Publications by authors named "Sylvie Zanetta"

22 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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October 2021

Everolimus or sunitinib as first-line treatment of metastatic papillary renal cell carcinoma: A retrospective study of the GETUG group (Groupe d'Etude des Tumeurs Uro-Génitales).

Eur J Cancer 2021 Oct 4;158:1-11. Epub 2021 Oct 4.

Department of Medical Oncology, Gustave Roussy, Villejuif, France.

Background: Two phase II trials (NCT00688753 and NCT00541008) reported efficacy data of sunitinib and everolimus in first-line treatment of metastatic papillary renal cell carcinoma (mpRCC). Although most patients receive sunitinib or a mammalian target of rapamycin (mTOR) inhibitor in first- and second-line treatment, the optimal strategy remained unknown.

Material And Methods: In 23 centres of the Groupe d'Etude des Tumeurs Urogénitales group, after centralised pathological review, we analysed retrospectively progression-free survival (PFS) of patients with mpRCC treated in first-line treatment (PFS-1) with sunitinib or everolimus (primary end-point), PFS in second-line treatment (PFS-2), overall survival (OS), objective response rate, disease control rate (DCR), overall sequence and prognostic factors for OS (secondary end-points).

Results: One hundred thirty-eight patients (119 men and 19 women), median age 62.5 years, with mpRCC type 1 (n = 24) or non-type 1 (n = 114), received first-line sunitinib (n = 107) or everolimus (n = 31). With a median follow-up of 92 months, we found no significant difference between the treatment groups in terms of PFS-1 (5.5 versus 6.2 months) and DCR (69% versus 83%). Ninety-eight patients received a second-line treatment, 69% with mTOR inhibitors after sunitinib and 100% with tyrosine kinase inhibitors after everolimus, with similar DCR (64% versus 58%), median PFS-2 (3.4 versus 4.8 months) and OS (16.0 versus 20.3 months). No factor was prognostic for PFS-1, whereas leukocytosis, anaemia and the time from diagnosis to first systemic therapy < 1 year were prognostic for OS. We found no prognostic difference between both pRCC subtypes. The International Metastatic Renal Cell Database Consortium risk factors were prognostic for OS.

Conclusion: Sunitinib and everolimus had similar efficacy in first-line treatment of patients with mpRCC.
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October 2021

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

Eur J Cancer 2021 05 27;148:359-370. Epub 2021 Feb 27.

Methodology and Biostatistics Unit, Centre Georges François Leclerc, Dijon, France.

Background: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection.

Methods: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown.

Findings: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients.

Interpretation: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.
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May 2021

Cetuximab, docetaxel, and cisplatin versus platinum, fluorouracil, and cetuximab as first-line treatment in patients with recurrent or metastatic head and neck squamous-cell carcinoma (GORTEC 2014-01 TPExtreme): a multicentre, open-label, randomised, phase 2 trial.

Lancet Oncol 2021 04 5;22(4):463-475. Epub 2021 Mar 5.

Department of Medical Oncology, Institut Català de Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain.

Background: Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14·0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting.

Methods: This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m and cisplatin 75 mg/m, both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m on day 1 of cycle 1 and 250 mg/m weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m on day 1-4, cisplatin 100 mg/m on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m on day 1 of cycle 1 and 250 mg/m weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at, NCT02268695.

Findings: Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34·4 months (IQR 26·6-44·8) in the TPEx group and 30·2 months (25·5-45·3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14·5 months [95% CI 12·5-15·7] in the TPEx group and 13·4 months [12·2-15·4] in the EXTREME group; hazard ratio 0·89 [95% CI 0·74-1·08]; p=0·23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p<0·0001). In the TPEx group, 118 (45%) of 263 patients had at least one serious adverse event versus 143 (54%) of 265 patients in the EXTREME group. 16 patients in the TPEx group and 21 in the EXTREME group died in association with adverse events, including seven patients in each group who had fatal infections (including febrile neutropenia). Eight deaths in the TPEx group and 11 deaths in the EXTREME group were assessed as treatment related, most frequently sepsis or septic shock (four in each treatment group).

Interpretation: Although the trial did not meet its primary endpoint, with no significant improvement in overall survival with TPEx versus EXTREME, the TPEx regimen had a favourable safety profile. The TPEx regimen could provide an alternative to standard of care with the EXTREME regimen in the first-line treatment of patients with recurrent or metastatic HNSCC, especially for those who might not be good candidates for up-front pembrolizumab treatment.

Funding: Merck Santé and Chugai Pharma.
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April 2021

Monitoring HSP70 exosomes in cancer patients' follow up: a clinical prospective pilot study.

J Extracell Vesicles 2020 20;9(1):1766192. Epub 2020 May 20.

Centre d'investigation Clinique INSERM 1432, CHU Dijon-Bourgogne, Dijon, France.

Exosomes are nanovesicles released by all cells that can be found in the blood. A key point for their use as potential biomarkers in cancer is to differentiate tumour-derived exosomes from other circulating nanovesicles. Heat shock protein-70 (HSP70) has been shown to be abundantly expressed by cancer cells and to be associated with bad prognosis. We previously showed that exosomes derived from cancer cells carried HSP70 in the membrane while those from non-cancerous cells did not. In this work, we opened a prospective clinical pilot study including breast and lung cancer patients to determine whether it was possible to detect and quantify HSP70 exosomes in the blood of patients with solid cancers. We found that circulating exosomal HSP70 levels, but not soluble HSP70, reflected HSP70 content within the tumour biopsies. Circulating HSP70 exosomes increased in metastatic patients compared to non-metastatic patients or healthy volunteers. Further, we demonstrated that HSP70-exosome levels correlated with the disease status and, when compared with circulating tumour cells, were more sensitive tumour dissemination predictors. Finally, our case studies indicated that HSP70-exosome levels inversely correlated with response to the therapy and that, therefore, monitoring changes in circulating exosomal HSP70 might be useful to predict tumour response and clinical outcome.
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May 2020

Phase I trial of afatinib and 3-weekly trastuzumab with optimal anti-diarrheal management in patients with HER2-positive metastatic cancer.

Cancer Chemother Pharmacol 2018 12 22;82(6):979-986. Epub 2018 Oct 22.

Institut Universitaire du Cancer de Toulouse, Oncopôle, 1 avenue Irène Joliot-Curie, 31059, Toulouse Cedex 9, France.

Background: Trastuzumab is the mainstay of therapy for patients with HER2-positive breast and gastric cancer but resistance frequently occurs. Afatinib, an irreversible oral ErbB family blocker, shows clinical activity in trastuzumab-refractory HER2-positive metastatic breast cancer.

Materials And Methods: This phase I study used a modified 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD) of oral once-daily afatinib in combination with 3-weekly intravenous trastuzumab (8 mg/kg week 1; 6 mg/kg 3-weekly thereafter) for patients with confirmed advanced or metastatic HER2-positive cancer.

Results: Of the 13 patients treated, 6 received daily afatinib 20 mg and 7 received 30 mg. One patient who received afatinib 30 mg developed a tumor lysis syndrome and was not evaluable for dose-limiting toxicity (DLT). Two of the six remaining patients receiving afatinib 30 mg and 1 of the 6 patients receiving afatinib 20 mg experienced DLTs (all CTCAE ≥ grade 2 diarrhea despite optimal management) in the first treatment cycle. The most common drug-related adverse events were diarrhea (n = 13, 100%), asthenia (n = 8, 61.5%), rash (n = 7, 53.8%) and paronychia (n = 5, 38.5%). No pharmacokinetic interaction was observed. One patient (7.7%) had an objective response (20 mg afatinib cohort). Nine patients (69.2%) experienced clinical benefit.

Conclusions: Despite optimal management of diarrhea including treatment of grade I symptoms, it was not possible to treat the patients above a dose of 20 mg of afatinib daily in combination with 3-weekly trastuzumab. The MTD of afatinib in combination with the recommended 3-weekly dose of trastuzumab was 20 mg daily.
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December 2018

Fluorouracil and bevacizumab plus anakinra for patients with metastatic colorectal cancer refractory to standard therapies (IRAFU): a single-arm phase 2 study.

Oncoimmunology 2018;7(9):e1474319. Epub 2018 Aug 1.

Platform of Transfer in Biological Oncology, Dijon, France.

In preclinical models, IL-1β inhibition could enhance the efficacy of fluorouracil (5-FU). In this phase 2 study, we assessed the activity and safety of 5-FU plus bevacizumab and anakinra (an IL-1β and α inhibitor) in patients with metastatic colorectal (mCRC) refractory to chemotherapy and anti-angiogenic therapy. Eligible patients had unresectable mCRC; were refractory or intolerant to fluoropyrimidine, irinotecan, oxaliplatin, anti-VEGF therapy, and anti-EGFR therapy (for tumors with wild-type ). Patients were treated with a simplified acid folinic plus 5-FU regimen and bevacizumab (5 mg/kg) both administered by intravenous infusion for 30 min every 2 weeks. Anakinra (100 mg) was injected subcutaneously once daily. The primary endpoint was the 2-month response rate determined upon CHOI criteria. Thirty two patients with metastatic colorectal cancer were enrolled. Five patients demonstrated response (Choi criteria) and 22 patients had stable disease as the best 2-month overall response. Median progression-free and overall survival were 5.4 (95% CI, 3.6-6.6) and 14.5 months (95% CI, 9-20.6) respectively. Twenty patients experienced grade 3 toxicity. No grade 4 or 5 toxicity related to therapy occurred. The most common grade 3 adverse events were neutropenia in 8 (25%) patients, digestive side effects in 7 (21.9%) patients and hypertension in 6 (18.75%) patients. No treatment-related deaths or serious adverse events were reported.5-FU plus bevacizumab and anakinra has promising activity and a manageable safety profile, suggesting that this combination might become a potential treatment option for patients with refractory mCRC.
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August 2018

Phase Ib/II trial evaluating the safety, tolerability and immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab (anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal cancer.

ESMO Open 2018 19;3(4):e000375. Epub 2018 Jun 19.

Department of Medical Oncology, Center Georges Francois Leclerc, Dijon, France.

Background: 5-Fluorouracil plus irinotecan or oxaliplatin alone or in association with target therapy are standard first-line therapy for metastatic colorectal cancer (mCRC). Checkpoint inhibitors targeting PD-1/PD-L1 demonstrated efficacy on mCRC with microsatellite instability but remain ineffective alone in microsatellite stable tumour. 5-Fluorouracil and oxaliplatin were known to present immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) that inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate whether the addition of PD-L1 and CTLA-4 inhibition to oxaliplatin, fluorouracil and leucovorin (FOLFOX) increases treatment efficacy.

Methods: This phase II study ( NCT03202758) will assess the efficacy and safety of FOLFOX/D/T association in patients with mCRC (n=48). Good performance status patients (Eastern Cooperative Oncology Group <2) with untreated, RAS mutational status mCRC will be eligible. Prior adjuvant therapy is allowed provided recurrence is >6 months postcompletion. There is a safety lead in nine patients receiving FOLFOX/D/T. Assuming no safety concerns the study will go on to include 39 additional patients. Patients will receive folinic acid (400 mg/m²)/5-fluorouracil (400 mg/m² as bolus followed by 2400 mg/m as a 46-hour infusion)/oxaliplatin (85 mg/m) every 14 days with D (750 mg) D1 every 14 days and T (75 mg) D1 every 28 days. After six cycles of FOLFOX only D/T will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Primary endpoint is safety and efficacy according to progression-free survival (PFS); secondary endpoints include overall response rate and quality of life. Hypothesis is that a PFS of 50% at 6 months is insufficient and a PFS of 70.7% is expected (with α=10%, β=10%). Blood, plasma and tumour tissue will be collected and assessed for potential prognostic and predictive biomarkers.
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June 2018

Anticancer Activity and Tolerance of Treatments Received Beyond Progression in Men Treated Upfront with Androgen Deprivation Therapy With or Without Docetaxel for Metastatic Castration-naïve Prostate Cancer in the GETUG-AFU 15 Phase 3 Trial.

Eur Urol 2018 05 23;73(5):696-703. Epub 2017 Oct 23.

Medical Oncology Department, Clinique Saint-Jean Languedoc, Toulouse, France.

Background: Androgen deprivation therapy (ADT) plus docetaxel is the standard of care in fit men with metastatic castration-naive prostate cancer (mCNPC) following results from GETUG-AFU 15, CHAARTED, and STAMPEDE. No data are available on the efficacy of treatments used for metastatic castration-resistant prostate cancer (mCRPC) in men treated upfront with ADT plus docetaxel for mCNPC.

Objective: To investigate the efficacy and tolerance of subsequent treatments in patients treated upfront with chemo-hormonal therapy for mCNPC.

Design, Setting, And Participants: Retrospective data from the GETUG-AFU 15 phase 3 trial were collected for treatments received for mCRPC.

Outcome Measurements And Statistical Analysis: For the first three lines of salvage treatment for mCRPC we investigated the biochemical progression-free survival, maximum prostate-specific antigen (PSA) decline, overall survival, and tolerance.

Results And Limitations: Overall, 245 patients received at least one treatment for mCRPC. For docetaxel used in first-line, a PSA decline ≥50% was observed in 25/66 (38%) and in 4/20 patients (20%) who had received upfront ADT alone and ADT plus docetaxel (p=0.14). The median biochemical progression-free survival was 6.0 mo (95% confidence interval: 3.6-7.7) and 4.1 mo (95% confidence interval: 1.3-4.9), respectively. For docetaxel used in first- or second-line, a PSA decline ≥50% was observed in 36/80 (45%) and in 4/29 patients (14%) who had received upfront ADT alone and ADT plus docetaxel (p=0.07). PSA declines ≥50% were observed with bicalutamide in 12/28 (43%) and 4/23 patients (17%) who had received upfront ADT alone and ADT plus docetaxel. Among men treated upfront with ADT plus docetaxel who received abiraterone or enzalutamide for mCRPC, 10/19 patients (53%) achieved a PSA decline ≥50%. Few grade 3-4 events occurred. Study limitations include the observational design and retrospective characteristics of this analysis, without standardized therapeutic salvage protocols, and the limited number of patients in some of the treatment subgroups.

Conclusions: Docetaxel rechallenge following progression to mCRPC after upfront ADT plus docetaxel for mCNPC was active only in a limited number of patients. Available data on abiraterone and enzalutamide support maintained efficacy in this setting. The lack of standardized therapeutic protocols for men developing mCRPC limits the comparability between patients.

Patient Summary: Rechallenging docetaxel at castration-resistance was active only in a limited number of patients treated upfront with chemo-hormonal therapy for metastatic castration-naive prostate cancer. Anticancer activity was suggested with abiraterone or enzalutamide in this setting.
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May 2018

Utility of serum anti-cetuximab immunoglobulin E levels to identify patients at a high risk of severe hypersensitivity reaction to cetuximab.

Br J Clin Pharmacol 2017 03 24;83(3):623-631. Epub 2016 Oct 24.

Medical Oncology Department, Centre François Baclesse, Caen, France.

Aim: Cetuximab is an anti-epidermal growth factor receptor antibody used for the treatment of metastatic colorectal cancer and head and neck cancer. Hypersensitivity reactions (HSRs) are associated with cetuximab use. The aim of the study was to evaluate the utility of anti-cetuximab immunoglobulin E (IgE) detection in order to identify patients at risk of HSR to cetuximab.

Methods: We included patients ready to receive a first cetuximab infusion in a prospective cohort carried out at nine French centres. Pretreatment anti-cetuximab IgE levels were measured. We compared the proportion of severe HSRs in the low anti-cetuximab IgE levels (≤29 IgE arbitrary units) subgroup with that in a historical cohort of 213 patients extracted from a previous study.

Results: Of the 301 assessable patients (mean age: 60.9 ± 9.3 years, head-and-neck cancer: 77%), 66 patients (22%) had high anti-cetuximab IgE levels, and 247 patients received cetuximab (including 38 with high anti-cetuximab levels). Severe HSRs occurred in eight patients (five grade 3 and three grade 4). The proportion of severe HSRs was lower in the low anti-cetuximab IgE levels subgroup vs. the historical cohort (3/209 [1.4%] vs. 11/213 [5.2%], odds ratio, 0.27, 95% confidence interval, 0.07-0.97), and higher in high vs. low anti-cetuximab IgE levels subgroup (5/38 [13.2%] vs. 3/209 [1.4%]; odds ratio, 10.4, 95% confidence interval, 2.4-45.6). Patients with severe HSRs had higher anti-cetuximab IgE levels than patients without reaction (median, 45 vs. 2 IgE arbitrary units, P = 0.006).

Conclusions: Detection of pretreatment anti-cetuximab IgE is feasible and helpful to identify patients at risk of severe cetuximab-induced HSRs.
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March 2017

Vandetanib for the treatment of advanced medullary thyroid cancer outside a clinical trial: results from a French cohort.

Thyroid 2015 Apr 18;25(4):386-91. Epub 2015 Feb 18.

1 Department of Nuclear Medicine, Hôpital Saint Louis , Paris, France .

Background: A randomized phase III trial demonstrated that vandetanib treatment is effective in patients with metastatic medullary thyroid cancer (MTC), leading to regulatory approval, but its use may be associated with toxicities that require specific monitoring and management. The objective of the present study performed in France was to describe the toxicity profile and efficacy of vandetanib treatment when given outside any trial.

Methods: Sixty-eight patients were treated with vandetanib in the frame of a temporary use authorization (ATU) in France from August 2010 to February 2012, when the drug was available on request for patients with locally advanced or metastatic MTC. Patients were registered by the French health authorities, and characteristics, treatment parameters, toxicity profile, and efficacy were retrospectively reviewed. Eight patients were excluded from the analysis because vandetanib treatment was not administered (n=3), had been given in a trial before ATU (n=3), or was given for a non-MTC cancer (n=2).

Results: Data from the 60 MTC patients were analyzed. Mean age was 58 years (range 11-83 years), 39 patients were male, and six had hereditary MTC. Fifty-six (93%) had metastatic disease in the mediastinum (82%), bones (65%), liver (53%), or lung (53%), and four had only locally advanced disease. At the time of study evaluation, with a median follow-up of 20 months and a median duration of treatment of 9.7 months (range 0.3-36 months), 15 patients were continuing vandetanib treatment (range 18-36 months). Median progression-free survival was 16.1 months. Twenty-five patients discontinued treatment for disease progression (range 0.3-29 months). Best tumor response was a complete response in one patient, a partial response in 12 (20%), stable disease in 33 (55%), and progression in seven patients (12%). All patients had at least one adverse event (AE) during treatment. The main AEs were skin toxicity, diarrhea, and asthenia. Sixteen patients (27%) discontinued treatment for toxicity, and one patient died from vandetanib-induced cardiac toxicity.

Conclusions: Vandetanib is an effective option for patients with advanced MTC. AEs should be monitored carefully and should be minimized by educating both patients and care providers and by applying symptomatic treatment and dose reduction.
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April 2015

Prognostic Factors for Survival in Noncastrate Metastatic Prostate Cancer: Validation of the Glass Model and Development of a Novel Simplified Prognostic Model.

Eur Urol 2015 Aug 30;68(2):196-204. Epub 2014 Sep 30.

Medical Oncology Department, Clinique Saint-Jean Languedoc, Toulouse, France.

Background: The Glass model developed in 2003 uses prognostic factors for noncastrate metastatic prostate cancer (NCMPC) to define subgroups with good, intermediate, and poor prognosis.

Objective: To validate NCMPC risk groups in a more recently diagnosed population and to develop a more sensitive prognostic model.

Design, Setting, And Participants: NCMPC patients were randomized to receive continuous androgen deprivation therapy (ADT) with or without docetaxel in the GETUG-15 phase 3 trial. Potential prognostic factors were recorded: age, performance status, Gleason score, hemoglobin (Hb), prostate-specific antigen, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), metastatic localization, body mass index, and pain.

Outcome Measurements And Statistical Analysis: These factors were used to develop a new prognostic model using a recursive partitioning method. Before analysis, the data were split into learning and validation sets. The outcome was overall survival (OS).

Results And Limitations: For the 385 patients included, those with good (49%), intermediate (29%), and poor (22%) prognosis had median OS of 69.0, 46.5 and 36.6 mo (p=0.001), and 5-yr survival estimates of 60.7%, 39.4%, and 32.1%, respectively (p=0.001). The most discriminatory variables in univariate analysis were ALP, pain intensity, Hb, LDH, and bone metastases. ALP was the strongest prognostic factor in discriminating patients with good or poor prognosis. In the learning set, median OS in patients with normal and abnormal ALP was 69.1 and 33.6 mo, and 5-yr survival estimates were 62.1% and 23.2%, respectively. The hazard ratio for ALP was 3.11 and 3.13 in the learning and validation sets, respectively. The discriminatory ability of ALP (concordance [C] index 0.64, 95% confidence interval [CI] 0.58-0.71) was superior to that of the Glass risk model (C-index 0.59, 95% CI 0.52-0.66). The study limitations include the limited number of patients and low values for the C-index.

Conclusion: A new and simple prognostic model was developed for patients with NCMPC, underlying the role of normal or abnormal ALP.

Patient Summary: We analyzed clinical and biological factors that could affect overall survival in noncastrate metastatic prostate cancer. We showed that normal or abnormal alkaline phosphatase at baseline might be useful in predicting survival.
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August 2015

Patients' self-assessment versus investigators' evaluation in a phase III trial in non-castrate metastatic prostate cancer (GETUG-AFU 15).

Eur J Cancer 2014 Mar 11;50(5):953-62. Epub 2014 Jan 11.

Medical Oncology, Institut Jean Godinot, Reims, France.

Background: Toxicity, which is a key parameter in the evaluation of cancer treatments, can be underestimated by clinicians. We investigated differences between patients and physicians in reporting adverse events of androgen deprivation therapy (ADT) with or without docetaxel in a multicentre phase III trial in non-castrate metastatic prostate cancer.

Methods: The 385 patients included were invited to complete a 26-symptom questionnaire 3 and 6 months after the start of treatment, among which eighteen symptoms were also assessed by physicians, reported in medical records and graded using the Common Toxicity Criteria of the National Cancer Institute. Positive and negative agreements as well as Kappa concordance coefficients were computed.

Findings: Data were available for 220 and 165 patients at 3 and 6 months respectively. Physicians systematically under-reported patients' symptoms. Positive agreement rates (at respectively 3 and 6 months) for the five most commonly reported symptoms were: 61.0% and 64.3% hot flushes, 50.0% and 43.6% fatigue, 29.4% and 31.1% sexual dysfunction, 24.4% and 14.4% weigh gain/loss, 16.7% and 19.3% for joint/muscle pain. For symptoms most frequently reported as disturbing or very disturbing by patients, the clinicians' failure to report them ranged from 50.8% (hot flushes) to 89.5% (joint/muscle pain) at 3 months, and from 48.2% (hot flushes) to 88.4% (joint/muscle pain) at 6 months.

Interpretation: Physicians often failed to report treatment-related symptoms, even the most common and disturbing ones. Patients' self-evaluation of toxicity should be used in clinical trials to improve the process of drug assessment in oncology.

Funding: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, Astra-Zeneca, and Amgen.
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March 2014

Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors.

BMC Cancer 2013 Apr 2;13:172. Epub 2013 Apr 2.

INSERM CIC-P803, CHU de Dijon, Batiment du Pr Marion, 14 rue Gaffarel, BP77908, 21079, Dijon Cedex, France.

Background: Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on Toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was conducted to determine the maximum tolerated dose, the recommended phase II dose and biological response associated with OM-174 administered as intravenous infusion.

Methods: Patients received OM-174 twice weekly for a total of 5, 10 or 15 injections of either 600, 800 or 1000 μg/m(2). Blood samples for pharmacokinetic analysis and cytokine dosages were collected. NK cells activity and Toll-like receptors 4 polymorphism analysis were also performed.

Results: Seventeen patients were included. The highest dose administered was 1000 μg/m(2) repeated in 15 injections. The most common toxicities were a chills, fever, nausea/vomiting, diarrhea, fatigue and headache. No patient experienced haematological side effects. As no dose limiting toxicity was observed, despite a grade 3 respiratory complication, the maximal tolerated dose and recommended dose were not established. Three patients exhibited disease stabilization with a mean duration of 4 months. Pharmacokinetic profile of OM-174 was characterized by a low distribution volume and clearance. Analysis of TLR 4 polymorphysm showed that most (16/17) patients carried the wild type alleles. A progressive increase in NK cell number and activity was observed only in patients receiving 1000 μg/m(2) of OM-174. A peak of IL-8 and IL-10 concentrations were observed after each OM-174 injection. Peaks of TNF-alpha and IL-6 concentrations were detected after the first infusion and decreased progressively suggesting tolerance.

Conclusion: OM-174 therapy was well tolerated at biologically active concentrations. Whereas the recommended dose was not determined, further studies are planned in combination with chemotherapy as animal models suggest a strong synergistic antitumor effect.

Trial Registration: NCT01800812 ( Identifier).
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April 2013

Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.

Lancet Oncol 2013 Feb 8;14(2):149-58. Epub 2013 Jan 8.

Medical Oncology and Biostatistics, Institut Paoli-Calmettes, Marseille, France.

Background: Early chemotherapy might improve the overall outcomes of patients with metastatic non-castrate (ie, hormone-sensitive) prostate cancer. We investigated the effects of the addition of docetaxel to androgen-deprivation therapy (ADT) for patients with metastatic non-castrate prostate cancer.

Methods: In this randomised, open-label, phase 3 study, we enrolled patients in 29 centres in France and one in Belgium. Eligible patients were older than 18 years and had histologically confirmed adenocarcinoma of the prostate and radiologically proven metastatic disease; a Karnofsky score of at least 70%; a life expectancy of at least 3 months; and adequate hepatic, haematological, and renal function. They were randomly assigned to receive to ADT (orchiectomy or luteinising hormone-releasing hormone agonists, alone or combined with non-steroidal antiandrogens) alone or in combination with docetaxel (75 mg/m(2) intravenously on the first day of each 21-day cycle; up to nine cycles). Patients were randomised in a 1:1 ratio, with dynamic minimisation to minimise imbalances in previous systemic treatment with ADT, chemotherapy for local disease or isolated rising concentration of serum prostate-specific antigen, and Glass risk groups. Patients, physicians, and data analysts were not masked to treatment allocation. The primary endpoint was overall survival. Efficacy analyses were done by intention to treat. This trial is registered with, number NCT00104715.

Findings: Between Oct 18, 2004, and Dec 31, 2008, 192 patients were randomly allocated to receive ADT plus docetaxel and 193 to receive ADT alone. Median follow-up was 50 months (IQR 39-63). Median overall survival was 58·9 months (95% CI 50·8-69·1) in the group given ADT plus docetaxel and 54·2 months (42·2-not reached) in that given ADT alone (hazard ratio 1·01, 95% CI 0·75-1·36). 72 serious adverse events were reported in the group given ADT plus docetaxel, of which the most frequent were neutropenia (40 [21%]), febrile neutropenia (six [3%]), abnormal liver function tests (three [2%]), and neutropenia with infection (two [1%]). Four treatment-related deaths occurred in the ADT plus docetaxel group (two of which were neutropenia-related), after which the data monitoring committee recommended treatment with granulocyte colony-stimulating factor. After this recommendation, no further treatment-related deaths occurred. No serious adverse events were reported in the ADT alone group.

Interpretation: Docetaxel should not be used as part of first-line treatment for patients with non-castrate metastatic prostate cancer.

Funding: French Health Ministry and Institut National du Cancer (PHRC), Sanofi-Aventis, AstraZeneca, and Amgen.
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February 2013

Phase I dose-escalation study of intravenous aflibercept in combination with docetaxel in patients with advanced solid tumors.

Clin Cancer Res 2012 Mar 18;18(6):1743-50. Epub 2012 Jan 18.

Centre Georges François Leclerc, France.

Purpose: This phase I study cohort investigated aflibercept in combination with docetaxel in patients with advanced solid tumors.

Materials And Methods: Eligible patients had metastatic or nonresectable cancer for which docetaxel was considered appropriate. Patients received intravenous aflibercept (either 2, 4, 5, 6, 7, or 9 mg/kg) with docetaxel (75 mg/m(2)) on day 1 every 3 weeks until disease progression or unacceptable toxicity. Primary objectives were to evaluate dose-limiting toxicities (DLT) during cycle 1 and to determine the aflibercept recommended phase II trial dose (RP2D) for combination with docetaxel. Pharmacokinetics, tolerability, and antitumor activity were also investigated.

Results: Fifty-four patients (mean age, 56 y) were enrolled. Most had prior chemotherapy (96%) and most (24.1%) had breast cancer. In the dose-escalation phase (n = 34), there were three DLTs: grade 4 neutropenic infection (2 mg/kg), grade 3 dysphonia (7 mg/kg), and grade 2 hypertension (9 mg/kg). An excess of free-over-bound aflibercept was observed at doses of 5 mg/kg or more. The pharmacokinetics of aflibercept and docetaxel were not modified by coadministration. Aflibercept (6 mg/kg) was defined as the RP2D based on DLT and pharmacokinetic data. Overall, the most frequent grade 3/4 adverse events (AE) were neutropenia (85.2%), leukopenia (74.1%), hypertension (18.5%), and stomatitis (16.7%). AEs associated with vascular endothelial growth factor blockade included epistaxis (all grades, 83.3%), proteinuria (68.5%), dysphonia (68.5%), and hypertension (53.7%). Seven patients had partial responses, and 32 patients had stable disease (>3 months in 18 patients).

Conclusion: On the basis of findings from this study, aflibercept (6 mg/kg) was the dose recommended for further clinical development.
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March 2012

Visceral fat area as a new independent predictive factor of survival in patients with metastatic renal cell carcinoma treated with antiangiogenic agents.

Oncologist 2011 6;16(1):71-81. Epub 2011 Jan 6.

Centre Georges François Leclerc, Centre de Recherche INSERM 866, Faculté de Médecine, 7 Boulevard Jeanne d'Arc, 21000 Dijon, France.

Purpose. A better identification of patients who are more likely to benefit from vascular endothelial growth factor-targeted therapy is warranted in metastatic renal cell carcinoma (mRCC). As adipose tissue releases angiogenic factors, we determined whether parameters such as visceral fat area (VFA) were associated with outcome in these patients. Experimental Design. In 113 patients with mRCC who received antiangiogenic agents (bevacizumab, sunitinib, or sorafenib) (n = 64) or cytokines (n = 49) as first-line treatment, we used computed tomography to measure VFA and subcutaneous fat area (SFA). We evaluated associations linking body mass index (BMI), SFA, and VFA to time to progression (TTP) and overall survival (OS). Results. High SFA and VFA values were significantly associated with shorter TTP and OS. By multivariate analysis, high VFA was independently associated with shorter TTP and OS. These results were internally validated using bootstrap analysis. By contrast, VFA was not associated with survival in the cytokine group. In the whole population, interaction between VFA and treatment group was significant for TTP and OS, thereby confirming the results. Conclusion. Our study provides the first evidence that high VFA could be a predictive biomarker from shorter survival in patients given first-line antiangiogenic agents for mRCC.
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June 2011

Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure.

Anticancer Res 2010 Oct;30(10):4317-23

Department of Medical Oncology, Georges François Leclerc Center, Centre de Recherche INSERM 866, Faculté de Médecine, Dijon, France.

Background: There is currently no standard of treatment for patients with hormone refractory prostate cancer (HRPC) after failure of docetaxel-based chemotherapy. The purpose of this study was to assess the anticancer activity and tolerance of metronomic cyclophosphamide prednisolone combination in this setting.

Patients And Methods: From 2005 to 2010, patients with HRPC who failed at least docetaxel-based chemotherapy were proposed metronomic cyclophosphamide-prednisolone regimen, and were prospectively registered. Twenty-three patients received 50 mg cyclophosphamide and 10 mg prednisolone per os daily until disease progression. Treatment tolerance and efficacy on PSA decrease and pain were studied.

Results: Metronomic cyclophosphamide prednisolone was safe, well tolerated, and demonstrated interesting clinical activity, yielding a prostate specific antigen decrease by ≥50% in 26% of patients and decrease by ≥30% in 48% of patients, but also favorable palliative effects on pain in 43% of patients. The median progression-free survival was 6 months (95% CI: 4-8 months) and the median overall survival was 11 months (95% CI: 7-19 months).

Conclusion: For this patient population, low dose metronomic cyclophosphamide prednisolone might be a viable alternative. Its convenient oral administration, low cost, and lack of toxicity justify further studies alone, or in combination with other agents in HRPC patients.
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October 2010

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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January 2010

Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer.

Breast 2008 Feb 14;17(1):36-41. Epub 2007 Aug 14.

Department of Medical Oncology, Centre Georges-François Leclerc, 1 rue du Professeur Marion, 21000 Dijon, France.

The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand-foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally.
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February 2008

Feasibility of using intraperitoneal epinephrine and cisplatin in patients with advanced peritoneal carcinomatosis.

Anticancer Drugs 2006 Nov;17(10):1211-7

GF Leclerc Regional Anticancer Center, Dijon Cedex, France.

Intraperitoneal epinephrine above 1 mg/l concentration has been shown to enhance the intratumoral accumulation and antitumor activity of intraperitoneal cisplatin in rats with advanced peritoneal carcinomatosis. The aim of this study was to determine the tolerance of intraperitoneal epinephrine combined with intraperitoneal cisplatin in patients with advanced peritoneal carcinomatosis (17 ovarian cancers, one peritoneal mesothelioma). Intraperitoneal epinephrine (1-5 mg/l) and cisplatin (50 mg/l; 100 mg total dose) were infused in 2 l of saline solution over 2 h. The maximal tolerated concentration of intraperitoneal epinephrine was not reached at 5 mg/l. Cardiovascular symptoms were infrequent and not strictly related to the epinephrine concentration. Tumor responses were obtained in some patients with disease resistant to intravenous platinum compounds. This work demonstrates for the first time that intraperitoneal epinephrine at sufficient concentration enhances the cisplatin effect and can be safely infused into the peritoneal cavity of patients with peritoneal carcinomatosis. The greatest limitation was abdominal pain and limited intraperitoneal distribution of the peritoneal fluid in this closed-abdomen procedure.
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November 2006

Are older French patients as willing as older American patients to undertake chemotherapy?

J Clin Oncol 2003 Sep 21;21(17):3214-9. Epub 2003 Jul 21.

H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Purpose: A view often held in Europe is that older Europeans are less willing than older Americans to undertake chemotherapy. This study assesses whether this view is valid.

Patients And Methods: Three-hundred twenty outpatients aged 70 years and older were interviewed via anonymous questionnaires: French patients with and without cancer and American patients with and without cancer. The response rate was 61% (195 of 320 questionnaires). Ages ranged from 70 to 95 years (29% aged 80 years and older). Two scenarios were presented: a strong chemotherapy (platinum/taxane combination-like) and a milder chemotherapy (weekly vinorelbine-like). The options were to refuse chemotherapy or to accept for a threshold chance of cure, of life prolongation, or of symptom relief. Functional status, education, self-rated health, and depression were controlled for.

Results: French noncancer patients (34%) were less willing to accept the strong chemotherapy than French cancer patients (77.8%), American noncancer patients (73.8%), and American cancer patients (70.5%) (P <.001 for each pair). This was also true for the moderate chemotherapy (67.9% v 100%, 95.2%, and 88.5%, respectively; P <.001). Age and sex did not correlate with response, but self-rated health, cancer status, and nationality did. Thresholds varied from patient to patient.

Conclusion: Whereas older French people without cancer are more reluctant than older Americans to envision chemotherapy, older cancer patients in both countries have the same amenability to treatment. Chemotherapy options should be fully discussed with older cancer patients, given that most are willing to consider them.
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September 2003