Adapted EXTREME regimen in the first-line treatment of fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (ELAN-FIT): a multicentre, single-arm, phase 2 trial.

BACKGROUND: A standard treatment for fit, older patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) is yet to be established. In the previous EXTREME trial, few older patients were included. We aimed to evaluate the efficacy and tolerance of an adapted EXTREME regimen in fit, older patients with recurrent or metastatic HNSCC. METHODS: This single-arm, phase 2 study was done at 22 centres in France. Eligible patients were aged 70 years or older and assessed as not frail (fit) using the ELAN Geriatric Evaluation (EGE) and had recurrent or metastatic HNSCC in the first-line setting that was not eligible for local therapy (surgery or radiotherapy), and an Eastern Cooperative Oncology Group performance status of 0-1. The adapted EXTREME regimen consisted of six cycles of fluorouracil 4000 mg/m2 on days 1-4, carboplatin with an area under the curve of 5 on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m2 on cycle 1-day 1, and 250 mg/m2 subsequently), all intravenously, with cycles starting every 21 days. In patients with disease control after two to six cycles, cetuximab 500 mg/m2 was continued once every 2 weeks as maintenance therapy until disease progression or unacceptable toxicity. Granulocyte colony-stimulating factor was systematically administered and erythropoietin was recommended during chemotherapy. The study was based on the two-stage Bryant and Day design, combining efficacy and toxicity endpoints. The primary efficacy endpoint was objective response rate at week 12 after the start of treatment, assessed by central review (with an unacceptable rate of ≤15%). The primary toxicity endpoint was morbidity, defined as grade 4-5 adverse events, or cutaneous rash (grade ≥3) that required cetuximab to be discontinued, during the chemotherapy phase, or a decrease in functional autonomy (Activities of Daily Living score decrease ≥2 points from baseline) at 1 month after the end of chemotherapy (with an unacceptable morbidity rate of >40%). Analysis of the coprimary endpoints, and of safety in the chemotherapy phase, was based on the per-protocol population, defined as eligible patients who received at least one cycle of the adapted EXTREME regimen. Safety in the maintenance phase was assessed in all patients who received at least one dose of cetuximab as maintenance therapy. The study is registered with ClinicalTrials.gov, NCT01864772, and is completed. FINDINGS: Between Sept 27, 2013, and June 20, 2018, 85 patients were enrolled, of whom 78 were in the per-protocol population. 66 (85%) patients were male and 12 (15%) were female, and the median age was 75 years (IQR 72-79). The median number of chemotherapy cycles received was five (IQR 3-6). Objective response at week 12 was observed in 31 patients (40% [95% CI 30-51]) and morbidity events were observed in 24 patients (31% [22-42]). No fatal adverse events occurred. Four patients presented with a decrease in functional autonomy 1 month after the end of chemotherapy versus baseline. During chemotherapy, the most common grade 3-4 adverse events were haematological events (leukopenia [22 patients; 28%], neutropenia [20; 26%], thrombocytopenia [15; 19%], and anaemia [12; 15%]), oral mucositis (14; 18%), fatigue (11; 14%), rash acneiform (ten; 13%), and hypomagnesaemia (nine; 12%). Among 44 patients who received cetuximab during the maintenance phase, the most common grade 3-4 adverse events were hypomagnesaemia (six patients; 14%) and acneiform rash (six; 14%). INTERPRETATION: The study met its primary objectives on objective response and morbidity, and showed overall survival to be as good as in younger patients treated with standard regimens, indicating that the adapted EXTREME regimen could be used in older patients with recurrent or metastatic HNSCC who are deemed fit with use of a geriatric evaluation tool adapted to patients with head and neck cancer, such as the EGE. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC, and the Ligue Contre le Cancer), Sandoz, GEFLUC, and GEMLUC. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Twelve years after: The french national network on rare head and neck tumours (REFCOR).

BACKGROUND: Rare cancers constitute less than 10% of head and neck cancers and lack sufficient evidence for standardized care. The French Rare Head and Neck Cancer Expert Network (REFCOR) as established a national database to collect data on these rare cancers. This study aims to describe patient and tumour characteristics in this database. METHODS: Prospective data collection was conducted across multiple centers. Survival analyses were performed using Kaplan Meier method and Log Rank test. Odds ratios were used for comparing proportions. RESULTS: A total of 7208 patients were included over a period of 10 years. The most frequent histologies were: Not Otherwise Specified (NOS) adenocarcinoma 13 %, adenoid cystic carcinoma 12 %, squamous cell carcinoma of rare locations 10 %, mucoepidermoid carcinoma 9 %, intestinal-type adenocarcinoma (8 %). Tumours were located in sinonasal area (38 %); salivary glands (32 %); oral cavity / oropharynx / nasopharynx (16 %); larynx / hypopharynx (3 %); ears (1 %); others (3 %). Tumours were predominantly classified as T4 (23 %), N0 (54 %), and M0 (62 %). Primary treatment approach involved tumour resection (78 %) and / or radiotherapy (63 %). Patients with salivary gland cancers exhibited better 5-year overall survival (OS) rates (p < 0.05), and lower recurrence rates compared to patients with sinonasal, laryngeal/ hypopharyngeal cancers. No significant differences were observed in the other comparisons. Acinar cell carcinoma demonstrated the best OS while mucous melanoma had the poorest prognosis. CONCLUSION: Melanoma, carcinoma NOS, and sinonasal undifferenciated carcinoma still have poor prognoses. Efforts are being made, including training and guidelines, to expand network coverage (REFCOR, EURACAN), improve data collection and contribute to personalized therapies.

Locoregional treatment of primary tumor in synchronous metastatic head and neck squamous cell carcinomas.

PURPOSE: Patients with synchronous metastatic head and neck squamous cell carcinomas (mHNSCC) are at risk of locoregional progression associated with significant morbidity and mortality. The aim of this study is to assess whether the addition of aggressive locoregional treatment to systemic therapy could be associated with an improved overall survival (OS) compared to systemic therapy alone in upfront mHNSCC patients. MATERIAL AND METHODS: This retrospective study included patients presenting with previously untreated mHNSCC who underwent first-line systemic therapy at a single institution between 1998 and 2018. Locoregional treatment was defined as either exclusive locoregional radiotherapy (RT) or surgery with or without adjuvant RT. RESULTS: One hundred forty-eight patients were included. Eighty patients were treated with systemic therapy alone and 68 patients were treated with a combination of locoregional treatment and systemic therapy. Median overall survival (OS) was 13 months [10.7-15] and median progression free survival (PFS) was 7.7 month [6.5-8.9]. The addition of a locoregional treatment to systemic therapy compared to systemic therapy alone was associated with improved survival (1-year OS, 65.8% vs. 41.1%, p < .001, and 1-year PFS, 42.5% vs. 18.5%, p < .001). Moreover, RT dose equal to 70 Gy was associated with even longer OS compared to a RT dose below 70 Gy and to no locoregional treatment (23.4 vs. 12.7 vs 7.5 months respectively). In a subgroup analysis on 75 patients presenting with a responding or stable metastatic disease after first-line systemic therapy, oropharyngeal primary tumor site and the addition of a locoregional treatment, especially a high radiation dose of 70 Gy, were evidenced as independent prognostic factors for improved OS. CONCLUSION: The addition of a high-dose RT locoregional treatment to systemic therapy is associated with prolonged OS in patients with synchronous mHNSCC and should be discussed for patients who respond to or have a stable disease after first-line systemic therapy.

Survival outcomes, prognostic factors, and effect of adjuvant radiotherapy and prophylactic neck dissection in salivary acinic cell carcinoma: A prospective multicenter REFCOR study of 187 patients.

BACKGROUND: Acinic cell carcinomas (AciCCs) are malignant tumours of the salivary glands. The aim of this work was to analyse data from the national REFCOR multicenter cohort (i) to investigate the prognostic factors influencing survival outcomes in AciCC, (ii) to assess the impact on survival of postoperative radiotherapy (RT) in patients treated for AciCC without high-grade transformation and (iii) to explore the prognostic impact of prophylactic neck dissection (ND) in patients treated for AciCC of the major salivary glands. PATIENTS AND METHODS: Data from all the patients treated for salivary AciCC between 2009 and 2020 were extracted from the REFCOR database. Survival outcomes and prognostic factors influencing Disease-Free Survival (DFS) and Overall Survival (OS) were investigated using univariate and multivariate analyses. Propensity score matching was used to assess the impact of postoperative RT and prophylactic ND on DFS. RESULTS: A total of 187 patients were included. After a median follow-up of 53 months, their 5-year OS and DFS rates were 92.8% and 76.2%, respectively. In multivariate analysis, male sex, older age, higher T and N status, and high grade were independently associated with a worse DFS. In the subpopulation analysed after propensity score matching, patients with cN0 AciCC without high-grade transformation who were treated by surgery and RT did not have an improved DFS compared to patients who were treated by surgery alone (hazard ratio (HR) = 0.87, p = 0.8). Factors associated with nodal invasion were T3-T4 status and intermediate/high histological grade. After propensity score matching, prophylactic ND was associated with a trend toward a better DFS (HR = 0.46, p = 0.16). CONCLUSIONS: These results suggest that (i) long-term follow-up (>5 years) should be considered in patients with AciCC, (ii) treatment by surgery alone could be an option in selected cN0 patients with AciCC without high-grade transformation and (iii) prophylactic ND may be considered preferentially in patients with T3-T4 status and/or intermediate/high histological grade.

[Sinonasal cancers]. / Cancers nasosinusiens.

Sinonasal cancers. Sinonasal cancers (SNC) belong to the spectrum of rare tumors, with respect to other tumors of the head and neck and intrinsically by the multiple histological entities that they cover. It is important to raise awareness among physicians about the diagnostic and therapeutic elements of SNC, as well as their functional consequences, so that these patients are better diagnosed and monitored during and following specific oncological treatment. We also shed light on the various histological entities and new therapeutic options, in particular endoscopic surgery, conformational radiotherapy and systemic treatments. Finally, we underline the importance of the REFCOR network of expertise, which makes it possible to offer optimal management of these rare tumors, and of the CORASSO association, which provides patients a major additional extra-medical support.

Cancers nasosinusiens. Les cancers nasosinusiens (CNS) appartiennent au spectre des tumeurs rares, comparés aux autres tumeurs de la tête et du cou et, intrinsèquement, du fait des multiples entités histologiques qu'ils recouvrent. Il est important de sensibiliser les médecins sur leurs éléments diagnostiques et thérapeutiques ainsi que sur leurs conséquences fonctionnelles, afin que ces maladies soient mieux diagnostiquées et que les patients soient mieux suivis, au cours et dans les suites du traitement oncologique spécifique. Il convient aussi d'éclairer les praticiens sur les diverses entités histologiques et les nouvelles options thérapeutiques, en particulier la chirurgie endoscopique, la radiothérapie conformationelle et les traitements systémiques. Enfin, ils doivent connaître le réseau d'expertise REFCOR, qui permet de proposer une prise en charge optimale de ces tumeurs rares, et l'association CORASSO, qui assure aux patients un soutien extramédical complémentaire majeur.

[Cancers of the upper aerodigestive tract: the particular case of nasopharyngeal cancer]. / Cancers des voies aérodigestives supérieures : le cas particulier du_cancer du nasopharynx.

Nasopharyngeal carcinomas belong -in France- to the spectrum of rare diseases with several specificities owing to their etiology, epidemiology, diagnosis and therapeutics compared with other head and neck tumors. Educating physicians about the diagnostic and therapeutic elements of NPC and its functional consequences allows these patients to be better diagnosed and followed up during and after specific oncological treatment, and to enlighten them about the therapeutic options, in particular conformal radiotherapy, the mainstay of the management, and particularly effective systemic treatments. Prospects for treatment and follow-up are emerging, related or not to the specificity of this tumor often induced by the Epstein-Barr virus.

RÉSUMÉ CANCERS DES VOIES AÉRODIGESTIVES SUPÉRIEURES : LE CAS PARTICULIER DU CANCER DU NASOPHARYNX. Les carcinomes nasopharyngés (CNP) appartiennent ­ en France ­ au spectre des tumeurs rares, avec une singularité étiologique, épidémiologique, diagnostique et thérapeutique par rapport aux autres tumeurs de la tête et du cou. Sensibiliser les médecins aux éléments diagnostiques et thérapeutiques des CNP ainsi qu'aux conséquences fonctionnelles permet aux patients d'être mieux diagnostiqués et suivis au cours et dans les suites du traitement oncologique spécifique, et de les éclairer sur les options thérapeutiques, notamment la radiothérapie conformationnelle, pilier de la prise en charge, et les traitements systémiques particulièrement efficaces. Des perspectives de traitement et de suivi, liées ou non à la spécificité de cette tumeur souvent induite par le virus d'Epstein-Barr, se dessinent.

Precision Postoperative Radiotherapy in Sinonasal Carcinomas after Endonasal Endoscopic Surgery.

Radiotherapy plays an important role in the treatment of sinonasal cancer, mainly in the adjuvant setting after surgical resection. Many technological approaches have been described, including intensity-modulated radiotherapy, concomitant chemoradiotherapy, charged particle therapy or combined approaches. The choice is based on general criteria related to the oncological results and morbidity of each technique and their availability, as well as specific criteria related to the tumor (tumor extensions, pathology and quality of margins). The aims of this review are: (i) to provide an overview of the radiotherapy techniques available for the management of sinonasal malignant tumors and (ii) to describe the constraints and opportunities of radiotherapy owing to the recent developments of endonasal endoscopic surgery. The indication and morbidity of the different techniques will be discussed based on a critical literature review.

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

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.

Emerging therapeutic targets for nasopharyngeal carcinoma: opportunities and challenges.

Introduction: Nasopharyngeal carcinoma (NPC) is a major public health problem in several countries, especially those in Southeast Asia and North Africa. In its typical poorly differentiated form, the Epstein-Barr virus (EBV) genome is present in the nuclei of all malignant cells with restricted expression of a few viral genes. The malignant phenotype of NPC cells results from the influence of these viral products in combination with cellular genetic, epigenetic and functional alterations. With regard to host/tumor interactions, NPC is a remarkable example of immune escape in the context of a hot tumor.Areas covered: This article has an emphasis on emerging therapeutic targets that are considered upstream or at an early stage of clinical application. It examines targets related to cellular oncogenic alterations, latent EBV infection and tumor interactions with the immune system.Expert opinion: There is a remarkable emergence of new agents that target EBV products. The clinical application of these agents would benefit from a systematic and comprehensive molecular classification of NPCs and from easy access to pre-clinical models in public repositories. There is a strong rationale for more investigations on the potential of immune modulators, especially those related to NK cells.

Multimodal strategy for the management of sphenoid osteoradionecrosis: Preliminary results.

OBJECTIVE: Osteoradionecrosis (ORN) of the sphenoid is a rare but potentially lethal complication that can occur after irradiation of nasopharyngeal and clival malignancies. The objective of this study was to describe a multimodal treatment strategy tailored to the clinical signs and to the radiological extent of the disease, and to report on its preliminary results. METHODS: Retrospective monocentric study at a tertiary skull base center. Patients treated for a sphenoid ORN from January 2014 to August 2018 were identified and charts were retrospectively reviewed for demographics, histologic tumor type, previous treatments of the tumor, clinical signs at presentation, radiological data, treatment, and outcomes. Sphenoid ORN was treated by a combination of medical therapy, endovascular treatment, and/or surgery. The use of each of these therapeutic modalities was based on the extent of ORN and on the presenting signs. RESULTS: Seven patients were included: four patients underwent endovascular treatment with occlusion of the internal carotid artery, five patients underwent surgical debridement, and covering of the exposed bone by a local flap, seven patients received antibiotics (in combination with pentoxyphilline, tocopherol, and clodronate in one case). Three patients died after progression of the ORN. The global survival rate was 57% (4/7) with a mean follow-up of 24 months. In one case, ORN was treated successfully by medical treatment only, with a combination of antibiotics, pentoxyphilline, tocopherol, and clodronate. CONCLUSION: This retrospective study describes the results of a management strategy adapted to the extent of the disease in sphenoid ORN and based on medical therapy only, or on a combination of medical therapy, interventional radiology, and/or surgery. LEVEL OF EVIDENCE: 4.

[Diagnostic and treatment pitfalls and guidelines for variants of squamous cell carcinomas of the head and neck: on behalf of the REFCOR]. / Variants des carcinomes épidermoïdes dans les voies aérodigestives supérieures (VADS), implications pour le diagnostic et la prise en charge, selon les référentiels du REFCOR.

Among the 20,000 new cases of head and neck neoplasms in France each year, squamous cell carcinomas (HNSCC) represent about 90 % of the cases. Among these, variants of conventional squamous cell carcinomas represent between 5% and 10% of cases. Patient history and risk factors are often similar from those of conventional HSNCC. Variants may, however, be misdiagnosed, which can lead to therapeutic mismanagement due to confusion with sarcomas, glandular tumors or even benign tumors. Diagnostic workup needs to be more cautionary or to include additional exams not to omit their most aggressive component in the case of composite tumors or to under stage the tumor. Immunohistochemistry and specific molecular analyses may be required for proper diagnosis. Central pathological review may also be essential for some of these variants. In addition, some variants are radioresistant and, conversely, others are radiosensitive. An update of the REFCOR 2008 standards was carried out in the light of the international literature and the 2017 WHO/IARC classification for the seven main variants of HNSCC, verrucous, acantholytic (to be named adenoid carcinomas), basaloid, papillary, spindle cell (incorrectly named sarcomatoid), adenosquamous and lymphoepithelial carcinomas.

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

OBJECTIVES: 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. METHODS: Data from 104 nonmetastatic SNSCC patients treated with curative intent were retrospectively analysed. Uni- and multivariate analyses were used to assess prognostic factors of overall survival (OS) and locoregional control (LRC). RESULTS: Median follow-up was 4.5 years. Eighty-five percent of tumours were stage III-IV. Treatments included induction chemotherapy (52.9 %), surgery (72 %) and radiotherapy (RT; 87 %). The 5­year OS, progression-free survival, and LRC rates were 48, 44 and 57 %, respectively. Absence of surgery predicted a decrease of OS (hazard ratio [HR] 2.6; 95 % confidence interval [CI] 1.4-4.7), and LRC (HR 3.5; 95 % CI 1.8-6.8). Regional relapse was observed in 13/104 (13 %) patients and most common sites were level II (n = 12; 70.6 %), level III (n = 5; 29.4 %) and level Ib (n = 4; 23.5 %). Management of the neck in N0 patients (n = 87) included 11 % SND alone, 32 % ENI alone, 20 % SND + ENI and 37 % no neck treatment. In this population, a better LRC was found according to the management of the neck in favour of SND (94 % vs. 47 %; p = 0.002) but not ENI. CONCLUSION: SND may detect occult cervical positive nodes, allowing selective postoperative RT. ENI (ipsilateral level II, ±Ib and III or bilateral) needs to be proposed in selected patients, especially when SND has not been performed.

[Prognosis prediction of febrile neutropenia by MASCC score: A retrospective study]. / Prédiction de la gravité des neutropénies fébriles par le score de MASCC : une étude de cohorte rétrospective.

INTRODUCTION: The score of the MASCC, by means of clinical criteria, estimates the risk of serious complications in patients with neutropenic fever induced by chemotherapy. METHODS: We retrospectively studied a cohort of patients hospitalized for a neutropenic fever and analyzed complications according to the criteria defined by the MASCC. RESULTS: Eighty-one neutropenic fevers in 71 patients were identified. Microbiological documentation was obtained in 33% of cases only. Fifty-eight patients (72%) presented with a MASCC score≥21 and were considered as low risk of complications. In the total population, 10 patients died during their hospitalizations for neutropenic fever, 7 in the high-risk group versus 3 in the low risk group, including 2 patients suffering from significant comorbidities not taken into account by MASCC score. Within the low risk group, presence of a metastatic disease and existence of 2 or more comorbidities were associated with a longer duration of hospitalization. CONCLUSION: This analysis suggests that the criteria of the MASCC are not always enough to thoroughly identify which patients were at risk of complications or could be treated through outpatient management. By better taking into account the comorbidities and tumoral stage, a better selection of the patients who are likely to receive an ambulatory treatment could be made. To date, hospitalization remains frequently necessary in neutropenic fevers, at least in its initial steps, and the place of the general practitioner remains to be better defined.

Quick, non-invasive and quantitative assessment of small fiber neuropathy in patients receiving chemotherapy.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect; however, it is poorly investigated at an early stage due to the lack of a simple assessment tool. As sweat glands are innervated by small autonomic C-fibers, sudomotor function testing has been suggested for early screening of peripheral neuropathy. This study aimed to evaluate Sudoscan, a non-invasive and quantitative method to assess sudomotor function, in the detection and follow-up of CIPN. Eighty-eight patients receiving at least two infusions of Oxaliplatin only (45.4%), Paclitaxel only (14.8%), another drug only (28.4%) or two drugs (11.4%) were enrolled in the study. At each chemotherapy infusion the accumulated dose of chemotherapy was calculated and the Total Neuropathy Score clinical version (TNSc) was carried out. Small fiber neuropathy was assessed using Sudoscan (a 3-min test). The device measures the Electrochemical Skin Conductance (ESC) of the hands and feet expressed in microSiemens (µS). For patients receiving Oxaliplatin mean hands ESC changed from 73 ± 2 to 63 ± 2 and feet ESC from 77 ± 2 to 66 ± 3 µS (p < 0.001) while TNSc changed from 2.9 ± 0.5 to 4.3 ± 0.4. Similar results were observed in patients receiving Paclitaxel or another neurotoxic chemotherapy. During the follow-up, ESC values of both hands and feet with a corresponding TNSc < 2 were 70 ± 2 and 73 ± 2 µS respectively while they were 59 ± 1.4 and 64 ± 1.5 µS with a corresponding TNSc ≥ 6 (p < 0.0001 and p = 0.0003 respectively). This preliminary study suggests that small fiber neuropathy could be screened and followed using Sudoscan in patients receiving chemotherapy.

Safety of spinal radiotherapy in metastatic cancer patients receiving bevacizumab therapy: a bi-institutional case series.

We retrospectively assessed the outcome of patients receiving emergency spinal radiation therapy (RT) concurrently with bevacizumab. Clinical records of 18 consecutive patients receiving emergency spinal RT for symptomatic vertebral metastases during the course of bevacizumab-based therapy were examined. Patients were receiving biweekly bevacizumab combined with paclitaxel (n=17) or with docetaxel/carboplatin (n=1) or as a single agent (n=1) for advanced metastatic carcinoma. RT was delivered at doses of 30 Gy in 10 fractions (n=8), 20 Gy in five fractions (n=9) or 18 Gy in nine fractions (n=1). In 10 patients (56%), irradiation field encompassed the thoracic vertebrae. The median time interval between the bevacizumab infusion and the RT course was 1.5 days (0-8 days). The median follow-up was 8.3 months (2 days-42 months). A clinical benefit of RT was reported in 13 patients (72%), including four patients with complete pain relief. Two of the three patients with neurological impairment at the time of RT experienced a partial improvement in their symptoms. No pain recrudescence was reported within the irradiated field after RT completion. All toxicities were mild to moderate, with no acute toxicity reported in 13 patients (72%). No RT disruption was necessary because of acute toxicity. No delayed toxicity was reported within RT fields among 11 patients with at least 6 months of follow-up. Spinal RT during the course of bevacizumab-based therapy was not associated with the occurrence of unexpected adverse effects. This suggests that emergency RT should not be contraindicated in these patients, provided that doses and treatment volumes are defined carefully.

[Disseminated intravascular coagulation in solid tumours]. / Coagulation intravasculaire disséminée et tumeurs solides.

Disseminated intravascular coagulation (DIC) is a complex abnormality of hemostasis with dramatic consequences and long described as associated with tumors. Yet the diagnosis and management of paraneoplastic DIC are poorly defined. The purpose of this paper is to review DIC associated with solid tumors, at the pathophysiological and therapeutic levels in particular. We also report data from a recent retrospective series of patients with DIC in the context of a solid tumor, to illustrate the epidemiological, clinical and prognostic.

Treatment of nasopharyngeal carcinoma cells with the histone-deacetylase inhibitor abexinostat: cooperative effects with cis-platin and radiotherapy on patient-derived xenografts.

EBV-related nasopharyngeal carcinomas (NPCs) still raise serious therapeutic problems. The therapeutic potential of the histone-deacetylase (HDAC) inhibitor Abexinostat was investigated using 5 preclinical NPC models including 2 patient-derived xenografts (C15 and C17). The cytotoxicity of Abexinostat used either alone or in combination with cis-platin or irradiation was assessed in vitro by MTT and clonogenic assays using 2 EBV-negative (CNE1 and HONE1) and 3 EBV-positive NPC models (C15, C17 and C666-1). Subsequently, the 3 EBV-positive models were used under the form of xenografts to assess the impact of systemic treatments by Abexinostat or combinations of Abexinostat with cis-platin or irradiation. Several cell proteins known to be affected by HDAC inhibitors and the small viral non-coding RNA EBER1 were investigated in the treated tumors. Synergistic cytotoxic effects of Abexinostat combined with cis-platin or irradiation were demonstrated in vitro for each NPC model. When using xenografts, Abexinostat by itself (12.5 mg/kg, BID, 4 days a week for 3 weeks) had significant anti-tumor effects against C17. Cooperative effects with cis-platin (2 mg/kg, IP, at days 3, 10 and 17) and irradiation (1 Gy) were observed for the C15 and C17 xenografts. Simultaneously two types of biological alterations were induced in the tumor tissue, especially in the C17 model: a depletion of the DNA-repair protein RAD51 and a stronger in situ detection of the small viral RNA EBER1. Overall, these results support implementation of phase I/II clinical trials of Abexinostat for the treatment of NPC. A depletion of RAD51 is likely to contribute to the cooperation of Abexinostat with DNA damaging agents. Reduction of RAD51 combined to enhanced detection of EBER 1 might be helpful for early assessment of tumor response.

Consistent high concentration of the viral microRNA BART17 in plasma samples from nasopharyngeal carcinoma patients--evidence of non-exosomal transport.

BACKGROUND: Because latent Epstein Barr (EBV)-infection is a specific characteristic of malignant nasopharyngeal carcinoma (NPC), various molecules of viral origin are obvious candidate biomarkers in this disease. In a previous study, we could show in a few clinical samples that it was possible to detect a category of EBV microRNAs called miR-BARTs in the plasma of at least a fraction of NPC patients. The first aim of the present study was to investigate the status of circulating miR-BART17-5p (one of the miR-BARTs hereafter called miR-BART17) and EBV DNA in a larger series of NPC plasma samples. The second aim was to determine whether or not circulating miR-BART17 was carried by plasma exosomes. PATIENTS AND METHODS: Plasma samples were collected from 26 NPC patients and 10 control donors, including 9 patients with non-NPC Head and Neck squamous cell carcinoma and one healthy EBV carrier. Concentrations of miR-BART17 and two cellular microRNAs (hsa-miR-16 and -146a) were assessed by real-time quantitative PCR with spike-in normalization and absolute quantification. In addition, for 2 patients, exosome distributions of miR-BART17 and miR-16 were investigated following plasma lipoprotein fractionation by isopycnic density gradient ultrcentrifugation. RESULTS: The miR-BART17 was significantly more abundant in plasma samples from NPC patients compared to non-NPC donors. Above a threshold of 506 copies/mL, detection of miR-BART17 was highly specific for NPC patients (ROC curve analysis: AUC=0.87 with true positive rate = 0.77, false positive rate = 0.10). In this relatively small series, the concentration of plasma miR-BART17 and the plasma EBV DNA load were not correlated. When plasma samples were fractionated, miR-BART17 co-purified with a protein-rich fraction but not with exosomes. CONCLUSIONS: Detection of high concentrations of plasma miR-BART17 is consistent in NPC patients. This parameter is, at least in part, independent of the viral DNA load. Circulating miR-BART17 does not co-purify with exosomes.

[Disseminated and circulating tumor cells in gastrointestinal oncology]. / Cellules tumorales circulantes et disséminées en oncologie digestive.

Circulating (CTC) and disseminated tumor cells (DTC) represent two different steps of the metastatic process. As with other types of cancer, the recent development of techniques for the detection of CTC and DTC respectively in the blood and bone marrow of patients generated many results in digestive cancers. However, the interpretation of these results and of the prognostic value of CTC/DTC is often limited by the small cohort size and the heterogeneity of detection methods. The aim of this article is to review the different results and their clinical impact, and discuss the possible use of CTC and DTC as new biomarkers. First of all, it is important to take into account the variability of epithelial markers used for the initial stage of immunoselection of CTC/DTC as well as that of molecular or cytological markers used for the second stage of detection. In esophageal, gastric, pancreatic and hepatocellular carcinomas, and in the ileal and pancreatic neuroendocrine tumors, some studies showed a correlation between the detection of CTC and/or DTC and a clinical pejorative course, whether these tumors were at localized or metastatic stages. On colorectal cancer in the adjuvant setting, a recent meta-analysis showed an association between the detection of CTC in peripheral blood and disease-free survival or overall survival. These results are consistent with those of a study that identified detection of CTC as a prognostic factor for relapse in stage II. This last study concluded that it was necessary to achieve long-term evaluation of CTC as a biomarker to guide the decisions of chemotherapy for stage II. In metastatic colorectal cancer, the FDA approved in 2007 the use of pretherapeutic levels of CTC and its variations per-treatment, determined by CellSearch(®) technology, as a tool in treatments management. However, the modalities of this monitoring have to be specified and clinical benefit or the cost-effectiveness of a treatment based on this new biomarker has to be evaluated. Finally, the qualitative and quantitative monitoring of CTC could be a non-invasive tool to monitor changes in tumor biology throughout the disease, and thereby improve the understanding of the processes of dissemination and therapeutic resistance.

Effectiveness and safe use of modified FOLFOX-6 for metastatic gastric cancer with signet ring cell components complicated by disseminated intravascular coagulation and diffuse bone marrow carcinomatosis.

We report the case of a 62-year-old woman with a metastatic gastric cancer complicated by diffuse bone marrow carcinomatosis, disseminated intravascular coagulation (DIC) and microangiopathic hemolytic anemia (MHA) treated by modified FOLFOX-6 as front-line chemotherapy regimen. This chemotherapy showed clinical, morphological and biological efficiency and safety in this rare and severe hematological complication at initial diagnosis. Furthermore, this is the first case of diffuse bone carcinomatosis from a gastric cancer to be monitored by positron emission tomography integrated computed tomography (PET-CT) scan using 18-fluorodeoxyglucose (18-FDG).