Oral and oropharyngeal cancer surgery with free-flap reconstruction in the elderly: Factors associated with long-term quality of life, patient needs and concerns. A GETTEC cross-sectional study

Objectives: To assess the factors associated with long-term quality of life (QoL) and patient concerns in elderly oral or oropharyngeal cancer (OOPC) patients after oncologic surgery and free-flap reconstruction. Methods: Patients aged over 70 years who were still alive and disease-free at least 1 year after surgery were enrolled in this cross-sectional multicentric study. Patients completed the EORTC QLQ-C30, -H&N35 and -ELD14 QoL questionnaires, and the Hospital Anxiety and Depression Scale (HADS). Patient needs were evaluated using the Patient Concerns Inventory (PCI). Factors associated with these clinical outcomes were determined in univariate and multivariate analysis. Results: Sixty-four patients were included in this study. Long-term QoL, functioning scales and patient autonomy were well-preserved. Main persistent symptoms were fatigue, constipation and oral function-related disorders. Salivary and mastication/swallowing problems were the main patient concerns. The mean number of patient concerns increased with the deterioration of their QoL. Psychological distress (HADS score ≥ 15) and patient frailty (G8 score < 15) were significantly associated with poor QoL outcomes. Conclusions: We found a negative correlation between the number of patient concerns and QoL. Dental rehabilitation and psychological and nutritional supportive measures are of critical importance in the multidisciplinary management of elderly OOPC patients

Circulating tumor cells in the future of personalized radio(chimio)therapy for HNSCC patients

International audienceThe majority of Head and Neck Squamous Cell Carcinoma (HNSCC) patients have a locally advanced stage at diagnosis and unresectable tumors are treated by a combination of radio- and chemo-therapy. Locoregional recurrences and distant metastases appear in most patients, leading to a 5-year overall survival less than 50%. Metastases occur as the result of a cascade of events that begins with transition of cells from an epithelial to a mesenchymal phenotype (EMT), resulting in detachment from the primary tumor site, followed by intravasation of cells into the blood. The surviving cells, known as circulating tumor cells (CTCs), can extravasate into distant tissues where they form metastases. The presence of CTCs has been associated in different types of cancers (breast, lung) to a poor prognosis. In addition, CTCs may be partly cancer stem cells (CSCs). Early determination of the molecular profile of CTCs, which may be considered as a liquid biopsy, could therefore predict the response of HNSCC patients to radio(chemo)therapy and tumor escape.Our work focuses on the counting and molecular characterization of CTCs in a cohort of 20 patients with HNSCC recruited between May 2016 and March 2018 (NCT02714920). The 24-month follow-up is still ongoing. Blood samples and biopsies were taken at inclusion of patients and other blood samples were collected during treatment (radiochemotherapy). During the follow-up period, blood samples are taken in case of local relapse (with additional biopsy) or metastases.CTCs were isolated for each sample, counted, and their phenotype (epithelial, mesenchymal or CSC) characterized after immunohistochemical staining of specific proteins. The gene expression profile of CTCs and initial biopsies, focused on tumor progression and DNA repair pathways (Nanostring® technology), is being analyzed.Based on CTC counts and molecular signatures, we hope to rank patients as "good" and "bad" responders to treatment at an early stage of the disease and predict its progression. In the longer term, the collection of all these data will allow a better understanding of the tumor escape mechanisms to treatments and should lead to personalized and early treatment adaptation in addition to clinical data and imaging.Supported by Cancéropôle CLARA, Conseil Régional et Général du Rhône, LabEx PRIMES (ANR11LABX0063

Stratification of Head and Neck Cancers: DNA Repair Enzyme Signature to Identify Resistance and Toxicity Biomarkers

International audienceHead&Neck squamous cell carcinomas are highly heterogeneous tumors. Despite extensive research there are no prognostic and predictive biomarkers widely accepted for routine use in managing patients. In particular there is a critical need to identify patients who will benefit from radio and/or chemotherapy without developing resistance or sufferin from adverse effects.Indeed DNA is the principal target of these agents and the presence of defects in the DNA repair machinery can be associated with tumors resistance and individual sensitivity. Defining sub-group of patients according to their sensitivity/resistance is one of the main developments for increasing therapeutic effects.Tobacco consumption, a known carcinogen, is a strong risk factor for H&N cancer. Interestingly, its carcinogenic effect is directly linked to mutations associated with unrepaired DNA lesions it induces.The objective of this project was to characterize the effective individuals DNA repair capacity of tumor and blood samples obtained from patients treated for H&N cancer. Peripheral Blood Mononuclear Cells and tumor biopsies of patients were collected before and during the time course of chemo and/or radiotherapy. Whole cell extracts were prepared and tested for their DNA repair capacity toward a panel of different DNA lesions. In particular, we evaluated glycosylases/AP endonucleases and excision/synthesis repair activities with the patented Glyco-SPOT and ExSy-SPOT assays, respectively.Preliminary results revealed an inter-individual variability in DNA repair capacities at basal level and after treatment in both PBMCs and tumor cells which could be associated with treatment resistance or hypersensitivity.We believe the DNA Repair Enzyme signature could be a relevant strategy to stratify patients and tumours for a better personalisation of the treatments.The study was partly supported by the « Preuve du Concept » program from Cancéropôle Lyon Auvergne-Rhône-Alpes CLARA

Cellules Tumorales Circulantes : biomarqueurs prédictifs de l’échappement tumoral à la radio(chimio)thérapie dans les cancers des VADS ?

International audienceMalgré la combinaison de stratégies thérapeutiques comme la chirurgie, la chimio- et la radio-thérapie, la survie à 5 ans des patients atteints d’un cancer des VADS reste inférieure à 30% en raison de l’apparition de récidives locorégionales et/ou de métastases. Le phénomène métastatique est gouverné par une série complexe d’évènements incluant la migration, l’invasion et l’intravasation de cellules tumorales dans la circulation sanguine. Ces cellules dites cellules tumorales circulantes (CTCs), précurseurs de métastases, reflètent l’agressivité tumorale et son potentiel métastatique. Elles sont bien plus faciles d’accès que la tumeur d’origine et peuvent être considérées comme une « biopsie liquide » permettant d’avoir des informations en temps réel sur l’évolution du statut tumoral du patient. Les CTCs pourraient ainsi constituer un marqueur prédictif de la réponse tumorale et/ou de la rechute, indispensable aux cliniciens pour une adaptation thérapeutique individuelle. Notre étude se focalise sur leur comptage et leur caractérisation au cours du traitement par radio(chimio)thérapie et de la progression tumorale chez des patients atteints de cancers des VADS.Un prélèvement biopsique tumoral est réalisé à l’inclusion des patients atteints de cancer de l’oropharynx et de la cavité buccale et un prélèvement sanguin est fait à l’inclusion, à différents temps du traitement (chimiothérapie d’induction +/- radiothérapie ou RT seule), et en cas de récidive. Les CTCs sont isolées puis caractérisées par immuno-histochimie, avec des marqueurs de cellules souches cancéreuses et de la transition épithélio-mésenchymateuse. Leur profil d’expression génique est comparé à celui de la biopsie initiale.Les résultats préliminaires confirment que les techniques retenues permettent l’isolement, le comptage et la caractérisation des CTCs. Treize patients ont été inclus à ce jour. L’analyse préliminaire indique une grande hétérogénéité dans le nombre de CTCs comptées par patient. Différents phénotypes ont également été retrouvés au sein de ces CTCs, mésenchymateux pour certains patients, épithélial pour d’autres. L’analyse du profil d’expression génique est en cours sur notre plateforme Nanostring.Au terme du recrutement, les résultats de cette étude permettront de conclure si les résultats de l’analyse des CTCs sont prédictifs de la réponse individuelle à la radio(chimio)thérapie et/ou de l’échappement tumoral dans les cancers des VADS

A pyriform sinus cancer organ preservation strategy comprising induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil, followed by potentiated radiotherapy: a multicenter, retrospective study.

No specific study has evaluated the role of neoadjuvant DCF (docetaxel, cisplatin, 5-fluorouracil) followed by radiotherapy in pyriform sinus cancer, which are often included in studies focusing on laryngeal and hypopharyngeal cancer. We assessed the proportion of patients treated sequentially for a pyriform sinus cancer with a preserved larynx. Overall survival, event-free survival (EFS), survival with 'local control', and treatment tolerance were assessed as well. We retrospectively reviewed 88 patients with advanced pyriform sinus squamous cell carcinoma treated with DCF between 2005 and 2010. After induction, radiation could be potentiated with cetuximab or cisplatin. Most patients (82%) had been treated with organ preservation intent. The response rate to DCF was 85%, including 42% with complete response. Primary tumor was operated in 13 patients (eight with total laryngectomy). Radiotherapy had been delivered to 78 (89%) patients (30 with cisplatin, 39 with cetuximab). Potentiation had been achieved as planned in 52 and 79% of patients treated with cisplatin and cetuximab, respectively. Twenty-three local and three neck recurrences were found. Median overall survival was 16.8 months and 38.3% at 3 years. EFS at 3 years was 29.1% with a hazard ratio for partial responders versus nonresponders of 0.18 (P<0.001), and 0.13 (P<0.001) for complete responders versus nonresponders. Thirty-five percent of patients were alive with their larynx preserved at 3 years. This study confirms the efficacy of induction followed by chemoradiation for pyriform sinus cancer and that response to DCF is predictive of EFS

Circulating Tumor Cell Detection during Neoadjuvant Chemotherapy to Predict Early Response in Locally Advanced Oropharyngeal Cancers: A Prospective Pilot Study

Patients with locally advanced oropharyngeal carcinoma treated with neoadjuvant chemotherapy are reassessed both radiologically and clinically to adapt their treatment after the first cycle. However, some responders show early tumor progression after adjuvant radiotherapy. This cohort study evaluated circulating tumor cells (CTCs) from a population of locally advanced oropharyngeal carcinoma patients treated with docetaxel, cisplatin, and 5-fluorouracil (DCF) induction chemotherapy or DCF with a modified dose and fractioned administration. The counts and phenotypes of CTCs were assessed at baseline and at day 21 of treatment, after isolation using the RosetteSepTM technique based on negative enrichment. At baseline, 6 out of 21 patients had CTCs (28.6%). On day 21, 5 out of 11 patients had CTCs (41.6%). There was no significant difference in the overall and progression-free survival between patients with or without CTCs at baseline (p = 0.44 and 0.78) or day 21 (p = 0.88 and 0.5). Out of the 11 patients tested at day 21, 4 had a positive variation of CTCs (33%). Patients with a positive variation of CTCs display a lower overall survival. Our findings suggest that the variation in the number of CTCs would be a better guide to the management of treatment, with possible early changes in treatment strategy

CD44, gamma-H2AX, and p-ATM Expressions in Short-Term Ex Vivo Culture of Tumour Slices Predict the Treatment Response in Patients with Oral Squamous Cell Carcinoma

International audienceSquamous cell carcinoma is the most common type of head and neck cancer (HNSCC) with a disease-free survival at 3 years that does not exceed 30%. Biomarkers able to predict clinical outcomes are clearly needed. The purpose of this study was to investigate whether a short-term culture of tumour fragments irradiated ex vivo could anticipate patient responses to chemo- and/or radiotherapies. Biopsies were collected prior to treatment from a cohort of 28 patients with non-operable tumours of the oral cavity or oropharynx, and then cultured ex vivo. Short-term biopsy slice culture is a robust method that keeps cells viable for 7 days. Different biomarkers involved in the stemness status (CD44) or the DNA damage response (pATM and gamma-H2AX) were investigated for their potential to predict the treatment response. A higher expression of all these markers was predictive of a poor response to treatment. This allowed the stratification of responder or non-responder patients to treatment. Moreover, the ratio for the expression of the three markers 24 h after 4 Gy irradiation versus 0 Gy was higher in responder than in non-responder patients. Finally, combining these biomarkers greatly improved their predictive potential, especially when the gamma-H2AX ratio was associated with the CD44 ratio or the pATM ratio. These results encourage further evaluation of these biomarkers in a larger cohort of patients