Publications by authors named "Esma Saada-Bouzid"

45 Publications

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

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

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

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

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

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

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

Rare bone sarcomas: a retrospective analysis of 145 adult patients from the French Sarcoma Group.

Int J Cancer 2021 Oct 6. Epub 2021 Oct 6.

Department of Medical Oncology, Institut CURIE, Paris, France.

The benefit of chemotherapy (CT) in rare bone sarcomas is not documented in prospective studies. This retrospective study from the French sarcoma network for bone tumors ResOs was performed in adult patients (pts) from 1976 to 2014, with histologically verified diagnosis of leiomyosarcomas (LMS), undifferentiated pleomorphic (UPS), or radiation-associated sarcomas of bone. The median follow-up was 4.7 years (95% CI 3.7-6.5). Clinical features, treatment modalities and outcomes were recorded and analyzed from 145 pts (median age 53 years [range 20-87]). Site of disease was extremities (66%) or axial skeleton (34%), 111 (77%) presented with localized and potentially resectable disease. The most common histological subtypes were UPS (58%) and LMS (33%); 58% were high-grade tumors. Surgery was performed in 127 pts. In the 111 localized pts, 28 pts (25%) underwent upfront surgery or exclusive radiotherapy (RT; > 50 Grays) without CT, whereas 83 pts (75%) received either neo-adjuvant (n = 26) or adjuvant CT (n = 13) or both (n = 44). Neo-adjuvant and adjuvant CT was mostly doxorubicin- (95%/86%) and cisplatin- (67%/63%) based. R0 resection was achieved in 59 pts, and a good histological response in 15 patients (25%). Adjuvant RT was performed in 24 (22%) pts. For the whole cohort (n=145), the 5-year overall survival (OS) rate was 53% [42; 62]. In univariate analysis, age ≤60 was associated with a longer disease-free survival (DFS)(p = 0.0436). Neo-adjuvant and adjuvant CT tended to be associated with better DFS (p=0.056) with no significant impact on OS in this retrospective series. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33837DOI Listing
October 2021

Efficacy and safety of immune checkpoint inhibitors in elderly patients (≥70 years) with squamous cell carcinoma of the head and neck.

Eur J Cancer 2021 Nov 15;157:190-197. Epub 2021 Sep 15.

Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

Background: Recent meta-analysis showed that immune checkpoint inhibitors (ICIs) have comparable activity between younger and older patients. However, little is known about efficacy and safety of ICI in elderly patients with relapsed/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). The aim of this study is to compare the efficacy of ICI for patients aged ≥70 y to that for younger patients, while taking into account potential confounding factors.

Methods: A retrospective study was conducted at four hospitals in France. Patients treated with ICI for R/M SCCHN between September 2014 and December 2018 were eligible. Patients' charts were reviewed for clinical and radiological data as well as oncologic outcomes.

Results: We included 226 patients, of whom 67 were aged ≥70 years. Objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were 23%, 9.7 months and 2.7 months, respectively, for elderly patients, compared to 13%, 8.7 months and 1.9 months for younger patients (respective p-values: 0.071, 0.87 and 0.21). After adjustment for performance status, site of progression, number of ICI drugs, time between initial diagnosis and ICI start and number of previous lines, age ≥70 years was significantly associated with a better PFS (hazard ratio [HR], 0.66; p = 0.021) but not OS (HR, 0.91; p = 0.59). Grade 3-5 adverse events (AEs) occurred in 15% of patients aged ≥70 years and in 8% of younger patients (p = 0.13).

Conclusion: Patients aged ≥70 years with R/M SCCHN may respond to ICI similarly as younger patients in terms of ORR, OS and PFS, while maintaining comparable rate of AEs.
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http://dx.doi.org/10.1016/j.ejca.2021.08.030DOI Listing
November 2021

Metachronous second primary neoplasia in oropharyngeal cancer patients: Impact of tumor HPV status. A GETTEC multicentric study.

Oral Oncol 2021 Sep 6;122:105503. Epub 2021 Sep 6.

Otolaryngology and Head and Neck Surgery Department, European Hospital Georges Pompidou, APHP, Paris, France.

Introduction: Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk to develop a metachronous second primary neoplasia (MSPN). HPV and non-HPV-related OPSCC are 2 distinct entities with biological, clinical and prognostic differences. The aims of our study were to analyze the impact of tumor HPV status and other relevant clinical factors, such as tobacco and/or alcohol (T/A) consumption, on the risk and distribution of MSPN in OPSCC patients and to assess the impact of MSPN on patient survival.

Material And Methods: All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. P16 immunohistochemical expression was used as a surrogate maker of tumor HPV status. The impact of tumor p16 status on the risk of MSPN was assessed in uni- and multivariate analyses. Overall survival (OS) was determined by Kaplan-Meier analysis.

Results: Among the 1291 patients included in this study, 138 (10.7%) displayed a MSPN which was preferentially located in the head and neck area (H&N), lung and esophagus. Multivariate analyses showed that p16- tumor status (p = 0.003), T/A consumption (p = 0.005) and soft palate tumor site (p = 0.009) were significantly associated with a higher risk of MSPN. We found no impact of p16 tumor status on the median time between index OPSCC diagnosis and MSPN development, but a higher proportion of MSPN arising outside the H&N, lung and esophagus was found in p16 + than in p16- patients. MSPN development had an unfavorable impact (p = 0.04) on OS only in the p16 + patient group.

Conclusion: P16 tumor status and T/A consumption were the main predictive factors of MSPN in OPSCC patients. This study provides crucial results with a view to tailoring global management and follow-up of OPSCC patients.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105503DOI Listing
September 2021

Phase I trial of copanlisib, a selective PI3K inhibitor, in combination with cetuximab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Invest New Drugs 2021 Dec 28;39(6):1641-1648. Epub 2021 Jul 28.

Department of Drug Development and Innovation (D3i), Institut Curie, Paris & Saint-Cloud, France.

Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m loading dose followed by 250 mg/m on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients.Trial registration NCT02822482, Date of registration: June 2016.
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http://dx.doi.org/10.1007/s10637-021-01152-zDOI Listing
December 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.
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http://dx.doi.org/10.1186/s12885-021-08393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164290PMC
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 06 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).
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http://dx.doi.org/10.1016/j.ejca.2021.03.039DOI Listing
June 2021

Systemic treatment of metastatic squamous cell carcinoma of the head and neck: proposal for management changes.

Curr Opin Oncol 2021 05;33(3):160-167

Centre Antoine Lacassagne, Nice.

Purpose Of Review: Worldwide, head and neck carcinomas account for 5% of all malignancies. Two-thirds of patients relapse after initial multimodal therapy. Until early 2010, the median overall survival (OS) of metastatic patients was about 10 months.

Recent Findings: New drugs have been incorporated in patient management, thus enabling an increase in OS. Several first and second line protocols are now available but the lack of direct comparison makes the choice difficult between them.

Summary: This work aims to define the comprehensive medical management of patients with relapsing head and neck carcinoma. In September 2020, the French head and neck groups GORTEC, Unicancer head and Neck group, GROCC and GETTEC decided to promote a one-day meeting to propose how to incorporate these new regimens in first and second line treatment for recurrent and metastatic head and neck cancer (R/M SCCHNC). Twelve French medical oncologist involved in the management of R/M SCCHNC for more than 10 years examined the literature and proposed a simple and practical management based on five criteria: age, delay from last platinum injection, combined positive score expression level, FIT or UNFIT patient according to physician decision, fast response needed or not.
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http://dx.doi.org/10.1097/CCO.0000000000000738DOI Listing
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 ClinicalTrials.gov, 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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http://dx.doi.org/10.1016/S1470-2045(20)30755-5DOI Listing
April 2021

Upfront surgery or definitive radiotherapy for p16+ oropharyngeal cancer. A GETTEC multicentric study.

Eur J Surg Oncol 2021 06 1;47(6):1389-1397. Epub 2021 Jan 1.

Department of Otorhinolaryngology and Head and Neck Surgery, University Hospital of Montpellier, Montpellier, France.

Background: The aim of this study was to assess the impact of the initial therapeutic strategy on oncologic outcomes in patients with HPV-positive OPSCC.

Methods: All p16-positive OPSCCs treated from 2009 to 2014 in 7 centers were retrospectively included and classified according to the therapeutic strategy: surgical strategy (surgery ± adjuvant radiotherapy and chemotherapy) vs. non-surgical strategy (definitive radiotherapy ± chemotherapy). Univariate, multivariate propensity score matching analyses were performed to compare overall (OS), disease-specific (DSS) and recurrence-free survival (RFS).

Results: 382 patients were included (surgical group: 144; non-surgical group: 238). Five-year OS, DSS and RFS were 89.2, 96.8 and 83.9% in the surgical group and 84.2, 87.1 and 70.4% in the non-surgical group, respectively. These differences were statistically significant for DSS and RFS after multivariate analysis, but only for RFS after propensity score matching analysis.

Conclusion: In p16+ OPSCC patients, upfront surgery results in higher RFS than definitive radiotherapy ± chemotherapy but does not impact OS.
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http://dx.doi.org/10.1016/j.ejso.2020.12.011DOI Listing
June 2021

Oropharyngeal cancer: First relapse description and prognostic factor of salvage treatment according to p16 status, a GETTEC multicentric study.

Eur J Cancer 2021 01 14;143:168-177. Epub 2020 Dec 14.

Department of Otorhinolaryngology and Head and Neck Surgery, Gustave Roussy Institute, Villejuif, France.

Introduction: Although Human Papilloma Virus (HPV)-driven oropharyngeal cancer (OPC) prognosis is significantly better than that of other head and neck cancers, up to 25% of cases will recur within 5 years. Data on the pattern of disease recurrence and efficiency of salvage treatment are still sparse.

Material And Method: Observational study of all recurrent OPCs diagnosed, following a curative intent treatment, in seven French centers from 2009 to 2014. p16 Immunohistochemistry was used to determine HPV status. Clinical characteristics, distribution of recurrence site, and treatment modalities were compared by HPV tumor status. Overall survival was examined using Kaplan-Meier and multivariate Cox regression modeling.

Results: 350 recurrent OPC patients (246 p16-negative and 104 p16-positive patients). The site of recurrence was more frequently locoregional for p16-negative patients (65.4% versus 52.9% in p16-positive patients) and metastatic for p16-positive patients (47.1% versus 34.6% in p16-patients, p = 0.03). Time from diagnosis to recurrence did not differ between p16-positive and p16-negative patients (12 and 9.6 months, respectively, p-value = 0.2), as the main site of distant metastasis (all p-values ≥0.10). Overall and relapse-free survival following the first recurrence did not differ according to p16 status (p-values from log-rank 0.30 and 0.40, respectively). In multivariate analysis, prognosis factors for overall survival in p16-negative patients were distant metastasis (HR 2.11, 95% CI 1.30-3.43) and concurrent local and regional recurrences (HR 2.20, 95% CI 1.24-3.88).

Conclusion: With the exception of the initial site of recurrence, the pattern of disease relapse and the efficiency of salvage treatment are not different between p16-positive and negative OPCs.
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http://dx.doi.org/10.1016/j.ejca.2020.10.034DOI Listing
January 2021

Defining the needs of patients with recurrent and/or metastatic head and neck cancer: An expert opinion.

Crit Rev Oncol Hematol 2021 Jan 13;157:103200. Epub 2020 Dec 13.

Medical Oncology, Department of Medical & Surgical Specialties, Radiological Sciences & Public Health, University of Brescia, ASST Spedali Civili, 25123, Brescia, Italy. Electronic address:

The clinical and biological heterogeneity of head and neck cancer (HNC) is paralleled by a plethora of different symptoms that affect the patient's quality of life. These symptoms include, for instance, pain, fatigue, nutritional issues, airways obstruction, voice alterations and psychological distress. In addition, patients with HNC are prone to a high risk of infection, and may also suffer from acute complications, such as hypercalcemia, spine compression by bone metastasis or bleeding. Prolonging survival is also an inherent expectation for all patients. Addressing the above needs is crucial in all patients with HNC, and especially in those with recurrent and/or metastatic (RM) disease. However, research on how to address patients' needs in RM-HNC remains scarce. This paper defines patients' needs for RM HNC and presents an Expert Opinion on how to address them, proposing also some lines of research.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103200DOI Listing
January 2021

Synchronous primary neoplasia in patients with oropharyngeal cancer: Impact of tumor HPV status. A GETTEC multicentric study.

Oral Oncol 2021 01 28;112:105041. Epub 2020 Oct 28.

Department of Head and Neck Surgery, European Georges Pompidou Hospital, APHP, Paris, France.

Introduction: Patients with oropharyngeal squamous cell carcinoma (OPSCC) display a significant risk of synchronous primary neoplasia (SPN) which could impact their management. The aims of this study were to evaluate the risk and distribution of SPN in OPSCC patients according to their HPV (p16) status, the predictive factors of SPN and the impact of SPN on therapeutic strategy and oncologic outcomes.

Material And Methods: All OPSCC patients treated from 2009 to 2014 were included in this multicentric retrospective study. Univariate analyses were conducted using Chi-2 and Fisher exact tests. For multivariate analyses, all variables associated with a p ≤ 0.10 in univariate analysis were included in logistic regression models.

Results: Among the 1291 patients included in this study, 75 (5.8%) displayed a SPN which was preferentially located in the upper aerodigestive tract, lung and esophagus. Comorbidity level (p = 0.03), alcohol (p = 0.005) and tobacco (p = 0.01) consumptions, and p16 tumor status (p < 0.0001) were significant predictors of SPN. In multivariate analysis, p16+ status was significantly associated with a lower risk of SPN (OR = 0.251, IC95% [0.133;0.474]). Patients with a SPN were more frequently referred for non-curative treatment (p = 0.02). In patients treated with curative intent, there was no impact of SPN on the therapeutic strategy (surgical vs. non-surgical treatment). We observed no overall survival differences between patients with or without SPN.

Conclusion: P16 tumor status is the main predictive factor of SPN in OPSCC patients. This study provides crucial results which should help adapt the initial work-up and the global management of OPSCC patients.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105041DOI Listing
January 2021

Upfront surgery or definitive radiotherapy for patients with p16-negative oropharyngeal squamous cell carcinoma. A GETTEC multicentric study.

Eur J Surg Oncol 2021 02 10;47(2):367-374. Epub 2020 Sep 10.

Department of Otorhinolaryngology and Head and Neck Surgery, Gustave Roussy Institute, Villejuif, France.

Introduction: Therapeutic management of oropharyngeal squamous cell carcinomas (OPSCC) is still debated. Since the role of HPV was demonstrated, few studies have focused on HPV-negative OPSCC. The aim of our study was to assess the impact of therapeutic strategy (surgical vs. non-surgical) on oncologic outcomes in patients with HPV-negative OPSCC.

Material And Method: All p16-negative OPSCCs treated from 2009 to 2014 in 7 tertiary-care centers were included in this retrospective study and were classified according to the therapeutic strategy: surgical strategy (surgery ± adjuvant radiotherapy and chemotherapy) vs. non-surgical strategy (definitive radiotherapy ± chemotherapy). Patients not eligible for surgery (unresectable tumor, poor general-health status) were excluded. Univariate, multivariate and propensity score matching analyses were performed to compare overall (OS), disease-specific (DSS) and recurrence-free survival (RFS).

Results: Four hundred seventy-four (474) patients were included in the study (surgical group: 196; non-surgical group: 278). Five-year OS, DSS and RFS were 76.5, 81.3 and 61.3%, respectively, in the surgical group and 49.9, 61.8 and 43.4%, respectively, in the non-surgical group. The favorable impact of primary surgical treatment on oncologic outcomes was statistically significant after multivariate analysis. This effect was more marked for locally-advanced than for early-stage tumors. Propensity score matching analysis confirmed the prognostic impact of primary surgical treatment for RFS.

Conclusion: Therapeutic strategy is an independent prognostic factor in patients with p16-negative OPSCC and primary surgical treatment is associated with improved OS, DSS and RFS. These results suggest that surgical strategy is a reliable option for advanced stage OPSCC.
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http://dx.doi.org/10.1016/j.ejso.2020.07.034DOI 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.
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http://dx.doi.org/10.1136/bmjopen-2020-038391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513631PMC
September 2020

Author Correction: Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics.

Sci Rep 2020 Jun 12;10(1):9857. Epub 2020 Jun 12.

University Côte d'Azur, Centre Antoine Lacassagne, Medical Oncology Department, Nice, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-66841-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289853PMC
June 2020

Correction to: Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors.

Invest New Drugs 2021 Feb;39(1):287-292

Centre Antoine Lacassagne, Medical Oncology Department, University Côte d'Azur, F-06189, Nice, France.

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http://dx.doi.org/10.1007/s10637-020-00954-xDOI Listing
February 2021

Hyperprogression under Immune Checkpoint Inhibitor: a potential role for germinal immunogenetics.

Sci Rep 2020 02 27;10(1):3565. Epub 2020 Feb 27.

University Côte d'Azur, Centre Antoine Lacassagne, Medical Oncology Department, Nice, France.

Hyperprogressive disease (HPD), an unexpected acceleration of tumor growth kinetics, is described in cancer patients treated with anti-PD-1/anti-PD-L1 agents. Here, our aim was to take into consideration the host and explore whether single nucleotide polymorphisms (SNPs) in key genes involved in immune response might predispose to HPD. DNA was extracted from blood-samples from 98 patients treated under CPI monotherapy. Four candidate genes (PD-1, PD-L1, IDO1 and VEGFR2) and 15 potential SNPs were selected. The TGK (ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. Hyperprogression was defined as a TGK≥2. TGK calculation was feasible for 80 patients (82%). HPD was observed for 11 patients (14%) and was associated with shorter overall survival (P = 0.003). In univariate analysis, HPD was significantly associated with age ≥70 y (P = 0.025), immune-related toxicity (P = 0.016), VEGFR2 rs1870377 A/T or A/A (P = 0.005), PD-L1 rs2282055 G/T or G/G (P = 0.024) and PD-L1 rs2227981 G/A or A/A (P = 0.024). Multivariate analysis confirmed the correlation between HPD and age ≥70 y (P = 0.006), VEGFR2 rs1870377 A/T or A/A (P = 0.007) and PD-L1 rs2282055 G/T or G/G (P = 0.018). Immunogenetics could become integral predictive factors for CPI-based immunotherapy.
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http://dx.doi.org/10.1038/s41598-020-60437-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7046673PMC
February 2020

Surgical Margins and Adjuvant Therapies in Malignant Phyllodes Tumors of the Breast: A Multicenter Retrospective Study.

Ann Surg Oncol 2020 Jun 27;27(6):1818-1827. Epub 2020 Jan 27.

Department of Medical Oncology, Institut du Cancer Montpellier, Univ Montpellier, Montpellier, France.

Background: The optimal threshold of surgical margins for breast malignant phyllodes tumors (MPTs) and the impact of adjuvant chemotherapy and radiotherapy were investigated.

Patients And Methods: We conducted a multicenter nationwide retrospective study of all MPT cases with central pathological review within the French Sarcoma Group. Endpoints were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS) rates.

Results: Overall, 212 patients were included in the study. All non-metastatic patients underwent primary surgical treatment, including 58.6% of conservative surgeries. An R0 resection was achieved in 117 patients (59.4%: 26.9% of patients with 1-2 mm margins, 12.2% of patients with 3-7 mm margins, 20.3% of patients with ≥ 8 mm margins). Ninety-four patients (45%) underwent a second surgery (SS) to obtain R0 margins, with a final mastectomy rate of 72.6%. Radiotherapy and chemotherapy were performed in 91 (43.1%) and 23 patients (10.9%), respectively, but were not associated with better outcomes. Mastectomy was significantly associated with better LRFS (p < 0.001). Margins of 0, 1, or 2 mm with SS were associated with better MFS (hazard ratio [HR] 0.3, p = 0.005) and OS (HR 0.32, p = 0.005) compared with margins of 0-1-2 mm without SS. Wider margins (> 8 mm) were not superior to margins of 3-7 mm (3-7 mm vs. > 8 mm; HR 0.81, p = 0.69). Age (HR 2.14, p = 0.038) and tumor necrosis (HR 1.96, p = 0.047) were found to be poor prognostic factors and were associated with MFS.

Conclusions: This study suggests that 3 mm margins are necessary and sufficient for surgical management of MPTs, and emphasizes the importance of SS to obtain clear margins in case of 0-1-2 mm margins. No impact of adjuvant chemotherapy or radiotherapy was detected in this study.
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http://dx.doi.org/10.1245/s10434-020-08217-yDOI Listing
June 2020

A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib in non-adipocytic sarcoma patients previously treated with both chemotherapy and pazopanib.

Eur J Cancer 2020 02 6;126:45-55. Epub 2020 Jan 6.

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

Background: Metastatic soft tissue sarcomas (STSs) management remains an unmet medical need. We assessed the activity and safety of regorafenib in patients with metastatic non-adipocytic STS who were previously treated with both chemotherapy and pazopanib.

Patients And Methods: This double-blind, placebo-controlled, multicenter comparative randomized phase II trial included patients with histologically proven advanced and inoperable STS. Patients receiving placebo were offered optional cross-over for centrally confirmed disease progression. Primary end-point was centrally reviewed Response Evaluation Criteria in Solid Tumours-based progression-free survival (PFS), analysed on the intent-to-treat data set. In total, 24 events were required for 90% power, hazard ratio (HR) = 0.33 (median PFS, 3.6 versus 1.2 months), and 1-sided α = 0.1 (ClinicalTrials.gov, NCT01900743).

Results: From December 2015 to October 2017, 37 patients were randomized; 18 to regorafenib and 19 to placebo. Thirteen patients assigned to placebo switched to regorafenib after progression. Median follow-up was 27.2 months (95% confidence interval [CI]: 24.4-not reached). We observed a significant PFS benefit of regorafenib compared with placebo (adjusted HR = 0.33; 95% CI: 0.15-0.74; p = 0.0007 median PFS = 2.1 versus 1.1 months, respectively), and a large and nearly significant overall survival (OS) benefit despite the cross-over (adjusted HR = 0.49; 95% CI: 0.23-1.06; p = 0.007; median OS = 17.8 versus 8.2 months). Before cross-over, the most common grade III or higher adverse events were lymphopenia (5 versus 1, respectively), diarrhoea (4 versus 0), dyspnoea (3 versus 1), skin toxicity (3 versus 0), arterial hypertension (2 versus 0), and increased transaminases (2 versus 0).

Conclusion: The present study demonstrated a meaningful clinical anti-tumour activity with regorafenib in heavily pre-treated patients with non-adipocytic STS.
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http://dx.doi.org/10.1016/j.ejca.2019.12.001DOI Listing
February 2020

Impact of Metastasis Surgery and Alkylating-Agent-Based Chemotherapy on Outcomes of Metastatic Malignant Phyllodes Tumors: A Multicenter Retrospective Study.

Ann Surg Oncol 2020 May 26;27(5):1693-1699. Epub 2019 Nov 26.

Department of Medical Oncology, Institut du cancer Montpellier, Univ Montpellier, Montpellier, France.

Background: Metastatic phyllodes tumors have poor prognosis with median overall survival of 11.5 months. The objective of this study is to identify prognostic factors and the best options for management of metastatic malignant phyllode tumors (MMPTs).

Patients And Methods: A multicentric retrospective study, including cases of MMPT from 10 sarcoma centers, was conducted. The primary end-point was overall survival (OS), and the secondary end-point was the clinical benefit of chemotherapy (CBCT) rate.

Results: 51 MMPT patients were included. Median time from diagnosis to metastatic recurrence was 13 months. Management of MMPT consisted in surgery of the metastatic disease for 16 patients (31.3%), radiation therapy of the metastatic disease for 15 patients (31.9%), and chemotherapy for 37 patients (72.5%). Median follow-up was 62.1 months [95% confidence interval (CI) 31-80 months]. Median OS was 11.5 months (95% CI 7.5-18.7 months). On multivariate analysis, two or more metastatic sites [hazard ratio (HR) 2.81, 95% CI 1.27-6.19; p = 0.01] and surgery of metastasis (HR 0.33, 95% CI 0.14-0.78; p = 0.01) were independently associated with OS. The CBCT rate was 31.4% and 16.7% for the first and second lines. Polychemotherapy was not superior to single-agent therapy. Alkylating-agent-based chemotherapy, possibly associated with anthracyclines, was associated with a better CBCT rate than anthracyclines alone (p = 0.049).

Conclusions: The results of this study emphasize the impact of the number of metastatic sites on survival of MMPT patients and the leading role of metastasis surgery in MMPT management. If systemic therapy is used, it should include alkylating agents, which are associated with a better clinical benefit.
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http://dx.doi.org/10.1245/s10434-019-08097-xDOI Listing
May 2020

Methotrexate-Etoposide-Ifosfamide Compared with Doxorubicin-Cisplatin-Ifosfamide Chemotherapy in Osteosarcoma Treatment, Patients Aged 18-25 Years.

J Adolesc Young Adult Oncol 2020 04 8;9(2):172-182. Epub 2019 Nov 8.

Department of Medical Oncology, Institut Curie, Paris, France.

The French standard chemotherapy for osteosarcoma combines high-dose methotrexate (HDM) and etoposide-ifosfamide (EI) in children and adolescents, and API-AI (doxorubicin-cisplatin-ifosfamide) in adults. We herein present the results of M-EI and API-AI in 18- to 25-year-old patients. Patients, 18-25 years old, received either M-EI or API-AI regimens. M-EI comprised seven M and two EI doses preoperatively then M-EI in standard-risk patients (good histological response without metastasis) and five M-AP (methotrexate-doxorubicin-cisplatin) in high-risk patients (poor histological response, metastasis, and/or unresectable primary), postoperatively. API-AI comprised three API and two AI doses preoperatively, then two AI and two PI in standard-risk patients and five EI in high-risk patients, postoperatively. We analyzed 95 patients 18-25 years of age: 55 received M-EI and 40 API-AI. The groups had similar baseline characteristics. Eighty-nine patients (94%) had surgery. Twenty-nine of 55 M-EI patients (60%) and 16/40 API-AI patients (41%) had good histological responses to preoperative chemotherapy. At 5 years, event-free survival was 50% (95% confidence interval [CI]: 39-60) and overall survival was 65% (95% CI: 54-74). Acute toxicity was similar, without treatment-related deaths. Survival outcomes with M-EI and API-AI were not significantly different. Tolerance was acceptable with both regimens. HDM is thus feasible for young adults. However, our study limitations preclude any definitive conclusions.
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http://dx.doi.org/10.1089/jayao.2019.0085DOI Listing
April 2020

Hyperprogressive Disease during Anti-PD-1 (PDCD1) / PD-L1 (CD274) Therapy: A Systematic Review and Meta-Analysis.

Cancers (Basel) 2019 Nov 1;11(11). Epub 2019 Nov 1.

Internal Medicine V, Department of Hematology & Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria.

Hyperprogressive disease (HPD) is a recently acknowledged pattern of rapid tumor progression after the initiation of immune checkpoint inhibitors. HPD has been observed across various types of tumors and has been associated with poor survival. We performed a meta-analysis to identify baseline (i.e., prior to programmed cell death 1 [PD-1, PDCD1] / programmed cell death 1 ligand 1 [PD-L1, CD274] inhibitor therapy) patient factors associated with risks of developing HPD during PD-1/PD-L1 inhibitor therapy. We searched eight databases until 6 June 2019. We calculated the summary odds ratio (OR) and its 95% confidence interval (CI) using the random-effects model and explored between-study heterogeneity and small-study effects. A total of nine articles was eligible (217 HPD cases, 1519 cancer patients) for meta-analysis. There was no standard definition of HPD, and the incidence of HPD ranged from 1 to 30%. We identified twenty-three baseline patient factors, of which five factors were statistically significantly associated with HPD. These were serum lactate dehydrogenase (LDH) above the upper normal limit (OR = 1.89, 95% CI = 1.02-3.49, = 0.043), more than two metastatic sites (OR = 1.86, 1.34-2.57, < 0.001), liver metastases (OR = 3.33, 2.07-5.34, < 0.001), Royal Marsden Hospital prognostic score of 2 or above (OR = 3.33, 1.96-5.66, < 0.001), and positive PD-L1 expression status that was inversely correlated with HPD (OR = 0.60, 0.36-0.99, = 0.044). Between-study heterogeneity was low. Evidence of small-study effect was found in one association (PD-L1 expression). Subset analyses of patients with non-small cell lung cancer showed similar results. Future studies are warranted to identify underlying molecular mechanisms and to test their roles as predictive biomarkers of HPD.
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http://dx.doi.org/10.3390/cancers11111699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896059PMC
November 2019

Response to salvage chemotherapy after progression on immune checkpoint inhibitors in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck.

Eur J Cancer 2019 11 28;121:123-129. Epub 2019 Sep 28.

Department of Head and Neck Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

Background: Immune checkpoint inhibitors (ICI) are active in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Recent data suggest that exposure to ICI improves response to salvage chemotherapy (SCT) in advanced non-small-cell lung cancer. We evaluated response to chemotherapy in patients who had progressed on ICI in patients with R/M SCCHN.

Patients And Methods: A retrospective study was conducted at 4 French centres. Eligibility criteria were patients who progressed after treatment with ICI for R/M SCCHN and received SCT and for whom efficacy data were available between September 2014 and January 2018.

Results: Of 232 patients treated with ICI, 82 met eligibility criteria: 84% were male. ICI was given as monotherapy in 45% of patients or as combination in 55%. SCT included taxanes (56.1%), cetuximab in combination with taxanes or platinum (50%), platinum-based regimen (36.6%). The median number of treatment lines before SCT was 2 (range 1-6). The objective response rate (ORR) to SCT was 30%. Three patients (4%) presented complete response and 22 patients (27%) had partial response. Median progression-free survival was 3.6 months and median overall survival was 7.8 months. The age at SCT, initial tumour location, number of prior chemotherapy regimens, type of chemotherapy before ICI, best response to ICI, site of relapse and Eastern Cooperative Oncology Group at SCT were not associated with response to SCT on univariate analysis.

Conclusion: In R/M SCCHN, the ORR to SCT was high (30%) suggesting that exposure to ICI may increase tumour sensitivity to chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2019.08.026DOI Listing
November 2019

Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors.

Invest New Drugs 2020 02 11;38(1):160-171. Epub 2019 Aug 11.

Centre Antoine Lacassagne, Medical Oncology Department, University Côte d'Azur, F-06189, Nice, France.

Background Checkpoint inhibitors bring marked benefits but only in a minority of patients and may also be associated with severe adverse events. Treatment outcome still cannot be faithfully predicted. The following study hypothesized that host genetics could be applied as predictive biomarkers for checkpoint inhibitor response and immune-related adverse events. We conducted a study based on germinal polymorphisms from genes coding for proteins involved in immune regulation. Methods Germinal DNA was obtained from advanced cancer patients treated with anti-PD-1/PD-L1 checkpoint inhibitors. DNA was genotyped using a custom panel of 166 single nucleotide polymorphisms covering 86 preselected immunogenetic-related genes. Computational analysis using a GTEX portal was made to determine potential expression Quantitative Trait Loci in tissues. Results Ninety-four consecutive patients were included. Objective response rate (complete or partial response) was significantly correlated to tumor microenvironment-related SNPs concerning CCL2, NOS3, IL1RN, IL12B, CXCR3 and IL6R genes. Toxicity were linked to target-related gene SNPs including UNG, IFNW1, CTLA4, PD-L1 and IFNL4 genes. The Area Under the ROC curve (AUC) was 0.81 (95% CI: 0.72-0.9) for response and 0.89 (95% CI: 0.76-1.00) for toxicity. In silico functionality exploring pointed rs4845618 (IL6R), rs10964859 (IFNW1) and rs3087243 (CTLA4) as potentially impacting gene expression. Conclusion These results strongly support a role for distinct immunogenetic-related gene SNPs able to predict efficacy and safety of anti-PD1/PD-L1 therapies. The results highlight the existence of patient-specific, germinal biomarkers able predict response to checkpoint inhibitor efficacy and, possibly, to predict treatment-related adverse events.
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http://dx.doi.org/10.1007/s10637-019-00845-wDOI Listing
February 2020

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

Lancet Oncol 2019 08 8;20(8):1148-1159. Epub 2019 Jul 8.

Radiation Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain.

Background: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma.

Methods: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete.

Findings: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred.

Interpretation: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers.

Funding: Nanobiotix SA.
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http://dx.doi.org/10.1016/S1470-2045(19)30326-2DOI Listing
August 2019

Approach to the Patient with Recurrent/Metastatic Disease.

Curr Treat Options Oncol 2019 06 25;20(8):65. Epub 2019 Jun 25.

Centre Antoine Lacassagne, Cancer research center, Medical Oncology Department, FHU Oncoage, University Côte d'Azur, 33 av. de Valombrose, 06189, Nice Cedex 2, France.

Opinion Statement: For most of patients with a recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC), the treatment remains palliative: The main objective is to reduce the symptoms related to the locoregional relapse, prolong life while maintaining quality of life, which is a big challenge. The systemic treatment needs to be adapted to the performance status, comorbidities, and sequelae of patients. For fit patients, the combination of platinum-based chemotherapy and cetuximab (EXTREME) is the standard of care in first-line treatment since 2008, as no other targeted therapy has been approved in this setting until now. The replacement of 5-FU with a taxane (docetaxel) in the EXTREME regimen has been explored in the large randomized international study TPExtreme which results are awaited in a few months. Depending on the study results on survival, response rate, and tolerance, the TPEx regimen may become a treatment option for patients with R/M HNSCC. Unfit patients are usually treated with platinum-free combinations or with the monotherapies which are recommended in second-line setting (methotrexate, taxanes, cetuximab). However, the irruption of new immunotherapies (e.g., checkpoint inhibitors (CPI)) is changing the guidelines. The tolerance of anti-PD-1 CPI is better than that of chemotherapy, and they seem to be a good option for unfit patients. Anti-PD-1 nivolumab and pembrolizumab are now approved for platinum refractory patients, providing prolonged survival in the case of response, and improvement in quality of life. New options arise in first-line setting with pembrolizumab alone or combined with chemotherapy. Patients with a high PD-L1 biomarker level seem to benefit more from immunotherapy. Other situations (e.g., PD-L1-low, PD-L1-negative, high tumor burden) may more likely to benefit from other combinations, such as cetuximab plus chemotherapy, to avoid local failures and life-threatening fast progression. In terms of perspectives, chemo-free and CPI-free approaches, using other immune oncology agents, should be the next steps.
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http://dx.doi.org/10.1007/s11864-019-0664-zDOI Listing
June 2019

Correction to: F-DOPA PET/CT in brain tumors: impact on multidisciplinary brain tumor board decisions.

Eur J Nucl Med Mol Imaging 2019 Jul;46(7):1581

Department of Nuclear Medicine, Centre Antoine-Lacassagne, Université Côte d'Azur (UCA), 33 Avenue de Valombrose, 06100, Nice, France.

Jérôme Barriere was inadvertently missing in the original version of this article. He has participated to the study design, protocol writing and inclusion of a significant number of patients.
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http://dx.doi.org/10.1007/s00259-019-04321-8DOI Listing
July 2019

Molecular genetics of head and neck squamous cell carcinoma.

Curr Opin Oncol 2019 05;31(3):131-137

Department of Medical Oncology, Early Phase Trial Unit, Centre Antoine Lacassagne.

Purpose Of Review: The aim of this review is to summarize the current knowledge on the genomic characterization of squamous cell carcinomas of the head and neck (HNSCC) and discusses how these abnormalities could be incorporated into a therapeutic approach.

Recent Findings: Tobacco and HPV infection, the two main risk factors of HNSCC, allow the definition of two groups with distinct anatomoclinical and genetic features. As tobacco and HPV infection are not exclusive, exposure to both risk factors is associated with an intermediate prognostic. HPV-positive, nontobacco-related HNSCCs are associated with a better prognosis, a rather more simple genomic profile, frequent activating mutations of genes involved in pi3kinase pathway, and the very low incidence of mutations of tumor suppressor genes. HPV-negative, tobacco-related HNSCC are genetically more complex. HPV-negative HNSCC are characterized by almost mandatory inactivating mutations/deletions of tumor suppressor genes (especially TP53 and CDKN2A) and the occurrence, though less frequent, of activating mutations or amplifications of some oncogenes that encode for cell cycle proteins or receptors with tyrosine kinase activity. Despite many efforts to improve therapeutic targeting in RM HNSCC, Cetuximab, a monoclonal antibody targeting REGF, remains the sole approved targeted treatment in RM HNSCC.

Summary: Despite the increasingly precise genomic characterization of HNSCCs, precision medicine is struggling to find its place in the management of HNSCCs. Inclusion of enriched populations in dedicated trials is likely to help implement precision medicine in the management of HNSCCs.
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http://dx.doi.org/10.1097/CCO.0000000000000536DOI Listing
May 2019

Immunotherapy in recurrent and or metastatic squamous cell carcinoma of the head and neck.

Curr Opin Oncol 2019 05;31(3):146-151

Department of Medical Oncology, Centre Antoine Lacassagne.

Purpose Of Review: Checkpoint inhibitors (CPI) are revolutionizing the treatment of advanced cancers including recurrent and or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN).

Recent Findings: In this review, we will summarize the results of prospective trials evaluating CPI and particularly antiprogrammed death 1 (PD-1)/antiprogrammed death-ligand 1 (PD-L1) in RM-SCCHN.

Summary: Nivolumab and Pembrolizumab, two anti-PD-1 CPI, were associated with longer overall survival than standard chemotherapy in pretreated RM-SCCHN in two randomized phase 3 trials (respectively CHECKMATE-141 and KEYNOTE-040). Both are now approved in this setting. In the KEYNOTE-048 trial, the pembrolizumab was also associated with a longer survival when compared with the EXTREME regimen in first-line RM-SCCHN patients whose tumors overexpressed PD-L1 (combined positive score ≥20%). This trial also showed a superiority of platinum-based chemotherapy and pembrolizumab vs. EXTREME regimen in unselected first-line RM-SCCHN. Pembrolizumab will probably be the next standard of care for first-line RM-SCCHN with high expression of PD-L1. Further evaluation of CPI combined with other antitumoral agents is ongoing in advanced and locally advanced SCCHN.
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http://dx.doi.org/10.1097/CCO.0000000000000522DOI Listing
May 2019
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