[Clinical research in private sector: Which strategic analysis?] / Recherche clinique en structure libérale : quelle analyse stratégique ?

Clinical research in private practice has significantly increased in recent years and has become crucial for the attractiveness of centres both for patients who can access innovative treatments and molecules and for participating physicians. The responsiveness, the size and reduced number of interlocutors, flexibility, and decision-making autonomy of private practitioners are strengths in the strategic analysis of clinical research in the private sector. However, the varied medical activity allowing for broader recruitment, location of practice, and administrative time related leadership roles can become weakness in terms of quality and time dedicated to this research activity, which still relies heavily on strong individual involvement. Collaborations, which develop when clinical research in private centres is dynamic, are sources of opportunities, growth, and progress, allowing participation in various ambitious projects that can benefit patients in these facilities. Recent administrative and legislative complexities for trial integration and competition with academic structures can threaten this important clinical research activity for private practices, requiring reflection on its valorisation and promotion to ensure its sustainability.

[Real world data in radiotherapy: A data farming project by Unitrad]. / Données de vie réelle en radiothérapie : le data farming du groupe Unitrad.

The aim of the data farming project by the Unitrad group is to produce and use large quantities of structured real-life data throughout radiotherapy treatment. Starting in 2016, target real world data were selected at expert consensus conferences and regularly updated, then captured in MOSAIQ© as the patient was treated. For each partner institution, the data was then stored in a relational database, then extracted and used by researchers to create real world knowledge. This production was carried out in a multicentre, coordinated fashion. When necessary, the raw data was shared according to the research projects, in compliance with regulations. Feedack was provided at each stage, enabling the system to evolve flexibly and rapidly, using the "agile" method. This work, which is constantly evolving, has led to the creation of health data warehouses focused on data of interest in radiotherapy, and the publication of numerous academic studies. It forms part of the wider context of the exploitation of real-life data in cancerology. Unitrad data farming is a collaborative project for creating knowledge from real-life radiotherapy data, based on an active network of clinicians and researchers.

[Prognostic factors of acute radiodermatitis in breast cancer after adjuvant radiotherapy treated with RT3D or IMRT]. / Étude des facteurs pronostiques de radiodermite aiguë dans le cancer du sein traité par irradiation conformationnelle adjuvante avec ou sans modulation d'intensité.

PURPOSE: Real life study of prognostic factors of acute radiodermatitis in a monocentric cohort of 200 patients with breast cancer treated with RT3D or IMRT for adjuvant radiotherapy. PATIENTS AND METHODS: This study comprises 200 patients with breast cancer treated with adjuvant radiotherapy, included consecutively. For each patient, their clinical and tumoral characteristics and the irradiation schedule was retrospectively collected. The severity of acute radiodermatitis was also collected, during the treatment and 6weeks after the end of irradiation. The objective was to identify risk factors for acute radiodermatitis grade≥2. RESULTS: The univariate analysis found that a more important BMI (p<0.001), a more important volume of PTV (p<0.001) a normofractionated schedule (p=0.002) were statistically associated to a greater risk of occurrence of grade≥2 acute radiodermatitis. The multivariate analysis found BMI>30 (OR=9.31, p=0.04), light phototype (OR=0.04, p=0.02) and histology other than invasive breast carcinomas (OR=0.07, p=0.04) to be statistically associated to the occurrence of grade≥2 acute radiodermatitis. CONCLUSION: In this monocentric retrospective study, with a prospective collection of the severity of acute radiodermatitis, no grade 3 radiodermatitis has been observed and the frequency of occurrence of grade 2 radiodermatitis was lower than previously published. In contrast to previously published results, IMRT was not associated to a lower risk of grade≥2 acute radiodermatitis. Multivariate analysis found BMI, phototype, and histology to be risk factors of grade≥2 acute radiodermatitis.

Histosurgical mapping of endoscopic endonasal surgery of sinonasal tumours to improve radiotherapy guidance.

PURPOSE: Endoscopic endonasal surgery (EES) is becoming a standard for most malignant sinonasal tumours. Margin analysis after piecemeal resection is complex and optimally relies on accurate histosurgical mapping. Postoperative radiotherapy may be adapted based on margin assessment mapping to reduce the dose to some sinonasal subvolumes. We assessed the use of histosurgical mapping by radiation oncologists (RO). MATERIAL AND METHODS: A French practice survey was performed across 29 ENT expert RO (2 did not answer) regarding integration of information on EES, as well as quality of operative and pathology reportsto refine radiotherapy planning after EES. This was assessed through an electronic questionnaire. RESULTS: EES was ubiquitously performed in France. Operative and pathology reports yielded accurate description of EES samples according to 66.7% of interviewed RO. Accuracy of margin assessment was however insufficient according to more than 40.0% of RO. Additional margins/biopsies of the operative bed were available in 55.2% (16/29) of the centres. In the absence of additional margins, quality of resection after EES was considered as microscopically incomplete in 48.3% or dubious in 48.3% of RO. As performed, histosurgical mapping allowed radiotherapy dose and volumes adaptation according to 26.3% of RO only. CONCLUSIONS: Standardized histosurgical mapping with margin and additional margin analysis could be more systematic. Advantages of accurate EES reporting could be dose painting radiotherapy to further decrease morbidity in sinonasal tumours.

A priori quality assurance using a benchmark case of the randomized phase 2 GORTEC 2014-14 in oligometastatic head and neck cancer patients.

PURPOSE: A Benchmark Case (BC) was performed as part of the quality assurance process of the randomized phase 2 GORTEC 2014-14 OMET study, testing the possibility of multisite stereotactic radiation therapy (SBRT) alone in oligometastatic head and neck squamous cell carcinoma (HNSCC) as an alternative to systemic treatment and SBRT. MATERIAL AND METHODS: Compliance of the investigating centers with the prescription, delineation, planning and evaluation recommendations available in the research protocol was assessed. In addition, classical dosimetric analysis was supplemented by quantitative geometric analysis using conformation indices. RESULTS: Twenty centers participated in the BC analysis. Among them, four major deviations (MaD) were reported in two centers. Two (10%) centers in MaD had omitted the satellite tumor nodule and secondarily validated after revision. Their respective DICE indexes were 0.37 and 0 and use of extracranial SBRT devices suboptimal There were significant residual heterogeneities between participating centers, including those with a similar SBRT equipment, with impact of plan quality using standard indicators and geometric indices. CONCLUSION: A priori QA using a BC conditioning the participation of the clinical investigation centers showed deviations from good SBRT practice and led to the exclusion of one out of the twenty participating centers. The majority of centers have demonstrated rigorous compliance with the research protocol. The use of quality indexes adds a complementary approach to improve assessment of plan quality.

[New concepts of medical consultation in oncology]. / Nouveaux concepts de consultations médicales en oncologie.

New concepts of medical consultations are currently disrupting the practice of medicine. The use of standardized questionnaires, or patient-reported outcome (PRO and ePRO) has already significantly changed the relationship between the physician and the patient. Telemedicine, or even automatic conversational agents, such as chatbots, are also providing more convenient access to care and medical information for many patients. These tools have a major impact in oncology, precisely because of the rising chronicity of the diseases the radiation oncologists treat. In this article, we provide a detailed analysis of these new concepts.

[Radiotherapy of bone metastases in France: A descriptive monocentric retrospective study]. / Radiothérapie des métastases osseuses en France : étude descriptive rétrospective monocentrique.

PURPOSE: Bone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients. MATERIAL AND METHODS: A retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed. RESULTS: Ninety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25-88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re-irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001). CONCLUSION: This study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients.

[Prognostic factors for head and neck cancer reirradiation: A systematic review]. / Facteurs pronostiques de la ré-irradiation des cancers des voies aérodigestives supérieures : revue de la littérature.

PURPOSE: To specify the effectiveness of head and neck cancer reirradiation and make a synthesis of prognostic factors established by published series of patients. MATERIALS AND METHODS: Original series of external reirradiation of head and neck cancer with at least ten patients were sought in Medline database. RESULTS: Exclusive reirradiation with or without concurrent chemotherapy offers 11 months of median overall survival, versus 6 months for chemotherapy alone, and 20 to 40% of the patients are still alive two years after treatment. Postoperative reirradiation allows 3 years overall survival from 40 to 60%. However, side effects of grade 3 or more arise in more than half of patients. Patient-related good prognostic factors are male, young age, good performance status without comorbidities. Those related to the disease are low rT and rN stage, poor differentiation, other than squamous cell carcinomas and a nasopharyngeal, oropharyngeal or laryngeal location. Concerning the treatment, surgical resection, a dose higher than 50 to 60Gy in a smaller-irradiated volume, an interval between the two treatments of more than 2 years and the use of an innovating technology are the most commonly highlighted prognostic factors. Concurrent chemotherapy is often associated with higher toxicity rates, without improving overall survival, unless using cisplatin for selected patients. CONCLUSIONS: Head and neck cancer reirradiation achieves long-term survival outcomes. However, regarding to its associated side effects, patients need to be carefully selected based on prognostic factors.

[Choroidal metastasis from a lung adenocarcinoma treated by intravitreal injection of anti-VEGF and external beam radiotherapy: A case report]. / Métastases choroïdiennes d'un adénocarcinome pulmonaire traité par injections intravitréennes d'anti-VEGF et irradiation externe : à propos d'un cas.

Choroidal metastases of lung cancer are very uncommon. This localization should be suspected on blurred vision and confirmed with an ophthalmological examination. Its treatment is not entirely codified. We report a case of blurred vision secondary to bilateral choroidal metastasis in a patient with choroidal metastases from a lung adenocarcinoma, treated by intravitreal anti-vascular endothelial growth factor (VEGF) injection and external beam radiotherapy. According to a literature review, we analyzed the place of the targeted treatments used alone or combined with the radiotherapy.

Copy-number analysis identified new prognostic marker in acute myeloid leukemia.

Recent advances in genomic technologies have revolutionized acute myeloid leukemia (AML) understanding by identifying potential novel actionable genomic alterations. Consequently, current risk stratification at diagnosis not only relies on cytogenetics, but also on the inclusion of several of these abnormalities. Despite this progress, AML remains a heterogeneous and complex malignancy with variable response to current therapy. Although copy-number alterations (CNAs) are accepted prognostic markers in cancers, large-scale genomic studies aiming at identifying specific prognostic CNA-based markers in AML are still lacking. Using 367 AML, we identified four recurrent CNA on chromosomes 11 and 21 that predicted outcome even after adjusting for standard prognostic risk factors and potentially delineated two new subclasses of AML with poor prognosis. ERG amplification, the most frequent CNA, was related to cytarabine resistance, a cornerstone drug of AML therapy. These findings were further validated in The Cancer Genome Atlas data. Our results demonstrate that specific CNA are of independent prognostic relevance, and provide new molecular information into the genomic basis of AML and cytarabine response. Finally, these CNA identified two potential novel risk groups of AML, which when confirmed prospectively, may improve the clinical risk stratification and potentially the AML outcome.

[Orodental status before radiation therapy of the head and neck area: A prospective analysis on 48 patients]. / État buccodentaire des patients avant radiothérapie des voies aérodigestives supérieures : analyse prospective de 48 patients.

PURPOSE: The treatment by irradiation of tumours of the upper head and neck tract cause many complications on the oral sphere, such as mucositis, dysphagia, asialia and tooth decay. Associated manifestations are frequent and their severity has been poorly studied. However, the patient's quality of life is directly correlated with their oral health. PATIENTS AND METHODS: We carried out an evaluation of the oral health of 48 patients with an upper head and neck tract cancer treated by irradiation at the Paul-Strauss Centre in Strasbourg. The inclusion criteria of this study concerned the localization of the tumour in the upper head and neck tract and a treatment by irradiation associated or not to chemotherapy. RESULTS: The patients of the study were concerned by alcohol and smoking intoxication, on average, 22.2 pack-year and 2.2 glasses of alcohol per day. They received an irradiation of 60.9Gy on average. Their oral health was characterized by a DMFT (decayed, missing, filled teeth) index of 16.1, with, in mean, eight missing teeth and eight filling teeth and, by the presence of dental plaque in 70% of cases. Along the treatment by irradiation, the oral complications evaluation showed that on average, patients developed mucositis 18 days after the beginning of radiotherapy, xerostomia after 20 days, and dysphagia after 17 days. At the end of the treatment, we noted an oral hygiene improvement, with teeth brushing more frequent (two to three per day), mouthwash use, and daily fluoride prophylaxis. CONCLUSION: This study provides insights of the dental status of patients irradiated in the oral cavity. This series lays the groundwork for the study of prosthesis requirement and dosimetry calculation.

[Dental state in patients with head and neck cancers]. / État dentaire des patients atteints d'un cancer des voies aérodigestives supérieures.

In France, in 2005, there were approximately 16,000 new cases of head and neck cancer. These cancers have an unfavourable prognosis: the survival rates at 3 and 10 years are 50% and 10% respectively. The consumption of alcohol and tobacco is the most important risk factor; in some countries HPV infection was identified as a risk factor of head and neck tumours. Furthermore, a poor oral hygiene seems to raise this risk. We found many decay and periodontium problems in patients with an upper aerodigestive tract cancer. An evaluation of dental state is necessary before any cancer treatment. Treatments by radiotherapy engender noxious effects: hypocellular, hypovascularization, hypoxie of the irradiated tissues, which lead to immediate and chronically oral complications such as mucositis, fibrosis, xerostomia, decay, or osteoradionecrosis. An oral follow-up of these patients can prevent these complications, or reduce the severity of oral complications, and promote a good oral state.

[Constraints of the dentist are consistent with the results of an optimal irradiation with modulated intensity in N0 oropharyngeal cancer]. / Les contraintes du chirurgien dentiste sont compatibles avec les résultats d'une irradiation optimale avec modulation d'intensité dans les cancers de l'oropharynx de stade N0.

PURPOSE: We compared intensity-modulated radiotherapy and 3D-conformal irradiation in oropharyngeal cancers according to the requirement of dentists. MATERIAL AND METHODS: From the files of seven patients with cancer of the oropharynx, two dosimetry plannings for 3D-conformal radiotherapy and intensity-modulated radiotherapy with tomotherapy were performed. The dose distributions in the target volumes and organs at risk in relation to the dental sphere were compared. RESULTS: For the planning target volume of the primitive tumour sites, average values of V95%, D2%, D98% and of the conformal index were statistically in favour of tomotherapy. For the planning target volume of node areas, averages values of V95%, D2%, D98% were statistically in favour of tomotherapy. For ipsi- and controlateral parotide glands, average values of V15Gy, V26Gy, V30Gy, V40Gy were significantly lower for tomotherapy. For the submaxillary glands, average values of mean doses and V40Gy were statistically in favour of tomotherapy. For the buccal cavity, the average values of V45Gy were statistically in favour of tomotherapy. For ipsi- and controlateral masseter muscles, the average values of mean doses were statistically in favour of tomotherapy. For the ipsi- and controlateral temporomandibular joints, average values of mean doses and V60Gy were statistically in favour of tomotherapy. For mandibular bone, average values of mean doses and V40Gy, V50Gy, V60Gy and V70Gy were statistically in favour of tomotherapy. For maxillary bone, average values of V40Gy, V50Gy and V60Gy were statistically in favour of tomotherapy. CONCLUSION: The radiation oncologist can constrain the intensity-modulated radiotherapy dosimetry to the needs of dentists to prevent or improve dental care and quality of life.

[Stereotactic radiotherapy of intracranial benign tumors]. / Radiothérapie en conditions stéréotaxiques des tumeurs bénignes intracrâniennes.

Stereotactic radiotherapy can be delivered in one fraction or in multiple fractions schedule. It is used in benign tumours such as meningiomas, mainly localized in the base of the skull, for acoustic schwannoma and pituitary tumours. Whatever the tumour, results with the Gamma Knife(®) are the most numerous, but those obtained by linear accelerators, adapted or dedicated, are comparable. The peripheral dose is preferred to the dose delivered to the isocentre. One fraction stereotactic irradiation should be proposed in small lesions and fractionated treatment for tumours larger. Whatever the tumour, the results are satisfactory with a control rate of 90%. However, this value reflects a disparity assessment, radiological stability for meningiomas, radiological stability and preservation of useful hearing in schwannoma and radiological stability and a decrease in hormonal secretions for pituitary adenomas. Overall complication rates are low. In total, the treatment of benign lesions with stereotactic irradiation gives satisfactory results with few complications.

[High-risk human papilloma virus associated oropharynx squamous cell carcinomas: clinical, biological implications and therapeutical perspectives]. / Carcinomes épidermoïdes oropharyngés liés à l'infection par les papillomavirus humains de haut risque oncogénique : aspects cliniques, biologiques et perspectives thérapeutiques.

The infection of the head and neck epithelium by high-risk human papillomaviruses (HPV) is a risk factor for cancer onset and development. The incidence of HPV-related head and neck squamous cell carcinoma is currently increasing. These lesions display distinct clinical features. HPV positive patients are often younger and have a smaller history of tobacco smoking and alcohol drinking, but have a history of virus-transmitting sex practices. HPV-related tumours are mainly found in the oropharynx, are more associated to a local lymph node invasion and display a poorly differentiated morphology. Despite these more aggressive features, HPV-positive head and neck squamous cell carcinomas correlate with an improved local control, disease-free and global survival. It is thought that HPV-driven specific biologic abnormalities underlie higher tumour sensitivity to chemotherapeutic drugs and ionizing radiations. The expression of the HPV E6 and E7 oncoproteins induce cell transformation by interfering with cell signalling pathways involved in apoptosis, cell cycle, angiogenesis and induce the overexpression of the CDKN2A gene. Therefore, alternative treatments based on therapies targeting these pathways in combination with radiation dose de-escalation could be proposed to HPV-positive patients, if they are properly and reliably identified.

ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response.

The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.

[Merkel cell carcinoma, role of radiotherapy and literature review]. / Les tumeurs à cellules de Merkel, rôle de la radiothérapie. Analyse de la littérature.

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin with features of epithelial differentiation. It occurs in older patients, appears on sun exposed areas and its incidence is increasing. The surgical excision with negative margins is the first treatment and adjuvant local irradiation now is well established but regional adjuvant (lymph nodes dissection or radiation therapy) remains discussed. MCC is chemosensitive but rarely chemocurable in patients with metastasis or locally advanced tumors. The most used therapy is platinum-based polychemotherapy.