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Antonin Levy - Top 30 Publications

Metformin for non-small cell lung cancer patients: Opportunities and pitfalls.

Despite exciting advances of the anticancer armamentarium in the recent years, mortality of non-small cell lung cancer (NSCLC) remains high and novel treatments are requisite. Therapy intensification is explored with promising, but expensive and potentially toxic new compounds. Repositioning already existing drugs for cancer treatment could save money and improve patient outcomes in specific contexts. Observational data suggest that use of the standard antidiabetic agent metformin decreases lung cancer incidence and mortality. Several basic researches have shown various anticancer effects of metformin, acting both on the glycolytic metabolism and on the tumoral immune microenvironment. Synergistic actions of metformin with antitumoral agents in preclinical NSCLC models have then been highlighted. Recent retrospective studies advocated improved outcomes in NSCLC diabetic patients receiving metformin with chemoradiotherapy or systemic compounds (including conventional platinum-based chemotherapy and EGFR tyrosine kinase inhibitors). Several prospective randomized trials are therefore currently assessing the addition of metformin to standard therapy in non-diabetic lung cancer patients. This article reviews promises and possible limitations of concurrent metformin used as an anticancer agent in NSCLC patients.

Are We Ready to Safely Combine Anti-PD-1/PD-L1 with Cranial Irradiation in Non-Small Cell Lung Cancer Patients?

Diversity of brain metastases screening and management in non-small cell lung cancer in Europe: Results of the European Organisation for Research and Treatment of Cancer Lung Cancer Group survey.

Brain metastases (BM) are frequent in non-small cell lung cancer (NSCLC) patients, but there is a lack of evidence-based management of this patient group. We aimed to capture a snapshot of routine BM management in Europe to identify relevant research questions for future clinical trials.

Concerns about cardiotoxicity in the HERA trial.

Immunotherapy and pulmonary toxicities: can concomitant immune-checkpoint inhibitors with radiotherapy increase the risk of radiation pneumonitis?

Prophylactic cranial irradiation or no prophylactic cranial irradiation in metastatic small cell lung cancer: is it a relevant question once again?

Is dose de-escalation possible in sarcoma patients treated with enlarged limb sparing resection?

To evaluate the impact of dose de-escalation in a large series of resected limbs soft tissue sarcomas (STS).

Prognostic value of tissue necrosis, hypoxia-related markers and correlation with HPV status in head and neck cancer patients treated with bio- or chemo-radiotherapy.

The aim of the present study was to investigate the role of three hypoxia-related biomarkers in patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with concurrent chemoradiotherapy (3-weekly cisplatin) or bioradiotherapy (weekly cetuximab).

Clinical relevance of tumor infiltrating lymphocytes, PD-L1 expression and correlation with HPV/p16 in head and neck cancer treated with bio- or chemo-radiotherapy.

To investigate the prognostic value of tumor infiltrating lymphocytes (TILs: CD8+ and FoxP3+), and PD-L1 expression in patients with head and neck squamous cell carcinoma (HNSCC) treated with radiotherapy combined with cisplatin (CRT) or cetuximab (BRT). Immunohistochemistry for CD8, FoxP3 was performed on pretreatment tissue samples of 77 HNSCC patients. PD-L1 results were evaluable in 38 patients. Cox regression analysis was used to analyze the correlations of these biomarkers expression with clinicopathological characteristics and treatment outcomes. High CD8+ TILs level was identified in multivariate analysis (MVA) as an independent prognostic factor for improved progression-free survival with a non-significant trend for better overall survival (OS). High FoxP3+ TILs and PD-L1+ correlated with a favorable OS in the uni-variate analysis, respectively, but not in the MVA. In subgroup analysis, CD8+TILs appear to play a pivotal role, p16+/high CD8+TILs patients had superior 5-year OS compared with p16+/low CD8+TILs, p16-/ high CD8+TILs, and p16-/ low CD8+TILs patients. p16+/PD-L1+ patients had improved 3-year OS compared with p16+/PD-L1-, p16-/ PD-L1+, and p16-/ PD-L1- patients. In low CD8+ TILs tumors, 5-year loco-regional control of patients treated with CRT was improved vs. those with BRT (p = 0.01) while no significant difference in high CD8+ TILs was observed. CD8+ TILs correlated with an improved clinical outcome in HNSCC patients independent of Human papillomavirus status. The immunobiomarkers may provide information for selecting suitable patients for cisplatin or cetuximab treatment. Additionally, the impact of TILs and PD-L1 of deciphering among the p16+ population a very favorable outcome population could be of interest for patients tailored approaches.

The Current Role of Whole Brain Radiation Therapy in Non-Small Cell Lung Cancer Patients.

The incidence of brain metastases has increased in patients with NSCLC as a result of better systemic disease control and advances in imaging modalities. Whole brain radiotherapy (WBRT) has been the mainstay treatment of multiple symptomatic brain metastases for years. A number of recent publications have questioned its place in the absence of a survival and quality of life benefit and the possible risk for long-term neurotoxicity. Omission or deferral of WBRT and strategies consisting of stereotactic radiosurgery or delivery of systemic therapies alone are being proposed more and more. However, critical analysis of the literature shows that WBRT still has relevant indications in well-selected patients. Within this review, we discuss the place of WBRT in the modern management of patients with NSCLC.

Predictive and prognostic value of CT based radiomics signature in locally advanced head and neck cancers patients treated with concurrent chemoradiotherapy or bioradiotherapy and its added value to Human Papillomavirus status.

To explore prognostic and predictive value of radiomics in patients with locally advanced head and neck squamous cell carcinomas (LAHNSCC) treated with concurrent chemoradiotherapy (CRT) or bioradiotherapy (BRT).

Risk factors for burnout among caregivers working in nursing homes.

(i) To assess the level of burnout in nursing home caregivers within a unique healthcare network in France and (ii) to evaluate potential risk factors in this population.

Stereotactic ablative body radiation therapy or surgery for operable early non-small cell lung cancer patients: bound hand and foot to evidence.

Prognostic value of tumor mutations in radically treated locally advanced non-small cell lung cancer patients.

Chemo-radiation is standard treatment in locally advanced non-small cell lung cancers (NSCLC). The prognostic value of mutations has been poorly explored in this population.

Candidate immune biomarkers for radioimmunotherapy.

Newly available immune checkpoint blockers (ICBs), capable to revert tumor immune tolerance, are revolutionizing the anticancer armamentarium. Recent evidence also established that ionizing radiation (IR) could produce antitumor immune responses, and may as well synergize with ICBs. Multiple radioimmunotherapy combinations are thenceforth currently assessed in early clinical trials. Past examples have highlighted the need for treatment personalization, and there is an unmet need to decipher immunological biomarkers that could allow selecting patients who could benefit from these promising but expensive associations. Recent studies have identified potential predictive and prognostic immune assays at the cellular (tumor microenvironment composition), genomic (mutational/neoantigen load), and peripheral blood levels. Within this review, we collected the available evidence regarding potential personalized immune biomarker-directed radiation therapy strategies that might be used for patient selection in the era of radioimmunotherapy.

Contribution of image-guided adaptive brachytherapy to pelvic nodes treatment in locally advanced cervical cancer.

With the increasing use of simultaneous integrated boost in the treatment of cervical cancer, there is a need to anticipate the brachytherapy (BT) contribution at the level of the pathologic pelvic lymph nodes. This study aimed to report the dose delivered at their level during BT.

Outcomes and prognostic factors for squamous cell carcinoma of the oral tongue in young adults: a single-institution case-matched analysis.

There is controversy regarding prognosis and treatment of young patients with oral cavity cancer compared to their older counterparts. We conducted a retrospective case-matched analysis of all adult patients younger than 40 years and treated at our institution for a squamous cell carcinoma of the oral cavity. Only non-metastatic adult patients (age >18) with oral tongue cancer were eventually included and matched 1:1 with patients over 40 years of age, at least 20 years older than the cases, with same T and N category and treatment period. Sixty-three patients younger than 40 had an oral cavity squamous cell cancer out of which 57 had an oral tongue primary during the period 1999-2012, and 50 could be matched with an older control. No difference could be seen between younger and older patients with regard to overall, cancer-specific, or progression-free survival. The patterns of failure were similar, although in young patients, almost all failures occurred during the first 2 years following treatment. Although overall survival shows a trend toward lower survival in older patients, cancer-specific survival and analysis of pattern failure suggest that disease prognosis is similar between young and older adults with oral tongue cancer. Further work is needed to identify the younger patients with poorer prognosis who overwhelmingly fail during the first year after treatment and could benefit from treatment intensification. Until then, young adults ought to be treated using standard guidelines.

Induction chemotherapy with docetaxel, cisplatin and fluorouracil followed by concurrent chemoradiotherapy or chemoradiotherapy alone in locally advanced non-endemic nasopharyngeal carcinoma.

To evaluate the efficacy of induction chemotherapy with docetaxel, cisplatin and fluorouracil (TPF) followed by concurrent chemoradiotherapy (IC+CCRT) or CCRT alone in non-endemic locally advanced nasopharyngeal carcinoma (NPC) patients.

Stereotactic ablative radiotherapy for early stage non-small cell lung cancer: A critical literature review of predictive factors of relapse.

Stereotactic ablative radiation therapy (SABR) has become the standard treatment for peripheral medically non-operable patients with early stage non-small cell lung cancer (NSCLC). Previous attempts of trials to compare SABR and surgery have failed and new randomized studies (SABRtooth, STABLEMATES, and VALOR) are ongoing. While predictive factors of relapse have been extensively studied in patients receiving surgery, there is scarce data on such putative factors in SABR patients. The purpose of this review is to analyze such predictive factors through a critical review of the literature.

A phase II open-label multicenter study of gefitinib in combination with irradiation followed by chemotherapy in patients with inoperable stage III non-small cell lung cancer.

Gefitinib is an oral EGFR tyrosine kinase inhibitors which may act as a radiosensitizer.

Concurrent irradiation with the anti-programmed cell death ligand-1 immune checkpoint blocker durvalumab: Single centre subset analysis from a phase 1/2 trial.

To assess preliminary safety and efficacy results of the anti-programmed cell death ligand-1 (anti-PD-L1) durvalumab in combination with radiotherapy (RT) in an expansion cohort of patients included in a phase 1/2 trial at our institution.

Abscopal effect in a Hodgkin lymphoma patient treated by an anti-programmed death 1 antibody.

Primary Extremity Soft Tissue Sarcomas: Does Local Control Impact Survival?

The objective of this study was to evaluate the adequate margin in the local treatment of extremity soft tissue sarcomas (ESTS) and understand the relationship between local control and overall survival (OS).

Concurrent chemoradiotherapy with cisplatin or cetuximab for locally advanced head and neck squamous cell carcinomas: Does human papilloma virus play a role?

The optimal concurrent regimen, chemoradiotherapy (CRT) or bioradiotherapy (BRT), in locally advanced head and neck squamous cell carcinoma (LAHNSCC) remains controversial, especially in human papilloma virus-associated patients.

Sinonasal squamous cell carcinoma without clinical lymph node involvement : Which neck management is best?

The purpose of this work was to report outcomes of patients with nonmetastatic sinonasal squamous cell carcinoma (SNSCC) and to discuss the impact of elective neck irradiation (ENI) and selective neck dissection (SND) in clinically negative lymph node (N0) patients.

Can immunostimulatory agents enhance the abscopal effect of radiotherapy?

Ionising radiation (IR) may harm cancer cells through a rare indirect out-of-field phenomenon described as the abscopal effect. Increasing evidence demonstrates that radiotherapy could be capable of generating tumour-specific immune responses. On the other hand, effects of IR also include inhibitory immune signals on the tumour microenvironment. Following these observations, and in the context of newly available immunostimulatory agents in metastatic cancers (anti-cytotoxic T lymphocyte-associated antigen 4 and programmed cell death protein-1 or -ligand 1 [PD1 or PDL-1]), there is a remarkable potential for synergistic combinations of IR with such agents that act through the reactivation of immune surveillance. Here, we present and discuss the pre-clinical and clinical rationale supporting the enhancement of the abscopal effect of IR on the blockade of immune checkpoints and discuss the evolving potential of immunoradiotherapy.

Development and external validation of two nomograms to predict overall survival and occurrence of distant metastases in adults after surgical resection of localised soft-tissue sarcomas of the extremities: a retrospective analysis.

The current American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system does not have sufficient details to encompass the variety of soft-tissue sarcomas, and available prognostic methods need refinement. We aimed to develop and externally validate two prediction nomograms for overall survival and distant metastases in patients with soft-tissue sarcoma in their extremities.

Phase I trial evaluating the antiviral agent Cidofovir in combination with chemoradiation in cervical cancer patients.

This phase I trial aimed to assess the safety and determine the recommended Phase II dose (RP2D) of Cidofovir combined with chemoradiotherapy in patients with stage IB2-IVA cervical cancer.

Optimize and refine therapeutic index in radiation therapy: Overview of a century.

In 1936, Holthusen theorized the probability of achieving tumor control and of developing normal tissue complications after radiotherapy as a function of radiation dose. This concept was formalized and further developed in 1975. Several concepts for improving the therapeutic gain had been anticipated, including the possibility of modulating the tumor/normal tissue differential response. Eight decades later, it is possible to review and analyze progress achieved in the knowledge of radiation-induced toxicity. The clinical developments using new technologies and biological modulators of radiation response have corroborated a posteriori this model, however, many questions remain unanswered. A few randomized trials have validated the benefit of modern irradiation techniques for improving the therapeutic index; but the level I evidence of a survival improvement is still lacking. In the field of bio-modulation, large meta-analyses have shown that concurrent chemotherapy improves local control in many cancer types. Clinical investigations using molecularly targeted therapies have been rather disappointing, with only one exception: head and neck squamous cell carcinoma. Numerous recent biological findings question the possibility to target tumor tissue without impacting normal tissue response. Moreover, the abscopal and bystander effects suggest that normal tissue irradiation should not be perceived only as a source of toxicity, but may also result in downstream therapeutic effects. This paper reexamines the multiple efforts made to modulate the tumor versus normal tissue differential response, which have translated into incremental therapeutic gain and highlights the ongoing effort to better understand the optimal integration of radiation biology, chemotherapeutic, novel drugs and novel technologies.

Treatment of squamous cell carcinoma of the posterior pharyngeal wall: Radiotherapy versus surgery.

Treatment strategy in squamous cell carcinoma (SCC) of the posterior pharyngeal wall is still being debated.