Head and neck cancer patients under radiotherapy undergoing skin application of hydrogel dressing or hyaluronic acid: results from a prospective, randomized study.

PURPOSE: Acute radiodermatitis (ARD) is a frequent side effect of radiotherapy, a therapeutic option for head and neck squamous cell carcinoma (HNSCC). It is responsible for pain, quality of life (QoL) impairment, and increased risk of treatment discontinuation, which may compromise the prognosis for patients. Local therapies to prevent or alleviate ARD have been proposed without providing any high level of evidence to establish recommendations. METHODS: We implemented a prospective multicenter randomized study on patients with HNSCC treated with definitive radiotherapy to assess the impact on ear, nose, and throat (ENT) pain of the application of a hydrogel-based skin dressing (HydroTac®) compared with the application of hyaluronic acid (Ialuset®) during radiotherapy. RESULTS: Out of 130 enrolled patients, 48 patients per group were assessable for the main endpoint. No difference between groups was found: a worsening of ENT pain of 3 points or more on a visual analog scale from the initiation to 1 month after the end of the radiotherapy was observed for 8 patients (16.7%) who received HydroTac® compared to 13 patients (27%) who received Ialuset® (p = 0.342). The proportion of patients who experienced ARD and grades of ARD (CTCAE v4.0 criteria) were similar between groups. Patient compliance with radiodermatitis treatment was poor, with 56.1% of patients in the HydroTac® group having their treatment temporarily stopped. CONCLUSION: The application of a hydrogel dressing to prevent ARD during radiotherapy for HNSCC patients has failed to demonstrate a benefit. These results may be limited by the difficulties of applying the dressing.

Comparative analysis of response to treatments and molecular features of tumor-derived organoids versus cell lines and PDX derived from the same ovarian clear cell carcinoma.

BACKGROUND: In the era of personalized medicine, the establishment of preclinical models of cancer that faithfully recapitulate original tumors is essential to potentially guide clinical decisions. METHODS: We established 7 models [4 cell lines, 2 Patient-Derived Tumor Organoids (PDTO) and 1 Patient-Derived Xenograft (PDX)], all derived from the same Ovarian Clear Cell Carcinoma (OCCC). To determine the relevance of each of these models, comprehensive characterization was performed based on morphological, histological, and transcriptomic analyses as well as on the evaluation of their response to the treatments received by the patient. These results were compared to the clinical data. RESULTS: Only the PDX and PDTO models derived from the patient tumor were able to recapitulate the patient tumor heterogeneity. The patient was refractory to carboplatin, doxorubicin and gemcitabine, while tumor cell lines were sensitive to these treatments. In contrast, PDX and PDTO models displayed resistance to the 3 drugs. The transcriptomic analysis was consistent with these results since the models recapitulating faithfully the clinical response grouped together away from the other classical 2D cell culture models. We next investigated the potential of drugs that have not been used in the patient clinical management and we identified the HDAC inhibitor belinostat as a potential effective treatment based on PDTO response. CONCLUSIONS: PDX and PDTO appear to be the most relevant models, but only PDTO seem to present all the necessary prerequisites for predictive purposes and could constitute relevant tools for therapeutic decision support in the context of these particularly aggressive cancers refractory to conventional treatments.

ORGAVADS: establishment of tumor organoids from head and neck squamous cell carcinoma to assess their response to innovative therapies.

BACKGROUND: Radiotherapy is one of the cornerstones of the treatment of Head and Neck Squamous Cell Carcinomas (HNSCC). However, radioresistance is associated with a high risk of recurrence. To propose strategies (such as combinations with drugs) that could over intrinsic radioresistance, it is crucial to predict the response to treatment. Patient-Derived Tumor Organoids (PDTO) are in vitro tridimensional microtumors obtained from patient' own cancer samples. They have been shown to serve as reliable surrogates of the tumor response in patients. METHODS: The ORGAVADS study is a multicenter observational trial conducted to investigate the feasibility of generating and testing PDTO derived from HNSCC for the evaluation of sensitivity to treatments. PDTO are obtained after dissociation of resected tumors remaining from tissues necessary for the diagnosis. Embedding of tumor cells is then performed in extracellular matrix and culture in medium supplemented with growth factors and inhibitors. Histological and immunohistochemical characterizations are performed to validate the resemblance between PDTO and their original tumor. Response of PDTO to chemotherapy, radiotherapy and innovating combinations are assessed, as well as response to immunotherapy using co-cultures of PDTO with autologous immune cells collected from patient blood samples. Transcriptomic and genetic analyses of PDTO allow validation of the models compared to patients' own tumor and identification of potential predictive biomarkers. DISCUSSION: This study is designed to develop PDTO models from HNSCC. It will allow comparing the response of PDTO to treatment and the clinical response of the patients from whom they are derived. Our aim is to study the PDTO ability to predict the clinical response to treatment for each patient in view of a personalized medicine as well as to establish a collection of HNSCC models that will be useful for future innovative strategies evaluation. TRIAL REGISTRATION: NCT04261192, registered February 7, 2020, last amendment v4 accepted on June, 2021.

[Patient-derived tumor organoids (or tumoroid), a growing preclinical model for oncology]. / Les tumoroïdes, modèles précliniques en plein essor pour l'oncologie.

The recent emergence of tumor organoid cultures, or tumoroids, has enriched the repertoire of preclinical models in oncology. These microtumors are obtained in vitro by including cells from patient tumor samples in an extracellular matrix and cultured in specific media. Very close to the tumor of origin, tumoroids can be amplified fairly rapidly from a small quantity of tissue, established with high success rate for most tumor types, easily genetically engineered, and stored in biobanks. Tumoroids thus offer numerous possibilities in terms of basic research, such as the study of carcinogenesis or mechanisms of chemoresistance, but also the identification of new targets and preclinical validation of new anti-cancer compounds or personalized medicine. Technological developments and enrichment of tumoroids with other cell types are currently ongoing to optimally exploit the full potential of these models.

Title: Les tumoroïdes, modèles précliniques en plein essor pour l'oncologie. Abstract: La récente émergence des cultures d'organoïdes tumoraux, ou tumoroïdes, a permis d'enrichir le répertoire des modèles précliniques en oncologie. Très proches de la tumeur dont elles dérivent, ces microtumeurs offrent de nombreuses possibilités en termes de recherche fondamentale, telles que l'étude de la carcinogenèse ou de la chimioré-sistance, de validation préclinique de nouvelles molécules à visée anticancéreuse, ou encore de personnalisation des traitements. Divers développements techniques et l'enrichissement des tumoroïdes par l'addition d'autres types cellulaires sont actuellement en cours pour améliorer la pertinence de ces modèles et exploiter de façon optimale leur remarquable potentiel.

[Patient-derived tumor organoids (or tumoroid) as valuable precision medicine tools]. / Les organoïdes dérivés de tumeurs (ou tumoroïdes), des outils de choix pour la médecine de précision en oncologie.

Review of literature shows that it is possible to establish tumor-derived organoids, or tumoroids, from almost any type of tumor, and that these "micro-tumors" could be used to develop functional assays allowing the prediction of the patient response to treatments and/or the identification of predictive molecular signatures associated with the development of these therapies. Although it is still essential to optimize culture conditions to promote and accelerate the establishment of tumoroids, or to recapitulate tumor microenvironment, many applications are now possible in the field of prediction of response to treatments and in guiding therapeutic decision-making. Using tumoroids as standard tools in clinical oncology could make precision oncology enter a new era in the coming decade. Numerous ongoing research and clinical trials conducted throughout the world aim to validate the interest of this approach.

Title: Les organoïdes dérivés de tumeurs (ou tumoroïdes), des outils de choix pour la médecine de précision en oncologie. Abstract: Il est désormais possible d'établir des tumoroïdes à partir de presque tout type de tumeur, notamment en vue de la mise en place de tests fonctionnels prédictifs et/ou de l'identification de signatures moléculaires prédictives. Bien que l'optimisation des conditions de culture ou la complexification du micro-environnement des tumoroïdes soit encore nécessaire, de nombreuses applications sont déjà envisageables dans le domaine de la prédiction de la réponse aux traitements et de l'orientation de la décision thérapeutique. Par l'introduction de leur utilisation en clinique, l'oncologie de précision pourrait bien entrer dans une nouvelle ère dans le courant de la décennie à venir.

Salvage total glossectomy and total glosso-laryngectomy: Are they worth it? A GETTEC French multicenter study.

BACKGROUND: Salvage total glossectomy (TG) or total glosso-laryngectomy (TGL) remain controversial, as highly morbid procedures. The objective was to describe oncological and functional outcomes after salvage TG or TGL. METHODS: We performed a multicenter retrospective study, including patients with previous neck irradiation undergoing TG or TGL for squamous cell carcinoma involving the base of tongue. RESULTS: We included 42 patients: 27 in the TG group and 15 in the TGL group. For the entire cohort, median OS and DFS were estimated at 19 months (95% IC [14-44]) and 10 months (95% IC [7-13]) respectively, with no difference between the two groups. After a median follow-up of 90 months, 10 patients (24%) were alive and free of disease. Att he end of follow-up, we noted a gastrostomy dependency of 89% and 87 %respectively in the TG and TGL group, and 48% of patients in the TG group had a tracheotomy. CONCLUSION: Although local control is difficult to achieve after salvage TG or TGL, these procedures are associated with acceptable survival and chance of cure for a last-resort situation. TG and TGL can be proposed in selected motivated patients after careful shared decision-making.

Oral tongue squamous cell carcinomas in young patients according to their smoking status: a GETTEC study.

BACKGROUND: Incidence of oral tongue squamous cell carcinoma (OTSCC) is increasing, especially in young adults, despite decreasing tobacco and alcohol consumption. METHODS: This multicentric retrospective study of 185 young adults with OTSCC (median follow-up 43 months), investigated risk factors, tumour characteristics and oncological outcomes according to the smoking status. RESULTS: Overall, 38% of patients were smokers (S). Non-smokers (NS) were significantly younger than S. Sex ratios were 1.1 for N and 1.8 for S. NS patients were less frequently cannabis or alcohol users than S, but were more likely to have a history of leukoplakia. Second primaries were observed in NS (4.4%) and in S (12.7%). Despite more frequent local relapse in NS (p = 0.018), there was no difference in diagnostic stage and overall survival between groups. CONCLUSION: OTSCC affects differently young S and NS patients suggesting the existence of a specific clinical entity of OTSCC in non-smoking young adults.

Impact of previous nivolumab treatment on the response to taxanes in patients with recurrent/metastatic head and neck squamous cell carcinoma.

BACKGROUND: Immune checkpoint inhibitors are widely used in recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We aimed to describe response rates to taxanes after progression on nivolumab in R/M HNSCC patients. METHODS: In this multicentric retrospective comparative study, we included patients treated with taxane monotherapy from 2014 to 2020. Patients were divided into two groups depending on whether they received nivolumab before taxanes (post-nivolumab group) or not (control group). The primary end-point was objective response rate (ORR) comparison between the two groups. The secondary end-points included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and PFS ratio (PFSr=PFS associated with taxanes divided by PFS associated with the previous line of treatment), a survival marker used for comparison of different treatment lines. RESULTS: Between July 2014 and August 2020, 185 patients were included (114 in the control group and 71 in the post-nivolumab group). ORR was significantly higher in the post-nivolumab group (39.4% versus 26.3%, p = 0.03) as was DCR (69% versus 50%, P = 0.06). The median OS (7.5 months) and PFS (3.5 months) were not significantly different in the two groups, whereas PFSr was significantly improved in the post-nivolumab group (1.63 versus 1.11, P = 0.004). CONCLUSION: Response and DCRs with taxanes are improved after prior exposure to nivolumab. Thus, taxane monotherapy could be a good choice as third-line therapy after nivolumab following a platinum-based first line. These results currently apply to patients without access to or potential benefit from first-line pembrolizumab.