Publications by authors named "Nicolas Penel"

256 Publications

Starting Imatinib at 400 mg Daily in Patients with Gastrointestinal Stromal Tumors Harboring KIT Exon 9 Mutations: A Retrospective, Multicenter Study.

Target Oncol 2021 Jul 5;16(4):485-492. Epub 2021 Jun 5.

Department of Cancer Medicine, Gustave Roussy, Villejuif, France.

Background: Retrospective analyses suggest that patients with advanced KIT exon 9-mutated gastrointestinal stromal tumors (GISTs) receiving imatinib 800 mg (rather than 400 mg) daily have better outcomes. In the adjuvant setting, the question of the optimal dose of imatinib remains unsettled.

Objective: We aimed to retrospectively assess the activity of imatinib 400 mg in both the adjuvant and the advanced settings.

Patients And Methods: We performed a multicenter study of patients with KIT exon 9-mutated GIST starting imatinib at 400 mg daily. We examined the relapse-free survival (RFS) among high-risk patients either receiving or not receiving adjuvant imatinib. In patients with advanced disease, progression-free survival (PFS, progression under imatinib 400 mg), time to imatinib failure (TIF, progression under imatinib 400, then 800 mg upon first progression), and overall survival (OS) were analyzed.

Results: In the post-operative setting (n = 37), 20 patients received adjuvant imatinib. Median RFS in high-risk patients receiving adjuvant imatinib (n = 14) was not reached (95% CI 17.5-46.6) versus 13.6 months (95% CI 4.7-13.6) for those who did not (p = 0.37), after a median follow-up of 58 months. RFS at 36 months was 63% (30.3-96.6) versus 40% (95% CI 0-82.9), p = 0.2. In advanced disease (n = 28), median PFS, TIF and OS were 12.7 months (95% CI 6.1-18.2), 21.0 months (95% CI 17.4-28.1) and 47.0 months (95% CI 33.5-69.2), respectively.

Conclusions: Despite the limitations of a retrospective analysis and the small number of patients, the benefit of adjuvant imatinib 400 mg daily in high-risk patients appeared relevant. Patients with advanced disease receiving imatinib 400 mg with subsequent dose escalation had a TIF similar to that observed with an initial dose of 800 mg. Intra-patient dose escalation in this setting might be an option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11523-021-00820-7DOI Listing
July 2021

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BMC Cancer 2021 May 29;21(1):631. Epub 2021 May 29.

Lille University Medical School and Centre Oscar Lambret, Lille, France.

Background: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients.

Methods: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery.

Results: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities.

Conclusions: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-021-08393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164290PMC
May 2021

Desmoid-type fibromatosis: toward a holistic management.

Curr Opin Oncol 2021 Jul;33(4):309-314

Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam.

Purpose Of Review: Desmoid-type fibromatosis, a rare locally aggressive fibroblastic proliferation, is a treatment challenge. This review aimed to explore recent data about the management of desmoid-type fibromatosis.

Recent Findings: New data underline the role of kinases and ɣ-secretase in stimulating cell proliferation and invasiveness in desmoid-type fibromatosis. This explains the proven activity of multikinase inhibitors (sorafenib or pazopanib) in the management of desmoid-type fibromatosis or the emerging role of a ɣ-secretase inhibitor. An international guideline for management was recently published, and this guideline take into account patient point of view. Lastly, recent studies highlight the multidimensional burden of desmoid-type fibromatosis, particularly health-related quality of life (HRQoL).

Summary: Active surveillance with planned MRI is the first-line management in desmoid-type fibromatosis. A site-specific and stepwise approach should be considered for progressive desmoid-type fibromatosis. Further, a risk-benefit analysis that considers the side effects and long-term sequelae should be conducted before deciding to start any treatment. A less aggressive approach should be considered. Multikinase inhibitors are effective, but their tolerability and side effects should be discussed with the patients. The symptoms and HRQoL should be integrated in decision-making. Desmoid-type fibromatosis patients should be offered support to address their needs supportive care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCO.0000000000000743DOI Listing
July 2021

"TNM" at study entry in phase I trials.

Bull Cancer 2021 Jun 7;108(6):671-672. Epub 2021 May 7.

University Bordeaux, Inserm, Bordeaux Population Health Research Center, ISPED, Université de Bordeaux, Case 11, 146, rue Léo-Saignat, 33076 Bordeaux cedex, France; Institut Bergonie, Inserm CIC 1401, Clinical and Epidemiological Research Unit, 351 cours de la Libération, 33405 Talence cedex, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2021.01.020DOI Listing
June 2021

Cost-Utility Analysis of Continuation Versus Discontinuation of First-Line Chemotherapy in Patients With Metastatic Squamous-Cell Esophageal Cancer: Economic Evaluation Alongside the E-DIS Trial.

Value Health 2021 May 26;24(5):676-682. Epub 2021 Mar 26.

Gustave Roussy, Université Paris-Saclay, Service de Biostatistique et d'Epidémiologie, Villejuif, France; Université Paris-Saclay, Paris-Sud University, Villejuif, France. Electronic address:

Objectives: Continuous chemotherapy has been used to treat patients with metastatic esophageal squamous cell carcinoma (mESCC), despite weak evidence supporting a clinical benefit, associated side effects for the patients, and unjustified medical costs. In the French setting, we conducted a cost-utility analysis alongside the randomized E-DIS trial (NCT01248299), which compared first-line fluorouracil/platinum-based chemotherapy continuation (CT-CONT) to CT discontinuation (CT-DISC) in progressive-free patients after an initial 6-week treatment phase.

Methods: A partitioned survival analysis was performed using patient-level data collected during the trial for survival outcomes, quality of life (EQ-5D-3L), and medical costs. The mean quality-adjusted life-years (QALYs) and medical costs were estimated over an 18-month period to assess the incremental net monetary benefit and incremental cost-effectiveness ratio. Uncertainty was handled using the nonparametric bootstrap and univariate analysis. Sixty-seven patients with mESCC were randomized and included in the cost-utility analysis.

Results: On average, CT-CONT slightly decreased the number of QALYs (-0.038) and increased the cost per patient (+ €1177). At a willingness-to-pay threshold of €50 000/QALY, the incremental net monetary benefit was negative (-€3077 [95% confidence interval: -6564; 4359]), and the incremental cost-effectiveness ratio was -30 958€/QALY (CT-CONT dominated). The probability of the CT-CONT treatment option being cost-effective at a willingness-to-pay threshold of €50 000/QALY, compared to CT-DISC, was 29%.

Conclusions: CT-DISC may be considered as an alternative therapeutic option to CT-CONT in patients with mESCC who have stable disease after an initial chemotherapy treatment phase. A continuous chemotherapy could indeed reduce the number of QALYs because of the disutility associated with the continuous treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jval.2020.11.017DOI Listing
May 2021

Efficacy and safety of regorafenib in patients with metastatic or locally advanced chondrosarcoma: Results of a non-comparative, randomised, double-blind, placebo controlled, multicentre phase II study.

Eur J Cancer 2021 Jun 22;150:108-118. Epub 2021 Apr 22.

Medical Oncology Department, Centre Léon Bérard, Lyon, France.

Background: This multi-cohort trial explored the efficacy and safety of regorafenib for patients with advanced sarcomas of bone origin; this report details the cohort of patients with metastatic or locally advanced chondrosarcoma (CS), progressing after prior chemotherapy.

Patients And Methods: Patients with CS, progressing despite prior standard therapy, were randomised (2:1) to receive regorafenib or placebo. Patients on placebo could crossover to receive regorafenib after centrally confirmed progressive disease. The primary endpoint was progression-free rate (PFR) at 12 weeks. With one-sided α of 0.05, and 80% power, at least 16/24 progression-free patients at 12 weeks were needed for success (P0 = 50%, P1 = 75%).

Results: From September 2014 to February 2019, 46 patients were included in the CS cohort, and 40 patients were evaluable for efficacy: 16 on placebo and 24 on regorafenib. Thirteen patients (54.2%; 95% CI [35.8%-[) were non-progressive at 12 weeks on regorafenib versus 5 (31.3%; 95% CI [13.2%-[);) on placebo. Median PFS was 19.9 weeks on regorafenib, and 8.0 on placebo. Fourteen placebo patients crossed over to regorafenib after progression. The most common grade ≥3 treatment-related adverse events on regorafenib included hypertension (12%), asthenia (8%), thrombocytopenia (8%) and diarrhoea (8%). One episode of fatal liver dysfunction occurred on regorafenib.

Conclusion: Although the primary endpoint was not met statistically in this small randomised cohort, there is modest evidence to suggest that regorafenib might slow disease progression in patients with metastatic CS after the failure of prior chemotherapy.

Clinical Trial Registration: The trial is registered at ClinicalTrials.gov (NCT02389244).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.03.039DOI Listing
June 2021

[Manual for "Junior Doctors" in medical oncology].

Bull Cancer 2021 Apr 19;108(4):377-384. Epub 2021 Mar 19.

Hôpital Pitié-Salpétrière, Collège national des enseignants en cancérologie (CNEC), service d'oncologie médicale, 47-83, boulevard de l'Hôpital, 75013 Paris, France.

The reform of medical residency introduced in 2017 established the position of Junior Doctor, for its last phase, called the consolidation phase. Its goal is the increasing and supervised autonomy of the resident, in order to better support the transition toward senior practitioner. It appears necessary to define proper guidelines on the status and the specific role of Junior Doctor in medical oncology, in order to help the implementation of the reform of the 3rd cycle. This document is the result of a collaboration between AERIO and CNEC, that respectively represent medical oncology residents and university teachers. It aims to advise and guide local practices, without being compulsory, before the arrival of the first Junior Doctors in November 2021. It explains the Junior Doctors' principal jobs: consultation, multidisciplinary meeting, day clinic, hospitalization, clinical research, quality policy and teaching.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2021.02.002DOI Listing
April 2021

Systemic therapies in advanced epithelioid haemangioendothelioma: A retrospective international case series from the World Sarcoma Network and a review of literature.

Cancer Med 2021 04 13;10(8):2645-2659. Epub 2021 Mar 13.

Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale Tumori, Milano, Italy.

Background: This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra-rare sarcoma, marked by WWTR1-CAMTA1 or YAP1-TFE3 fusions.

Methods: Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method.

Results: Overall, 73 patients were included; 21 had more than one treatment. Thirty-three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m-) PFS and m-OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m-PFS and m-OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m-PFS and m-OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF-α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m-PFS and m-OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported.

Conclusion: Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026938PMC
April 2021

[Withholding or withdrawing life-sustaining treatments in acute oncology situations: History and regulatory aspects in France].

Bull Cancer 2021 Apr 4;108(4):415-423. Epub 2021 Mar 4.

Centre Oscar Lambret, département d'oncologie médicale, 3, rue Frédéric Combemale, 59000 Lille, France.

The management of oncology patients, especially hospitalized patients, can lead to almost daily discussions regarding therapeutic limitations. Here, we review the history and propose a summary of the texts framing the notion of "withholding and withdrawing life-sustaining treatment" in oncology practice in France. This decision is regulated by the Claeys-Léonetti Law of February 2, 2016 recommending a collegial discussion and its documentation in the medical record. The decision to withhold or withdraw life-sustaining treatments is the subject of discussion between the patient, his physicians and his family and may take place at any time during his management. The work of intensive-care physicians provides many useful recommendations for acute oncology situations, however articles specific for oncology practice are scarce; this is a topic that oncologists must take up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2020.11.020DOI Listing
April 2021

Nationwide incidence of sarcomas and connective tissue tumors of intermediate malignancy over four years using an expert pathology review network.

PLoS One 2021 25;16(2):e0246958. Epub 2021 Feb 25.

Department of Biopathology, Institut Claudius Regaud et Institut Universitaire du Cancer de Toulouse-Oncopôle, Toulouse, France.

Background: Since 2010, nationwide networks of reference centers for sarcomas (RREPS/NETSARC/RESOS) collected and prospectively reviewed all cases of sarcomas and connective tumors of intermediate malignancy (TIM) in France.

Methods: The nationwide incidence of sarcoma or TIM (2013-2016) was measured using the 2013 WHO classification and confirmed by a second independent review by expert pathologists. Simple clinical characteristics, yearly variations and correlation of incidence with published clinical trials are presented and analyzed.

Results: Over 150 different histological subtypes are reported from the 25172 patients with sarcomas (n = 18712, 74,3%) or TIM (n = 6460, 25.7%), with n = 5838, n = 6153, n = 6654, and n = 6527 yearly cases from 2013 to 2016. Over these 4 years, the yearly incidence of sarcomas and TIM was therefore 70.7 and 24.4 respectively, with a combined incidence of 95.1/106/year, higher than previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of tumors. Only GIST, as a single entity had a yearly incidence above 10/106/year. There were respectively 30, 64 and 66 different histological subtypes of sarcomas or TIM with an incidence ranging from 10 to 1/106, 1-0.1/106, or < 0.1/106/year respectively. The 2 latter incidence groups represented 21% of the patients with 130 histotypes. Published phase III and phase II clinical trials (p<10-6) are significantly higher with sarcomas subtypes with an incidence above 1/106 per.

Conclusions: This nationwide registry of sarcoma patients, with exhaustive histology review by sarcoma experts, shows that the incidence of sarcoma and TIM is higher than reported, and that tumors with a very low incidence (1<106/year) are less likely to be included in clinical trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246958PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7906477PMC
February 2021

Major impact of COVID-19 national containment on activities in the French northern comprehensive cancer center.

Med Oncol 2021 Feb 17;38(3):28. Epub 2021 Feb 17.

Centre Oscar Lambret, Lille, France.

The SARS-CoV-2 pandemic has significantly impacted cancer patient management. National and local recommendations to reduce SARS-CoV-2 transmission have been applied in a comprehensive cancer center located in Northern France. We prospectively measured key indicators for three successive eight-week periods: directly before, during, and right after the containment (from 16 March to 10 May 2020). Overall, the number of newly diagnosed and referred cancer patients in our hospital steadily increased (1027; 1135 and then 1704; +11% during containment and +50% just after). To reduce patient transportation, teleconsultations were implemented. Teleconsulting activity steadily increased during the three periods (5, 2025, and 2351). However, a marked decrease in the number of surgical procedures was observed (448; 330 and 288; -26% during containment and -13% just after). We observed a slight decrease in the number of radiation therapy sessions (7761; 7328 and 7075; -6% during containment and -3% just after) and in day-hospital cycles of IV systemic treatment (2891; 2736 and 2717; -5% during containment and -1% just after). We observed an increase in the number of patients admitted to palliative care and a dramatic reduction in clinical trial enrollment. During this 24-week period, organizational changes were mainly characterized by an increase in newly diagnosed cancer patient referral and the implementation of protective measures, such as teleconsultations. Activities in cancer surgery have decreased while radiotherapy and chemotherapy activities were stable.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12032-021-01467-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887549PMC
February 2021

Home hospitalization for palliative cancer care: factors associated with unplanned hospital admissions and death in hospital.

BMC Palliat Care 2021 Jan 26;20(1):24. Epub 2021 Jan 26.

Direction of Research and Innovation, Oscar Lambret Center, 3 rue Frédéric Combemale, 59020, Lille, France.

Background: Home hospitalization at the end of life can sometimes be perturbed by unplanned hospital admissions (UHAs, defined as any admission that is not part of a preplanned care procedure), which increase the likelihood of death in hospital. The objectives were to describe the occurrence and causes of UHAs in cancer patients receiving end-of-life care at home, and to identify factors associated with UHAs and death in hospital.

Methods: A retrospective, single-center study (performed at a regional cancer center in the city of Lille, northern France) of advanced cancer patients discharged to home hospitalization between January 2014 and December 2017. We estimated the incidence of UHA over time using Kaplan-Meier method and Kalbfleish and Prentice method. We investigated factors associated with the risk UHA in cause-specific Cox models. We evaluated factors associated with death in hospital in logistic regressions.

Results: One hundred and forty-two patients were included in the study. Eighty-two patients (57.7 %) experienced one or more UHAs, a high proportion of which occurred within 1 month after discharge to home. Most UHAs were related to physical symptoms and were initiated by the patient's family physician. A post-discharge palliative care consultation was associated with a significantly lower incidence of UHAs. Sixty-five patients (47.8 % of the deaths) died in hospital. In a multivariate analysis, living alone and the presence of one or more children at home were associated with death in hospital.

Conclusions: More than 40 % of cancer patients receiving end of life home hospitalization were not readmitted to hospital, reflecting the effectiveness of this type of palliative care setting. However, over half of the UHAs were due to an acute intercurrent event. Our results suggest that more efforts should be focused on anticipating these events at home - primarily via better upstream coordination between hospital physicians and family physicians.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12904-021-00720-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839201PMC
January 2021

[What should we remember from 2020?]

Bull Cancer 2021 Jan 6;108(1):55-66. Epub 2021 Jan 6.

Université de Bordeaux, Inserm U1218, 33000 Bordeaux, France.

The editorial committee of the Bulletin du Cancer is proud to comply with his annual analysis of some of the worldwide updates in oncology that emerge in 2020. We know that all new breakthroughs will not be addressed and apologise for not being comprehensive, but we hope that the topics deciphered herein will bring the reader interesting information in his daily practice in gyneco-oncology, uro-oncology, neuro-oncology, digestive oncology, pneumo-oncology, hemato-oncology, pediatric oncology, or in palliative care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2020.12.002DOI Listing
January 2021

Anti-Angiogenic Agents in Management of Sarcoma Patients: Overview of Published Trials.

Front Oncol 2020 24;10:594445. Epub 2020 Nov 24.

Lille University, Medical School, Lille, France.

We reviewed all fully published clinical trials assessing anti-angiogenic agents in sarcoma patients (last issue, January 13, 2020). Anti-angiogenic macromolecules (e.g., bevacizumab or ombrabulin) provide disappointing results. Many multikinase inhibitors have been assessed with non-randomized phase II trials with limited samples and without stratification according to histological subtypes, therefore interpretation of such trials is very challenging. On the contrary, pazopanib, regorafenib, and sorafenib have been assessed using double-blind placebo-controlled randomized phase II or phase III trials. Compared to placebo, sorafenib demonstrates activity in desmoid-type fibromatosis patients. Based on results of phase 3 trial, pazopanib had obtained approval for treatment of pretreated non-adipocytic soft tissue sarcoma. Regorafenib is currently assessed in several clinical settings and provides significant improvement of progression-free survival in pre-treated non-adipocytic soft tissue sarcoma and in advanced pretreated osteosarcoma. Multikinase inhibitors are a breakthrough in sarcoma management. Many trials are ongoing. Nevertheless, predictive factors are still missing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fonc.2020.594445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732617PMC
November 2020

Assessing Prognostic and Predictive Biomarkers of Regorafenib Response in Patients with Advanced Soft Tissue Sarcoma: REGOSARC Study.

Cancers (Basel) 2020 Dec 12;12(12). Epub 2020 Dec 12.

Direction of Research and Innovation, Centre Oscar Lambret, 59000 Lille, France.

Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46; < 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib ( = 71, 53%) or placebo ( = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers' values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 ( = 24, 18%), and TP53 ( = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763753PMC
December 2020

Is the survival of patients treated with ipilimumab affected by antibiotics? An analysis of 1585 patients from the French National hospital discharge summary database (PMSI).

Oncoimmunology 2020 11 22;9(1):1846914. Epub 2020 Nov 22.

CERIM, ULR 2694 METRICS, Univ. Lille, CHU Lille, Lille, France.

: The gut microbiota has a key role in the regulation of the immune system. Disruption of the gut microbiota's composition by antibiotics might significantly affect the efficacy of immune checkpoint inhibitors. In a study of patients treated with ipilimumab, we sought to assess the relationship between overall survival and in-hospital antibiotic administration. : Patients having been treated with ipilimumab between January 2012 and November 2014 were selected from the French National Hospital Discharge Summary Database. Exposure to antibiotics was defined as the presence of a hospital stay with a documented systemic bacterial infection in the 2 months before or the month after initiation of the patient's first ever course of ipilimumab. The primary outcome was overall survival. : We studied 43,124 hospital stays involving 1585 patients from 97 centers. All patients had received ipilimumab monotherapy for advanced melanoma. Overall, 117 of the 1585 patients (7.4%) were documented as having received systemic antibiotic therapy in hospital during the defined exposure period. The median overall survival time was shorter in patients with infection (6.3 months, vs. 15.4 months in patients without an infection; hazard ratio (HR) = 1.88, 95% confidence interval [1.46; 2.43], = 10). In a multivariate analysis adjusted for covariates, infection was still significantly associated with overall survival (HR = 1.68, [1.30; 2.18], = 10). : In patients treated with ipilimumab for advanced melanoma, infection, and antibiotic administration in hospital at around the time of the patient's first ever course of ipilimumab appears to be associated with significantly lower clinical benefit.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/2162402X.2020.1846914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714497PMC
November 2020

Pharmacogenetic Study of Trabectedin-Induced Severe Hepatotoxicity in Patients with Advanced Soft Tissue Sarcoma.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Centre de Recherches en Cancérologie de Toulouse (CRCT), Inserm UMR1037, 31059 Toulouse, France.

Hepatotoxicity is an important concern for nearly 40% of the patients treated with trabectedin for advanced soft tissue sarcoma (ASTS). The mechanisms underlying these liver damages have not yet been elucidated but they have been suggested to be related to the production of reactive metabolites. The aim of this pharmacogenetic study was to identify genetic variants of pharmacokinetic genes such as CYP450 and ABC drug transporters that could impair the trabectedin metabolism in hepatocytes. Sixty-three patients with ASTS from the TSAR clinical trial (NCT02672527) were genotyped by next-generation sequencing for 11 genes, and genotype-toxicity association analyses were performed with R package SNPassoc. Among the results, c.1249A allele (rs2273697) and intron variant c.-15994T (rs7699188) were associated with an increased risk of severe cytolysis, whereas c.3563A allele had a protective effect, as well as variants rs2032582 and rs1128503 (-value < 0.05). Furthermore, *1 rs776746 (c.6986A > G) increased the risk of severe overall hepatotoxicity ( = 0.012, odds ratio (OR) = 5.75), suggesting the implication of metabolites in the hepatotoxicity. However, these results did not remain significant after multiple analysis correction. These findings need to be validated on larger cohorts of patients, with mechanistic studies potentially being able to validate the functional consequences of these variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12123647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761985PMC
December 2020

[What's new in the management of meningeal solitary fibrous tumor/hemangiopericytoma?]

Bull Cancer 2020 Dec 5;107(12):1260-1273. Epub 2020 Nov 5.

Université de Lille, centre Oscar-Lambret, département d'oncologie médicale, Lille, France.

Meningeal fibrous solitary tumors/hemangiopericytoma are rare and aggressive mesenchymal neoplasms considered as sarcomas. They represent less than 1% of intracranial tumors and derive from the pericytes of Zimmerman which permit capillary contraction. They tend to occur more often in males in the fifth decade. They are often revealed by intracranial hypertension. Some scannographic and MRI characteristics permit to distinguish meningeal fibrous solitary tumor/hemangiopericytoma from other meningeal tumors. Meningeal hemangiopericytoma and fibrous solitary tumors were considered as different entities until 2016. Following the discovery of an identical genetic event, the locus 12q13 chromosome inversion leading to a NAB2-STAT6 fusion with nuclear immunoreactivity for STAT6 protein, the 2016 WHO classification defines these tumors as a single entity. Meningeal fibrous solitary tumors/hemangiopericytoma have a high recurrence rate. Long-term recurrences may occur. Local relapses are more frequent than extracranial metastasis. A multimodal management is recommended to treat a localized disease. It involves a complete resection followed by adjuvant radiotherapy. When local recurrences occur, surgery or stereotactic radiosurgery permit sometimes a local control. Metastatic disease has a poor prognostic and a weak chimiosensitivity. Targeted therapies, like pazopanib, are a hopeful option.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bulcan.2020.09.011DOI Listing
December 2020

Ramucirumab in Combination with Pembrolizumab in Treatment-Naïve Advanced Gastric or GEJ Adenocarcinoma: Safety and Antitumor Activity from the Phase 1a/b JVDF Trial.

Cancers (Basel) 2020 Oct 15;12(10). Epub 2020 Oct 15.

Yale Cancer Center, New Haven, CT 06520, USA.

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and -negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers12102985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7602637PMC
October 2020

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC.

J Thorac Oncol 2021 02 15;16(2):289-298. Epub 2020 Oct 15.

CNIO-H12o Lung Cancer Unit, Hospital Universitario 12 de Octubre, Universidad Complutense & CIBERONC, Madrid, Spain.

Introduction: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324).

Methods: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T cells) and CD274 gene expression.

Results: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry.

Conclusions: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtho.2020.10.004DOI Listing
February 2021

Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol.

BMJ Open 2020 09 23;10(9):e038391. Epub 2020 Sep 23.

Radiation oncology department, Centre de Lutte Contre le Cancer, Centre Francois Baclesse, Caen, France

Introduction: Up to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways.

Methods And Analysis: STEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103.

Trial Registration: The trial is registered on ClinicalTrials.gov (ID: NCT03548428).

Ethics And Dissemination: This study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-038391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513631PMC
September 2020

Switch in use of midazolam for cancer patients during the COVID-19 pandemic.

J Oncol Pharm Pract 2020 10 14;26(7):1817-1818. Epub 2020 Aug 14.

Medical School, Lille University, Lille, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1078155220948929DOI Listing
October 2020

Deleterious effect of ifosfamide in leiomyosarcoma: Convergence of weak signals.

Cancer 2020 10 7;126(20):4614-4615. Epub 2020 Aug 7.

Medical Oncology Department, Oscar Lambret Center, Lille, France.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cncr.33111DOI Listing
October 2020

Bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in advanced squamous cell carcinoma of the head and neck: results from a phase I cohort.

J Immunother Cancer 2020 07;8(2)

Department of Medical Oncology, Centre Oscar Lambret and Lille University Hospital, Lille, France.

Background: We report the clinical activity and safety of bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of the transforming growth factor β (TGF-β)RII receptor (a TGF-β 'trap') fused to a human IgG1 monoclonal antibody blocking programmed death-ligand 1 (PD-L1), in patients with heavily pretreated squamous cell carcinoma of the head and neck (SCCHN).

Methods: In this phase I dose-expansion cohort, patients with advanced SCCHN not amenable to curative therapy that progressed/recurred after platinum therapy in the recurrent/metastatic setting, or <6 months after platinum therapy in the locally advanced setting, received bintrafusp alfa 1200 mg intravenously every 2 weeks. The primary endpoint was confirmed best overall response (BOR; Response Evaluation Criteria for Solid Tumors (RECIST) 1.1) per independent review committee (IRC); other endpoints included BOR per investigator and safety.

Results: As of August 24, 2018, 32 patients had received bintrafusp alfa (median follow-up 86.4 weeks; range 2-97). Per IRC, the confirmed objective response rate (ORR) was 13% (95% CI 4% to 29%; 4 partial responses (PR)); 4 patients had stable disease (SD) (disease control rate 34%; 95% CI 12% to 43%). Per investigator, there were 5 PRs (ORR, 16%), including 2 patients who developed delayed PRs after initial disease increase (total clinical response rate 22%). Responses (ORRs) were observed in patients with PD-L1-positive (12%), PD-L1-negative (17%; 73-10 antibody for immunohistochemistry), human papillomavirus (HPV)-positive (33%) and HPV-negative tumors (5%). Grade 3 treatment-related adverse events (TRAEs) were reported in 11 patients (34%), with no grade 4 TRAEs or treatment-related deaths.

Conclusions: Bintrafusp alfa showed clinical activity across subgroups of PD-L1 expression and in HPV-positive tumors and had a manageable safety profile in patients with heavily pretreated advanced SCCHN. Activity in HPV-positive tumors is favorable compared with historical data from PD-L1 inhibitors and is being further investigated in an ongoing study of HPV-associated tumors.

Trial Registration Number: NCT02517398.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jitc-2020-000664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342865PMC
July 2020

A multicenter, phase I, pharmacokinetic study of osimertinib in cancer patients with normal renal function or severe renal impairment.

Pharmacol Res Perspect 2020 08;8(4):e00613

Medical Oncology Department, Bordeaux University Hospital, Saint-André Hospital, Bordeaux, France.

Osimertinib is a third-generation, irreversible, oral epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) that potently and selectively inhibits both EGFR-TKI sensitizing and EGFR T790M and has demonstrated efficacy in non-small cell lung cancer (NSCLC) central nervous system metastases. In this phase I study, we assessed the effects of normal renal function (NRF) and severe renal impairment (SRI) on the pharmacokinetics (PK) of osimertinib in patients with solid tumors. Part A: patients with NRF (creatinine clearance [CrCL] ≥90 mL/min), and SRI, (CrCL <30 mL/min), received a single 80-mg oral dose of osimertinib and standard PK measures were assessed. Part B: patients with SRI were treated for 3 months to obtain safety data, if deemed clinically appropriate. The geometric mean osimertinib plasma concentrations were higher in patients with SRI (n = 7) vs NRF (n = 8) and were highly variable. Osimertinib exposure based on C and area under the plasma concentration-time curve, was 1.19-fold (90% CI: 0.6, 2.0) and 1.85-fold (90% CI: 0.9, 3.6), respectively, higher for patients with SRI vs patients with NRF, with no clear correlation between CrCL and exposure. No new safety signals were identified after 12 weeks of osimertinib 80 mg continuous dosing. PK parameters pooled across this study and other phase I, II, and III osimertinib clinical studies (exploratory population PK analysis), showed minimal correlation between CrCL and total clearance. In conclusion, no dose adjustment is required for osimertinib for patients with SRI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prp2.613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307240PMC
August 2020

Midazolam sedation in palliative medicine: retrospective study in a French center for cancer control.

BMC Palliat Care 2020 Jun 19;19(1):85. Epub 2020 Jun 19.

Lille University Hospital and Medical School, Palliative care unit, 59000, Lille, France.

Background: French legislation about sedation in palliative medicine evolved in 2016 with the introduction of a right to deep and continuous sedation, maintained until death. The objective was to describe midazolam sedation at the COL (Centre Oscar Lambret [Oscar Lambret Center], French regional center for cancer control), in order to establish a current overview before the final legislative changes.

Methods: Descriptive, retrospective and single-center study, concerning major patients in palliative care hospitalized from 01/01/2014 to 12/31/2015, who had been sedated by midazolam. The proven sedations (explicitly named) and the probable sedations were distinguished.

Results: A total of 54 sedations were identified (48 proven, 6 probable). Refractory symptoms accounted for 48.1% of indications, complications with immediate risk of death 46.3%, existential suffering 5.6%. Titration was performed in 44.4% of cases. Sedation was continuous until death for 98.1% of the cases. Probable sedation had a higher failure rate than proven sedation. Significant differences existed for the palliative care unit compared to other units regarding information to the patient, their consent, anticipation, mention by correspondence and carrying out titrations. When patients had already been treated with midazolam, the induction doses, initial maintenance doses, and doses at the time of death were significantly higher. For those receiving opioids, the maintenance dose at the time of death was higher. No comparison found a difference in overall survival.

Conclusions: After a sufficient follow-up has enabled teams to familiarize with this new legislation, reflection on sedation should be conducted to adapt to final recommendations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12904-020-00592-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305615PMC
June 2020

Maintenance therapy and drug holiday in sarcoma patients: systematic review.

Acta Oncol 2020 Sep 13;59(9):1084-1090. Epub 2020 May 13.

Medical School, Lille University, Lille, France.

Overall prognosis of advanced sarcoma remains poor, optimization of systemic treatment is urgently needed in this setting. We systematically reviewed fully published English-speaking literature about maintenance therapy and drug holiday in sarcoma patients management. We found that switch maintenance therapy with cyclophosphamide/vinorelbine improves the outcome of localized high-risk rhabdomyosarcoma. There is no other maintenance therapy recommended in sarcoma patients. After classical chemotherapy, maintenance therapy with immune-stimulating agents for localized osteosarcoma, bevacizumab for advanced angiosarcoma or pediatric advanced sarcoma, or mTOR inhibitors for metastatic sarcoma does not improve the outcome. Drug holiday has been assessed for metastatic gastrointestinal stromal tumor treated with imatinib as the first-line therapy or for metastatic soft-tissue sarcoma treated with trabectedin. Drug holiday has been found to lead to rapid disease progression and should be avoided. Data about both maintenance and drug holiday are spare in sarcoma management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/0284186X.2020.1759825DOI Listing
September 2020

ESMO Clinical Research Observatory (ECRO): improving the efficiency of clinical research through rationalisation of bureaucracy.

ESMO Open 2020 05;5(3):e000662

Scientific and Medical Division, European Society for Medical Oncology (ESMO), Lugano, Switzerland.

During the last years, there has been a dramatic increase in the administrative and bureaucratic burden associated with clinical research, which has clearly had an impact on its overall efficiency and on the activity of clinical investigators and research teams. Indeed, the supervision of the adherence of clinical research to Good Clinical Practice (GCP) guidelines and legal regulations is of the utmost importance. Yet, while such regulations have remained largely unchanged during recent years, the number of administrative tasks and their complexity have grown markedly, as supported by the results of a survey performed among 940 clinical investigators that we report in this manuscript. Therefore, many investigators believe that it has become necessary to undertake a rigorous analysis of the causes and consequences of this issue, and to create a conduit to channel the advice from experienced investigators regarding clinical research procedures, in order to improve them. Based on these premises, ESMO has launched the ESMO Clinical Research Observatory (ECRO), a task force that will analyse different aspects of clinical research. ECRO will aim to provide the views of ESMO on clinical research procedures based on the feedback from clinical investigators, under complete adherence to the Declaration of Helsinki, the GCP guidelines and any other applicable legal regulations, while at the same time showing profound respect for all the stakeholders involved in clinical research. This manuscript provides the background and rationale for the creation of ECRO, its planned activity and an analysis of the current administrative burden in clinical research with recommendations to rationalise it. Indeed, we expect that this effort shall lead to a relevant improvement in the care of patients and in the development of clinical research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/esmoopen-2019-000662DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223268PMC
May 2020

Overview of « druggable » alterations by histological subtypes of sarcomas and connective tissue intermediate malignancies.

Crit Rev Oncol Hematol 2020 Jun 14;150:102960. Epub 2020 Apr 14.

Biopathology department, Centre Oscar Lambret, Lille, France; Lille University, Inserm U1192, Laboratoire « Protéomique, Réponse Inflammatoire et Spectrométrie de Masse » (PRISM), Villeneuve d'Ascq, France.

We summarize herein the literature data about molecular targeted therapies in sarcomas and conjunctive tissue intermediate malignancies. For each clinical setting, the level of evidence, the mechanism of action and the target are described. The two major axes include (i) identification of subgroups of tumors with druggable alteration irrespective of the histological diagnosis (e.g. NTRK), and (ii) druggable target of pathway related to the physiopathology of the tumor: denosumab and bone giant cell tumor, imatinib and soft tissue giant cell tumor, mTOR inhibitor and PECOMA.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.critrevonc.2020.102960DOI Listing
June 2020
-->