associated with a short CFI, and may be considered for maintenance chemotherapy after IC.

Clinical Trial Number: NCT00952029.
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http://dx.doi.org/10.1038/s41416-020-0735-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7109054PMC
March 2020

Artificial intelligence-guided tissue analysis combined with immune infiltrate assessment predicts stage III colon cancer outcomes in PETACC08 study.

Gut 2020 04 28;69(4):681-690. Epub 2019 Nov 28.

Département d'oncologie médicale, Georges-Francois Leclerc Centre, Dijon, Bourgogne-Franche-Comté, France

Objective: Diagnostic tests, such as Immunoscore, predict prognosis in patients with colon cancer. However, additional prognostic markers could be detected on pathological slides using artificial intelligence tools.

Design: We have developed a software to detect colon tumour, healthy mucosa, stroma and immune cells on CD3 and CD8 stained slides. The lymphocyte density and surface area were quantified automatically in the tumour core (TC) and invasive margin (IM). Using a LASSO algorithm, DGMate (DiGital tuMor pArameTErs), we detected digital parameters within the tumour cells related to patient outcomes.

Results: Within the dataset of 1018 patients, we observed that a poorer relapse-free survival (RFS) was associated with high IM stromal area (HR 5.65; 95% CI 2.34 to 13.67; p<0.0001) and high DGMate (HR 2.72; 95% CI 1.92 to 3.85; p<0.001). Higher CD3+ TC, CD3+ IM and CD8+ TC densities were significantly associated with a longer RFS. Analysis of variance showed that CD3+ TC yielded a similar prognostic value to the classical CD3/CD8 Immunoscore (p=0.44). A combination of the IM stromal area, DGMate and CD3, designated 'DGMuneS', outperformed Immunoscore when used in estimating patients' prognosis (C-index=0.601 vs 0.578, p=0.04) and was independently associated with patient outcomes following Cox multivariate analysis. A predictive nomogram based on DGMuneS and clinical variables identified a group of patients with less than 10% relapse risk and another group with a 50% relapse risk.

Conclusion: These findings suggest that artificial intelligence can potentially improve patient care by assisting pathologists in better defining stage III colon cancer patients' prognosis.
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http://dx.doi.org/10.1136/gutjnl-2019-319292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063404PMC
April 2020

Development and validation of a prognostic nomogram for overall survival in patients with platinum-resistant ovarian cancer treated with chemotherapy.

Eur J Cancer 2019 08 3;117:99-106. Epub 2019 Jul 3.

ARCAGY-GINECO.

Background: Platinum-resistant ovarian cancer (PROC) is associated with a variable prognosis and unpredictable survival times. We have developed and validated a prognostic nomogram with the objective of improving the prediction of overall survival (OS) in patients treated with chemotherapy.

Methods: The nomogram was developed using data from a training cohort of patients from two trials, including the chemotherapy-only arm in AURELIA and all randomised patients in CARTAXHY. Multivariable proportional hazards models were generated based on pretreatment characteristics to develop a nomogram that classifies patients based on OS. We subsequently assessed the performance of the nomogram in terms of discrimination and calibration in independent validation patient cohorts: PENELOPE and the bevacizumab-chemotherapy arm of AURELIA.

Results: The nomogram included six significant OS predictors, in order of importance: performance status, ascites, size of the largest tumour, CA-125, platinum-free interval and primary platinum resistance (C-statistic 0.69). In the training cohort, the median OS in the good, intermediate and poor prognosis groups was 25.3, 15.2 and 7.4 months, respectively. In the PENELOPE validation cohort (C-statistic 0.59), the median OS in the good, intermediate and poor prognosis groups was 18.5, 10.3 and 5.8 months, respectively. In the AURELIA bevacizumab-chemotherapy validation cohort (C-statistic 0.67), the median OS in good, intermediate and poor prognosis groups was 26.7, 13.8 and 10.0 months, respectively.

Conclusions: This nomogram with six pretreatment characteristics allows prediction of OS in PROC and could be used for stratification of patients in clinical trials as well as for counselling patients about prognosis.
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http://dx.doi.org/10.1016/j.ejca.2019.05.029DOI Listing
August 2019

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

Induction Chemotherapy Followed by Cetuximab Radiotherapy Is Not Superior to Concurrent Chemoradiotherapy for Head and Neck Carcinomas: Results of the GORTEC 2007-02 Phase III Randomized Trial.

J Clin Oncol 2018 Nov 17;36(31):3077-3083. Epub 2018 Jul 17.

Lionnel Geoffrois, Marie-Christine Kaminsky, Institut de Cancérologie de Lorraine, Vandoeuvre Lès Nancy; Laurent Martin, Centre Guillaume le Conquérant; Dominique De Raucourt, Bernard Gery, Centre François Baclesse; Emmanuel Babin, Hopital Universitaire, Caen; Xu Shan Sun, Joëlle Buffet, Centre Hospitalier Universitaire de Besançon, Besançon; Hôpital de Mulhouse, Mulhouse; Yungan Tao, Gustave-Roussy Institute, Villejuif; Philippe Maingon, Centre François Leclercq, Leclercq; Yoann Pointreau, Cédric Lafond, Marie-Hélène Calais, Pascal Garaud, Centre Jean Bernard, Le Mans; Centre Hospitalier Universitaire de Tours, Tours; Christian Sire, Centre Hospitalier de Lorient, Lorient; Claude Tuchais, Eric Jadaud, Centre Paul Papin, Angers; Alexandre Coutte, Centre Hospitalier Universitaire Amiens, Amiens; Frédéric Rolland, Centre René Gauducheau, Saint Herblain; Marc Alfonsi, Clinique Sainte Catherine, Avignon; Michel Lapeyre, Centre Jean Perrin, Clermont; Marie Saliou, Clinique Mutualiste, Saint Nazaire; Ayman Zawadi, Centre Hospitalier de La Roche-sur-Yon, La Roche-sur-Yon; Jean-Marc Tourani, Centre Hospitalier Universitaire, Poitiers, Poitiers; Cédric Khoury, Centre Saint Louis; Pierre Guillet, Hôpital Font-Pré, Toulon, Toulon; Ali Hasbini, Hopital de Saint Brieuc, Saint Brieuc; François Guichard, Polyclinique de Bordeaux-Nord, Bordeaux; Christian Borel, Centre Paul Strauss, Strasbourg, France; Anne Rose Henry, Hôpital Montigny le Tilleul, Montigny-le-Tilleul; Nicolas Meert, Centre Hospitalier de Charlebois, Charlebois, Belgium; and Jean Bourhis, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland.

Purpose: Both concurrent chemoradiotherapy (CT-RT) and cetuximab radiotherapy (cetux-RT) have been established as the standard of care for the treatment of locally advanced squamous cell carcinoma of the head and neck. It was not known whether the addition of induction chemotherapy before cetux-RT could improve outcomes compared with standard of care CT-RT.

Patients And Methods: The current trial was restricted to patients with nonmetastatic N2b, N2c, or N3 squamous cell carcinoma of the head and neck and fit for taxotere, cisplatin, fluorouracil (TPF). Patients were randomly assigned to receive three cycles of TPF followed by cetux-RT versus concurrent carboplatin fluorouracil and RT as recommended in National Comprehensive Cancer Network guidelines. The trial was powered to detect a hazard ratio (HR) of 0.66 in favor of TPF plus cetux-RT for progression-free survival at 2 years. The inclusion of 180 patients per arm was needed to achieve 80% power at a two-sided significance level of .05.

Results: Between 2009 and 2013, 370 patients were included. All patients and tumors characteristics were well balanced between arms. There were more cases of grade 3 and 4 neutropenia in the induction arm, and the induction TPF was associated with 6.6% treatment-related deaths. With a median follow-up of 2.8 years, 2-year progression-free survival was not different between both arms (CT-RT, 0.38 TPF + cetux-RT, 0.36; HR, 0.93 [95% CI, 0.73 to 1.20]; = .58). HR was 0.98 (95% CI, 0.74 to 1.3; = .90) for locoregional control and 1.12 (95% CI, 0.86 to 1.46; = .39) for overall survival. These effects were observed regardless of p16 status. The rate of distant metastases was lower in the TPF arm (HR, 0.54 [95% CI, 0.30 to 0.99]; = .05).

Conclusion: Induction TPF followed by cetux-RT did not improve outcomes compared with CT-RT in a population of patients with advanced cervical lymphadenopathy.
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http://dx.doi.org/10.1200/JCO.2017.76.2591DOI Listing
November 2018

Improved Outcome by Adding Concurrent Chemotherapy to Cetuximab and Radiotherapy for Locally Advanced Head and Neck Carcinomas: Results of the GORTEC 2007-01 Phase III Randomized Trial.

J Clin Oncol 2018 Jun 7:JCO2017762518. Epub 2018 Jun 7.

Yungan Tao, Anne Auperin, Alexandre Cornely, Nathalie Ollivier, Odile Casiraghi, and Jean Bourhis, Gustave-Roussy Institute, Villejuif; Christian Sire, Centre Hospitalier de Lorient, Lorient; Laurent Martin, Centre Guillaume le Conquérant, Le Havre; Cedric Khoury, Centre Hospitalier de Toulon, Toulon; Philippe Maingon, Centre Georges-François Leclerc, Dijon; Etienne Bardet, Centre René Gauducheau, Nantes; Marie-Christine Kaminsky, Centre Alexis Vautrin, Nancy; Michel Lapeyre, Centre Jean Perrin, Clermont; Thierry Chatellier, Clinique Mutualiste, Saint Nazaire; Marc Alfonsi, Clinique Sainte Catherine, Avignon; Yoann Pointreau, Centre Jean Bernard, Le Mans; Yoann Pointreau, Centre Hospitalier Universitaire (CHU) de Tours, Tours; Eric Jadaud, Centre Paul Papin, Angers; Bernard Géry, Centre François Baclesse, Caen; Ayman Zawadi, Centre Hospitalier de La Roche-sur-Yon, La Roche-sur-Yon; Jean-Marc Tourani, CHU, Poitiers; Brigitte Laguerre, Centre Eugène Marquis, Rennes; Alexandre Coutte, CHU, Amiens; Séverine Racadot, Centre Léon Bérard, Lyon; Ali Hasbini, Clinique Armoricaine, Saint-Brieuc; Emanuelle Malaurie, Centre Hospitalier Intercommunal de Créteil, Créteil; Christian Borel, Centre Paul Strauss, Strasbourg; Xu Shan Sun, Hopital Nord Franche-Comté de Montbéliard, Montbéliard; Xu Shan Sun, Centre Hospitalier Régional Universitaire de Besançon, Besançon, France; Nicolas Meert, Centre Hospitalier de Charleroi, Charleroi, Belgium; and Jean Bourhis, Centre Hospitalier Universitaire Vaudois Lausanne, Lausanne, Switzerland.

Purpose To investigate the effect of adding concurrent chemotherapy (CT) to cetuximab plus radiotherapy (RT; CT-cetux-RT) compared with cetuximab plus RT (cetux-RT) in locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Patients and Methods In this phase III randomized trial, patients with N0-2b, nonoperated, stage III or IV (nonmetastatic) LA-SCCHN were enrolled. Patients received once-daily RT up to 70 Gy with weekly cetuximab or with weekly cetuximab and concurrent carboplatin and fluorouracil (three cycles). To detect a hazard ratio (HR) of 0.64 for progression-free survival (PFS) with 85% power at a two-sided significance level of P = .05, 203 patients needed to be included in each arm. Results Four hundred six patients were randomly assigned to either CT-cetux-RT or cetux-RT. Patient and tumor characteristics were well balanced between arms, including p16 status. With a median follow-up of 4.4 years, the HR for PFS favored the CT-cetux-RT arm (HR, 0.73; 95% CI, 0.57 to 0.94; P = .015), with 3-year PFS rates of 52.3% and 40.5% and median PFS times of 37.9 and 22.4 months in the CT-cetux-RT and cetux-RT arms, respectively. The HR for locoregional control was 0.54 (95% CI, 0.38 to 0.76; P < .001) in favor of CT-cetux-RT. These benefits were observed regardless of p16 status for oropharynx carcinomas. Overall survival (HR, 0.80; P = .11) and distant metastases rates (HR, 1.19; P = .50) were not significantly different between the two arms. The CT-cetux-RT arm, compared with cetux-RT, had a higher incidence of grade 3 or 4 mucositis (73% v 61%, respectively; P = .014) and of hospitalizations for toxicity (42% v 22%, respectively; P < .001). Conclusion The addition of concurrent carboplatin and fluorouracil to cetux-RT improved PFS and locoregional control, with a nonsignificant gain in survival. To our knowledge, this is the first evidence of a clinical benefit for treatment intensification using cetux-RT as a backbone in LA-SCCHN.
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http://dx.doi.org/10.1200/JCO.2017.76.2518DOI Listing
June 2018

Validation of the modified Glasgow Prognostic Score (mGPS) in recurrent ovarian cancer (ROC) - Analysis of patients enrolled in the GCIG Symptom Benefit Study (SBS).

Gynecol Oncol 2018 01 26;148(1):36-41. Epub 2017 Oct 26.

Australia New Zealand Gynaecological Oncology Group (ANZGOG), Australia; Prince of Wales Hospital, Sydney, Australia.

Background: Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS).

Methods: mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS).

Results: Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p<0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p=0.02). Worse PS and higher mGPS were associated with poorer HRQL (p<0.001). Higher mGPS was associated with worse HRQL, independent of PS.

Conclusion: The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification.
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http://dx.doi.org/10.1016/j.ygyno.2017.10.019DOI Listing
January 2018

Phase Ib trial of the Toll-like receptor 9 agonist IMO-2055 in combination with 5-fluorouracil, cisplatin, and cetuximab as first-line palliative treatment in patients with recurrent/metastatic squamous cell carcinoma of the head and neck.

Invest New Drugs 2013 Oct 10;31(5):1207-16. Epub 2013 Feb 10.

Service d'Oncologie Médicale, Centre du Cancer, Cliniques Universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale (IREC, MIRO), Université Catholique de Louvain, Bruxelles, Belgium,

Background: This Phase Ib trial assessed the maximum tolerated dose (MTD) and safety of the Toll-like receptor 9 agonist IMO-2055 combined with 5-fluorouracil, cisplatin, and cetuximab (PFE) as first-line palliative treatment in patients with relapsed and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

Methods: A standard 3+3 study design was used. Patients were sequentially enrolled to be treated with IMO-2055 (0.16, 0.32, or 0.48 mg/kg/day; days 1, 8, 15), 5-fluorouracil (1,000 mg/m(2)/day; days 1-4), cisplatin (100 mg/m(2)/day; day 1) and cetuximab (400 mg/m(2)/day first dose; then 250 mg/m(2)/day; days 1, 8, 15) every 3 weeks.

Results: Thirteen patients received IMO-2055. Dose-limiting toxicities (DLTs; ie, any Grade [G]3/4 treatment-related adverse events [TEAEs] in cycle 1) occurred in 2/4 patients treated with IMO-2055 0.32 mg/kg (G4 hypokalemia and hypomagnesemia [n=1]; G4 septicemia, hyperthermia, febrile neutropenia, and G3 hypotension [n=1]). In the IMO-2055 0.16-mg/kg expansion cohort, 1 patient experienced DLTs of G3 sepsis, bacteremia, and hyperthermia. The most common G ≥ 3 TEAEs were neutropenia (n=9; not including febrile neutropenia [n=1]), hypokalemia (n=5), and hypomagnesemia (n=4). Serious adverse events (SAEs) occurred in 8 patients, including 4 with SAEs considered IMO-2055 related; 1 of these patients died. Best response achieved overall was partial response in 3 patients and stable disease in 9 patients. The overall safety profile led to early trial termination; the safety monitoring committee did not confirm the MTD (formally IMO-2055 0.16 mg/kg).

Conclusions: Regimens combining IMO-2055 and PFE cannot be recommended for further development in R/M SCCHN patients.
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http://dx.doi.org/10.1007/s10637-013-9933-zDOI Listing
October 2013

Responsiveness of EORTC QLQ-C30, QLQ-CR38 and FACT-C quality of life questionnaires in patients with colorectal cancer.

Health Qual Life Outcomes 2011 Aug 22;9:70. Epub 2011 Aug 22.

Centre Alexis Vautrin, Department of Medical Oncology, Nancy, France.

Background: The aim of this study was to compare the responsiveness of the European Organization for Research and Treatment (EORTC) quality of life questionnaires (QLQ-C30, QLQ-CR38) and the Functional Assessment of Cancer Therapy-colorectal version 4 questionnaire (FACT-C).

Method: This prospective study included 127 patients with colorectal cancer: 71 undergoing chemotherapy and 56 radiation therapy. Responsiveness statistics included the Standardized Response Mean (SRM) and the Effect Size (ES). The patient's overall assessment of his/her change in state of health status was the reference criterion to evaluate the responsiveness of the QoL questionnaires.

Results: 34 patients perceived their health as stable and 17 as improved between the first and the fourth courses of chemotherapy. 21 patients perceived their health as stable and 22 as improved between before and the last week of radiotherapy.The responsiveness of the 3 questionnaires differed according to treatments. The EORTC QLQ-C30 questionnaire was more responsive in patients receiving chemotherapy, particulary functional scales (SRM > 0.55). The QLQ-CR38 and the FACT-C questionnaires provided little clinically relevant information during chemotherapy or radiotherapy.

Conclusion: The EORTC QLQ-C30 questionnaire appears to be more responsive in patients receiving chemotherapy.
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http://dx.doi.org/10.1186/1477-7525-9-70DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170175PMC
August 2011

Phase II study of sunitinib in recurrent or metastatic squamous cell carcinoma of the head and neck: GORTEC 2006-01.

J Clin Oncol 2010 Jan 16;28(1):21-8. Epub 2009 Nov 16.

Medical Oncology Unit, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, 10 Avenue Hippocrate, 1200 Brussels, Belgium.

PURPOSE To assess the efficacy and toxicity of sunitinib monotherapy in palliative squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Thirty-eight patients with SCCHN having evidence of progressive disease (PD) were treated with sunitinib 37.5 mg/d given continuously until PD or unacceptable toxicity. The primary end point was the rate of disease control, defined as stable disease (SD) or partial response (PR) at 6 to 8 weeks after treatment initiation (two-stage design, Simon). Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed in a subset of patients before and 6 to 8 weeks after treatment. The volume transfer constant of the contrast agent (K(trans)) was used to measure changes in the microcirculation blood flow and endothelial permeability of the tumor. Results A PR was observed in one patient, SD in 18, and PD in 19 (Response Evaluation Criteria in Solid Tumors [RECIST]), resulting in a disease control rate of 50%. Among the 18 patients with SD, there were five unconfirmed PRs and six additional minor responses. A significant decrease in K(trans) was seen in three of the four patients who received DCE-MRI monitoring. Grade 5 head and neck bleeds occurred in four patients. Local complications, including the appearance or worsening of tumor skin ulceration or tumor fistula, were recorded in 15 patients. CONCLUSION Sunitinib demonstrated modest activity in palliative SSCHN. The severity of some of the complications highlights the importance of improved patient selection for future studies with sunitinib in head and neck cancer. Sunitinib should not be used outside clinical trials in SSCHN.
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http://dx.doi.org/10.1200/JCO.2009.23.8584DOI Listing
January 2010

Need for neck dissection after radiochemotherapy? A study of the French GETTEC Group.

Laryngoscope 2008 Oct;118(10):1775-80

Department of Otolaryngology-Head and Neck Surgery, Cannes Hospital, Cannes, France.

Background/hypothesis: The need for a neck dissection after radiochemotherapy (RCT) for patients with unresectable cancer of the head and neck remains questionable. We evaluated our strategy to perform a neck dissection in patients with a controlled primary tumor based on the response to RCT according to regional control, survival rates, and morbidity.

Study Design: The French "Groupe d'Etude des Tumeurs de la Tête et du Cou" (GETTEC) group retrospectively performed a multicenter review. One hundred and three stage III (N = 7) or IV (N = 96) patients with unresectable primary tumors and node-positive disease and no distant metastases treated between 1996 and 2002. Tumors were considered unresectable or with poor surgical curability based on advanced stage, or patients were surgically unfit for medical reasons.

Results: With a median follow-up of 30 months, the complete clinical and radiological nodal response rate was 61%. Among 39% (N = 40) of patients with residual neck disease, 70% (N = 28) underwent a neck dissection, whereas the remaining 30% either underwent watchful follow-up for probable scary nodes, or were deemed unresectable or medically unfit for surgery. Half of the neck dissection specimens showed pathological evidence of viable tumor. Grade 3 to 4 complications were recorded in four patients (14%) after neck dissection. Regional control was better for complete responders. Disease-free survival and overall survival were similar between patients with a complete response in the neck and no neck dissection, and patients with a neck dissection for residual neck disease.

Conclusions: The strategy to avoid a neck dissection is safe in patients with a complete response in the neck, regardless of initial nodal stage. In patients with residual neck disease, postRCT neck dissection can be performed with limited morbidity. Progress is warranted to optimize the pathological response in the nodes and to better assess ambiguous nodal responses with multi-modal imaging.
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http://dx.doi.org/10.1097/MLG.0b013e31817f192aDOI Listing
October 2008

Randomized multicenter phase II trial of a biweekly regimen of fluorouracil and leucovorin (LV5FU2), LV5FU2 plus cisplatin, or LV5FU2 plus irinotecan in patients with previously untreated metastatic gastric cancer: a Federation Francophone de Cancerologie Digestive Group Study--FFCD 9803.

J Clin Oncol 2004 Nov;22(21):4319-28

Centre Hospitalier Universitaire de Reims, Rims, France.

Purpose: To determine the efficacy and safety of a biweekly regimen of leucovorin (LV) plus fluorouracil (FU) alone or in combination with cisplatin or irinotecan in patients with previously untreated metastatic gastric adenocarcinoma and to select the best arm for a phase III study.

Patients And Methods: One hundred thirty-six patients (two were ineligible) were enrolled onto the randomized multicenter phase II trial. Patients received LV 200 mg/m(2) (2-hour infusion) followed by FU 400 mg/m(2) (bolus) and FU 600 mg/m(2) (22-hour continuous infusion) on days 1 and 2 every 14 days (LV5FU2; arm A), LV5FU2 plus cisplatin 50 mg/m(2) (1-hour infusion) on day 1 or 2 (arm B), or LV5FU2 plus irinotecan 180 mg/m(2) (2-hour infusion) on day 1 (arm C).

Results: The overall response rates, which were confirmed by an independent expert panel, were 13% (95% CI, 3.4% to 23.3%), 27% (95% CI, 14.1% to 40.4%), and 40% (95% CI, 25.7% to 54.3%) for arms A, B, and C, respectively. Median progression-free survival and overall survival times were 3.2 months (95% CI, 1.8 to 4.6 months) and 6.8 months (95% CI, 2.6 to 11.1 months) with LV5FU2, respectively; 4.9 months (95% CI, 3.5 to 6.3 months) and 9.5 months (95% CI, 6.9 to 12.2 months) with LV5FU2-cisplatin, respectively; and 6.9 months (95% CI, 5.5 to 8.3 months) and 11.3 months (95% CI, 9.3 to 13.3 months) with LV5FU2-irinotecan, respectively.

Conclusion: Of the three regimens tested, the combination of LV5FU2-irinotecan is the most promising and will be assessed in a phase III trial.
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http://dx.doi.org/10.1200/JCO.2004.01.140DOI Listing
November 2004

Postoperative brachytherapy alone and combined postoperative radiotherapy and brachytherapy boost for squamous cell carcinoma of the oral cavity, with positive or close margins.

Head Neck 2004 Mar;26(3):216-23

Radiotherapy Department, Centre Alexis Vautrin, Radiotherapy Department, Avenue de Bourgogne, 54511 Vandoeuvre-les-Nancy, France.

Background: Postoperative radiotherapy is necessary for squamous cell carcinoma (SCC) of the oral cavity with positive or close margins. The aim of the study is to define the indications of postoperative brachytherapy (BRT).

Methods: From 1979 to 1993, 82 patients with positive or close margins had postoperative BRT (58 T1-2, 24 T3-4, 45 mobile tongue, 37 floor of mouth). Forty-six patients had combined radiotherapy (RT) with a mean dose of 48 Gy, and BRT boost with a mean dose of 24 Gy. Thirty-six patients had BRT alone with a mean dose of 60 Gy. BRT was performed with interstitial low dose rate Iridium 192.

Results: Overall survival (OS), cause-specific survival (CSS), and local control (LC) at 5 years were, respectively, for T1-2/N0N- with BRT, 75%, 85%, and 88%,and with RT-BRT 70%, 92%, and 92%; for T1-2/N+ with RT-BRT, 44%, 67%, and 78%; for T3-4/N- with RT-BRT, 42%, 90%, and 80%; and for T3-4/N+ with RT-BRT, 22%, 43%, and 57%. Prognostic factors for OS, CSS, and LC were N+ (p
Conclusions: BRT alone for SCC T1-2/N0N- is better than RT-BRT because, with equivalent results, it avoids the adverse events of postoperative RT (xerostomia) and permits the treatment of a second head and neck primary in nonirradiated tissue. The results for the T3-4/N- are acceptable with this approach (ie, RT-BRT) but may be improved for N+.
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http://dx.doi.org/10.1002/hed.10377DOI Listing
March 2004

[Clinical practice guidelines: Standards, Options and Recommendations for the diagnosis of carcinomas of unknown primary site].

Bull Cancer 2003 Dec;90(12):1071-96

Oncologue médical, Centre Eugène Marquis, Rennes.

Context: The "Standards, Options and Recommendations" (SOR) project, which started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Regional Cancer Centers, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients.

Objectives: To define Clinical Practice Guidelines (CPG) for the diagnosis of carcinomas of unknown primary site.

Methods: The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts who define the CPGs according to the definitions of the Standards, Options and Recommendations project. Once the guidelines has been defined, the document is submitted for review by independent reviewers.

Results: The main recommendations for the diagnosis of carcinomas of unknown primary site are: 1) Diagnostic strategy should aim to identify anatomoclinical entities of carcinomas of unknown primary site for which there is a specific treatment. For other anatomoclinical entities, identification of the primary tumour has no impact on the prognostic or therapeutic consequences, thus a systematic complete assessment is unnecessary. 2) An immunohistochemical investigation for the diagnosis should be performed using an appropriate panel of specific antibodies. This should enable the diagnosis of lymphoma, melanoma, germ cell tumour and sarcoma to be eliminated and the diagnosis of prostate, breast, ovary, thyroid or neuroendocrine tumours to be positively identified. 3) A sample can be frozen to enable typing, cytogenetic and, particularly, molecular biological studies to be performed later. 4) The clinician and pathologist should compare their opinions before and after the pathological diagnosis.
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December 2003

Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01).

J Clin Oncol 2003 Sep;21(18):3479-82

Department of Medical Oncology, Centre Régional de Lutte Contre le Cancer, Val d'Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5, France.

Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site.

Patients And Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done.

Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively.

Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.
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http://dx.doi.org/10.1200/JCO.2003.12.104DOI Listing
September 2003

[Standards, Options and Recommendations for the management of patient with carcinoma of unknown primary site].

Bull Cancer 2002 Oct;89(10):869-75

FNCLCC, Standards, Options, Recommandations, 101, rue de Tolbiac, 75654 Paris Cedex 13, France.

Context: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centers (FNCLCC), the 20 French Cancer Centers, and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery.

Objectives: To develop clinical practice guidelines for carcinoma of unknown primary site (CUPS) patients according to the definitions of the Standards, Options and Recommendations project.

Methods: Data were identified by searching Medline , web sites, and using the personal reference lists of members of the expert groups. Once the guidelines were defined, the document was submitted for review to 81 independent reviewers.

Results: The main recommendations for the management of patients CUPS are presented below: 1) An adapted immunochemistry test using a specific antibody battery should be performed for the anatomopathologic diagnosis. 2) The aim of the diagnosis is to identify specific anatomoclinical forms that can be treated by a specific treatment (standard, level of evidence B2). Except these forms, searching for the primary tumor site have no prognosis or therapeutic interest that can justify a systematic diagnosis assessment (standard, level of evidence B2). 3) The management of poorly differentiated neuroendocrine carcinoma consists of platin/etoposide based chemotherapy. There is no standard treatment for the differentiated forms. 4) Surgical node excision and adjuvant radiotherapy should be performed in case of epidermoid carcinoma with cervical node metastases. In the event of a non operable tumor, an irradiation should be performed. 5) The management of axillary node metastases in women with adenocarcinoma should be the same as the management of patients with lymph node metastases in breast cancer. If mammary MRI is negative, surgical treatment and mammary irradiation are not recommended and an axillary node excision should be performed. 6) The standard treatment for women with primary papillary serous carcinoma of the peritoneum is a surgical resection followed by chemotherapy, as recommended for ovarian cancer. 7) CUPS not belonging to any specific anatomoclinical forms can be treated by chemotherapy, symptomatic treatment alone or treatment based on biphosphonates in presence bone metastases.
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October 2002
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