Search

Objective: Radiotherapy (RT) against head and neck squamous cell carcinomas (HNSCC) may lead to severe toxicity in 30-40% of patients. The normal tissue complication probability (NTCP) models, based on dosimetric data refined the normal tissue dose/volume tolerance guidelines. In parallel, the radiation-induced nucleoshuttling (RIANS) of the Ataxia-Telangiectasia Mutated protein (pATM) is a predictive approach of individual intrinsic radiosensitivity. Here, we combined NTCP with RADIODTECT©, a blood assay derived from the RIANS model, to predict RT toxicity in HNSCC patients. Methods: RADIODTECT© cutoff values (i.e. 57.8 ng/mL for grade⩾2 toxicity and 46 ng/mL for grade⩾3 toxicity) have been previously assessed. Validation was performed on a prospective cohort of 36 HNSCC patients treated with postoperative RT. Toxicity was graded with the Common Terminology Criteria for Adverse Events (CTCAE) scale and two criteria were considered: grade⩾2 oral mucositis (OM2), grade⩾3 mucositis (OM3) and grade⩾2 dysphagia (DY2), grade⩾3 dysphagia (DY3). pATM quantification was assessed in lymphocytes of HNSCC patients. The discrimination power of the pATM assay was evaluated through the Area Under the Receiver Operator Characteristics Curve (AUC-ROC). Two previously described NTCP models were considered, including the dose to the oral cavity and the mean dose to the parotid glands (OM2 and OM3) and the dose to the oral cavity, to the larynx and the volume of pharyngeal constrictor muscles (DY2 and DY3). Results: Combining NTCP models with RADIODTECT© blood test improved the AUC-ROC. Considering the prediction of mucositis, AUC-ROCNTCP+RADIODTECT©=0.80 was for OM2, and AUC-ROCNTCP+RADIODTECT©=0.78 for OM3. Considering the prediction of acute dysphagia, AUC-ROCNTCP+RADIODTECT©=0.71 for DY2 and for DY3. Conclusions: Combining NTCP models with a radiosensitivity biomarker might significantly improve the prediction of toxicities for HNSCC patients.

BackgroundHead and Neck Squamous Cell Carcinoma is the 8th leading cancer worldwide and it is associated with significant morbidity and mortality.1 2 Tumor microenvironment (TME) is dynamic and it plays an important role in head and neck carcinogenesis.3 4 Cytotoxic T-cells, immune checkpoint molecules such as programmed cell death 1 (PD-1), its ligand (PD-L1), and other checkpoints molecules have been described in these tumors.1 3 This study aimed to characterize the TME of oral squamous cell carcinoma (OSCC) and compare with their pathology features.MethodsFour microns thickness consecutives slides from representative OSCC (N=46) cases were stained and analyzed using 11 biomarkers (CK, CD3, CD8, CD68, PD1, PDL1, LAG3, TIM3, ICOS, VISTA, OX40) placed in two multiplex immunofluorescence panels to characterize the TME. For image analysis, the samples were divided in tumor, stroma and peritumoral compartment. Co-expression of markers (cell phenotypes) where analyzed as densities by mm2 in each compartment. For PD-L1 expression by malignant cells (CK+PD-L1+) we set up a cutoff of positive case as ≥ than 1%. Cell phenotypes were correlated with anatomopathological information retrieved from records such as tumor size, margin status, stage and perineural, lymphovascular, and bone invasion among others. Statistical analyses and plots were performed using SPSS and Graphpad prism8 software packages.ResultsWe found significant higher cell density for CK+PDL1+ (P= 0.038), CD3+PDL1+ (P= 0.027), CD3+CD8+PDL1+ (P=0.040) in female patients compared with the male population. Interestingly, smaller tumor size (≤ median, 25mm) showed higher densities of CD3+ (P= 0.006), CD3+CD8+ (P= 0.007), CD3+PDL1+ (P= 0.037), CD3+CD8+PDL1+ (P= 0.016), CD3+ICOS+ (P= 0.036), CD3+VISTA+ (P= 0.001), CD68+ (P= 0.001) and CD68+PD-L1+ (P= 0.008) than large tumors. Additionally, high cell density CD3+OX40+ (P= 0.011) was observed in tumors without margin invasion and high cell density for macrophages CD68+ (p= 0.005) in tumors without bone invasion. In ulcerative and infiltrative tumor pattern we observed higher cell density of CD3+PDL1+ (P= 0.020), CD3+CD8+PDL1+ (P=0.006) and CD3+OX40+ (P= 0.022) than non-ulcerate and no infiltrative pattern. Lastly, 58.7% of cases were PDL1+.ConclusionsOur findings of a diminished immune response in larger tumors might be correlated to their potential role in tumor aggressiveness and progression. Furthermore, high cell density of macrophages on tumor bone invasion may suggest an immune suppressive M2 response supported by the presence of PDL1+ expression. All these results can be the first approach for the development of a treatment based of immune interception.AcknowledgementsThis study was supported by a strategic alliance between the Translational Molecular Pathology-Immunoprofiling las (TMP-IL) at the Department Translational Molecular Pathology, the University of Texas MD Anderson Cancer Center and the Université Claude Bernard Lyon, Centre de Recherche en Cancérologie de Lyon and the Department of Translational Medicine, Centre Léon Bérard, Lyon, France. The authors would acknowledge ITMO Cancer 2020, ”Formation à la Recherche Fondamentale et Translationnelle en Cancérologie” (JB); CLARA 2020 ”Soutien à la mobilité des jeunes chercheurs en oncologie, N° CVPPRCAN000198” (JB); Fondation de France 2020 ”Aide à la mobilité international de médecins et pharmaciens, N° 00112162” (JB); Ligue contre le cancer 2021, comité de Saône-et-Loire (PS); 2017-INCa-DGOS-Inserm_12563: INCa SIRIC-LYriCAN INCa-DGOS-Inserm_12563 (PS)ReferencesCohen EEW, Bell RB, Bifulco CB, Burtness B, Gillison ML, Harrington KJ, et al. The society for immunotherapy of cancer consensus statement on immunotherapy for the treatment of squamous cell carcinoma of the head and neck (HNSCC). J Immunother Cancer 2019;7(1):184. Bouaoud J, Foy JP, Tortereau A, Michon L, Lavergne V, Gadot N, et al. Early changes in the immune microenvironment of oral potentially malignant disorders reveal an unexpected association of M2 macrophages with oral cancer free survival. Oncoimmunology 2021;10(1):1944554.Mei Z, Huang J, Qiao B, Lam AK. Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma. Int J Oral Sci 2020;12(1):16.Yokota T, Homma A, Kiyota N, Tahara M, Hanai N, Asakage T, et al. Immunotherapy for squamous cell carcinoma of the head and neck. Jpn J Clin Oncol 2020;50(10):1089–96.Ethics ApprovalThe study was conducted in accordance with all applicable laws, rules, and requests of French and European government authorities. Written informed consent was obtained from all patients and the study was approved by the Centre Leon Bérard institutional review board (Lyon, France). Samples were obtained from the CRB Centre Léon Bérard (n°BB-0033-00050) which is quality certified according NFS96-900 French standard and ISO 9001 for clinical trials.

Simple Summary Early toxicity of radiotherapy (RT) (from the beginning of treatment to 3 months after its end) may compromise cancer treatments and its prediction is a medical, social and economic challenge. Beyond clinical/dosimetric factors, much of the variation in the risk of toxicity is currently unexplained and largely attributed to individual radiosensitivity (IRS). Thus, radiosensitivity tests would help several decision makings for choosing fractionation, preferring surgery to radiation or proton to photons for instance. Numerous initiatives failed in implementing predictive assays of IRS in clinical routine. Here we assess and validate the predictive ability of a new assay RADIODTECT® (RDT), based on phosphorylated ATM protein quantification in lymphocytes, for early toxicity after radiotherapy (RT). This study demonstrated promising results and implementing RTD as an easy managing test in common RT clinical practice for patients can be advisable. Abstract Radiation therapy (RT), either alone or in combination with surgery and/or chemotherapy is a keystone of cancers treatment. Early toxicity is common, sometimes leading to discontinuation of treatment. Recent studies stressed the role of the phosphorylated ATM (pATM) protein in RT-toxicity genesis and its ability in predicting individual radiosensitivity (IRS) in fibroblasts. Here we assessed the reliability of the pATM quantification in lymphocytes to predict IRS. A first retrospective study was performed on 150 blood lymphocytes of patients with several cancer types. Patients were divided into 2 groups, according to the grade of experienced toxicity. The global quantity of pATM molecules was assessed by ELISA on lymphocytes to determine the best threshold value. Then, the binary assay was assessed on a validation cohort of 36 patients with head and neck cancers. The quantity of pATM molecules in each sample of the training cohort was found in agreement with the observed Common Terminology Criteria for Adverse Events (CTCAE) grades with an AUC = 0.71 alone and of 0.77 combined to chemotherapy information. In the validation cohort, the same test was conducted with the following performances: sensitivity = 0.84, specificity = 0.54, AUC = 0.70 and 0.72 combined to chemotherapy. This study provides the basis of an easy to perform assay for clinical use.

Pignat’s partial laryngectomy with crico-hyoido-epiglotto-plasty (CHEPL) is a vertical laryngectomy with resection of the anterior portion of the thyroid cartilage and reconstruction with a wires net and the subhyoid muscles. The aim of this retrospective study was to evaluate and analyze oncologic and functional outcomes in patients affected by laryngeal squamous cell carcinoma and treated with Pignat’s partial laryngectomy. Seventy patients with cT1–cT3 glottic cancer were surgically treated with Pignat’s technique. Exclusion criteria: invasion of posterior cricoid arch, more than 3 mm under glottis, of more than one arytenoid, of posterior portion of thyroid cartilage, of the suprahyoid epiglottis. Overall survival, disease free survival, rates of decannulation and enteral feeding were analyzed. 23 (32.9%) pT1, 37 (52.9%) pT2, 5 (7.1%) pT3, 5 (7.1%) pT4a, 64 (91.5%) pN0, 5 (7.1%) pN1, 1 (1.4%) pN2. Adjuvant treatment was administered to 13 patients (18.6%). All patients had tracheotomy. Five year OS and DFS were 81.66 and 77.95%, respectively. A statistically significant DFS difference was observed between early and late stages. Five year local control was 81.16%. Five year larynx preservation rate was 89.16%. Median decannulation time was 12 days. Median duration of enteral nutrition was 16 days. All patients achieved efficient phonation. Pignat’s partial laryngectomy with CHEPL can represent an alternative to horizontal supracricoid laryngectomy to achieve laryngeal preservation. Good oncologic and functional outcomes are possible as long as indications are followed.

International audience; Understanding the dynamics of the immune microenvironment is critical to the development of immunobased strategies for the prevention of oral potentially malignant disorders transformation to oral squamous cell carcinoma (OSCC). We used laser capture microdissection and RNA-sequencing to profile the expression of 13 matched pairs of epithelial versus stromal compartments from normal mucosa, hyperplasia, dysplasia, and invasive tumors in the 4-nitroquinolein (4-NQO) murine model of oral carcinogenesis. Genes differentially expressed at each step of transformation were defined. Immune cell deconvolution and enrichment scores of various biological processes including immune-related ones were computed. Immunohistochemistry was also performed to characterize the immune infiltrates by T-cells (T-cells CD3+, helper CD4+, cytotoxic CD8+, regulatory FoxP3+), B-cells (B220+), and macrophages (M1 iNOS+, M2 CD163+) at each histological step. Enrichment of three independent M2 macrophages signatures were computed in 86 oral leukoplakia with available clinical outcome. Most gene expression changes were observed in the stromal compartment and related to immune biological processes. Immune cell deconvolution identified infiltration by the macrophage population as the most important quantitatively especially at the stage of dysplasia. In 86 patients with oral leukoplakia, three M2 macrophages signatures were independently associated with improved oral cancer-free survival. This study provides a better understanding of the dynamics of the immune microenvironment during oral carcinogenesis and highlights an unexpected association of M2 macrophages gene expression signatures with oral cancer free survival in patients with oral leukoplakia.

Background Cancer patients presenting with COVID-19 have a high risk of death. In this work, predictive factors for survival in cancer patients with suspected SARS-COV-2 infection were investigated. Methods PRE-COVID-19 is a retrospective study of all 302 cancer patients presenting to this institute with a suspicion of COVID-19 from March 1st to April 25th 2020. Data were collected using a web-based tool within electronic patient record approved by the Institutional Review Board. Patient characteristics symptoms and survival were collected and compared in SARS-COV-2 real-time or reverse-transcriptase PCR (RT-PCR)–positive and RT-PCR–negative patients. Results Fifty-five of the 302 (18.2%) patients with suspected COVID-19 had detectable SARS-COV-2 with RT-PCR in nasopharyngeal samples. RT-PCR–positive patients were older, had more frequently haematological malignancies, respiratory symptoms and suspected COVID-19 pneumonia of computed tomography (CT) scan. However, respectively, 38% and 20% of SARS-COV-2 RT-PCR–negative patients presented similar respiratory symptoms and CT scan images. Thirty of the 302 (9.9%) patients died during the observation period, including 24 (80%) with advanced disease. At the median follow-up of 25 days after the first symptoms, the death rate in RT-PCR–positive and RT-PCR–negative patients were 21% and 10%, respectively. In both groups, independent risk factors for death were male gender, Karnofsky performance status, Highlights • Cancer patients with SARS-COV-2 real-time or reverse-transcriptase PCR (RT-PCR have a death rate of 20% at 30 days. • Cancer patients with clinical symptoms of COVID-19 but SARS-COV-2 RT-PCR have high death rate. • 70% cancer patients suspected COVID-19 dying before day 30 have no SARS-COV-2 on RT-PCR or computed tomography. • For both groups, the risk factors of death include "relapsing cancer", Karnofsky performance status

published in International Journal of Radiation Oncology*Biology*Physics 105(1 Supplement):S221, September 2019; International audience; Purpose/Objective(s): Radiotherapy (RT) used alone or added to surgery in head and neck squamous cell carcinomas (HNSCC) leads to severe acute toxicity in up 30-40% patients (pts). Recent studies have stressed the role of the nucleoshuttling of the phosphorylated form of the ATM protein (pATM) in the response to radiation, and the discrimination power of this molecular endpoint in predicting individual radiosensitivity. Furthermore, a predictive assay based on the quantification of the pATM by ELISA method was developed on fibroblasts. In order to simplify the existing assay, and make it closer to a possible use in the clinics, we assessed the reliability of pATM quantification on lymphocytes to predict the pts’ risk of acute toxicity. We here propose and evaluate a model combining dosimetry and the lymphocyte assay.Materials/Methods: A retroprospective study was performed on HNSCC pts treated with IMRT/VMAT/3DCRT and IMRT system. Acute toxicity was assessed with CTCAE and two endpoints were selected: grade≥3 mucositis (OM3) and grade≥3 dysphagia (DY3). Global quantity of pATM molecules was assessed by ELISA on lymphocytes. Two previously developed dosimetric models were considered: including dose to oral cavity (Equivalent Uniform Dose, EUD, with n=0.05, OR=1.02 for 1 Gy increase) and mean dose to parotid glands (OR=1.06 for 1 Gy increase) for OM3 and including EUD to the oral cavity (n=0.15, OR=1.04 for 1 Gy increase), EUD to larynx (n=0.35, OR=1.02 for 1 Gy increase) and the volume of pharyngeal constrictor muscles receiving more than 50Gy (V50Gy, OR=1.02, for 1% V50Gy increase) for DY3. The combined model was defined as a logistic model including prediction from the previously published dosimetric model (without any adjustment, continuous variable with possible values in the 0-100 range) and classification by the pATM assay (radiosensitive vs not-radiosensitive, without any adjustment, dichotomous yes/no variable). Discrimination of models was evaluated through area under the ROC curve (AUC).Results: Thirty-five pts were available for evaluation of OM3 (8/35 events, 23.8%) and 33 for DY3 (12/33 events, 36.4%). Detailed results are presented in Figures 1 and 2. When OM3 was considered, the dosimetric model resulted in AUC=0.61, while the pATM assay had AUC=0.68. The combined model resulted with OR=1.06 for the dosimetric model and OR=7.1 for the pATM assay, AUC=0.79. For DY3, the dosimetric model and the pATM assay resulted in AUC=0.56 and AUC=0.77, respectively. The combined model had OR=1.01 for the dosimetric model and OR=27 for pATM assay, with AUC=0.8.Conclusion: A better prediction of occurrence of radio-induced toxicities can help treatment optimization and personalization, minimize treatment interruptions and improve management of side effects. Results from this small validation study suggest that molecular assays may improve the performance of dosimetric predictive models, leading to combined dosimetric-biological tools which might improve management of HNSCC pts during RT.

TPF (docetaxel, cisplatin, fluorouracil) is the standard chemotherapy used for induction in locally advanced head and neck squamous cell carcinoma (LAHNSCC). Its toxicity limits it to younger patients with good functional status and without significant comorbidity. Since modified TPF (mTPF) demonstrated higher tolerability with similar efficacy in gastric cancer, we tested this scheme on frail patients. From July 2010 to July 2014, the files of the 48 patients treated for LAHNSCC with mTPF in three French institutions were retrospectively collected. mTPF was chosen because of age>70 years, or severe denutrition, or PS>1, or severe comorbidities or after severe toxicity of standard TPF. During the first 4 cycles, 2 patients died, 14 secondary hospitalizations were required and 10 patients stopped treatment due to no lethal toxicity. Two patients died during radiotherapy. The response rate was 83% (19% complete response). With a median follow-up of 15.2 months, 4 patients died during treatment, 8 died of non-head and neck cancer related disorders, 18 progressed (17 deaths) and 18 were free of disease. The median overall survival was 18.5 months (95% IC: 16.9-30.0). mTPF is effective in terms of response rate compared with the standard TPF and could become a new option in induction for frail patients with LAHNSCC.

The importance of occupational exposures in patients with head and neck squamous cell carcinomas (HNSCC) has received little attention. In a single-center study, we prospectively characterized occupational exposures in 154 HNSCC cancer patients in a systematic occupational consultation and examined the association between most frequent exposures, HNSCC stage and localization. Patients occupied a mean of 3.3 different positions during their working life. The prevalence of asbestos, the most frequent exposure (46 patients; 29.9%) was higher than in the French population > 50 years. Other frequent exposures were solvents (n = 26; 16.9%) and silica (n = 19; 12.3%). For 37 patients (24%) a possible link was identified between occupational exposures and HNSCC. Duration of asbestos exposure was significantly higher (p = 0.04) in patients with hypopharyngeal and laryngeal cancer compared to other localizations. Occupational exposures are frequent in patients with HNSCC and should receive increased attention by physicians.

International audience; Background: The combination platinum, 5-fluorouracil (5-FU) and cetuximab is the standard first-line regimen of recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC). Due to the toxicity of this treatment, alternative therapies are often offered to patients. The aim of this study was to evaluate the overall survival obtained with a first line chemotherapy adapted to patients functional status and the administration of all active drugs within successive lines of chemotherapy.Methods: This series included a total of 194 patients with recurrent and/or metastatic HNSCC treated from 2006 to 2011 in a single institution where the administration of successive lines of chemotherapies has been the standard clinical approach. Treatment was administered according to clinical practice guidelines.Results: Most patients received at least two treatment lines. Only 11 patients (6%) were treated with a combination of cisplatin, 5-FU and cetuximab in front line, but most patients received at least one platinum-based regimen (n = 154 patients, 78%); 162 (82%) received taxanes, 36 (18%) received 5-FU, 27 (14%) received capecitabine, 67 (34%) received methotrexate and 134 (68%) received cetuximab. The median overall survival was 9.8 months (95% CI: 8.1-11.4 months) and reached 13.1 months among the subgroup of 131 patients eligible for inclusion in a clinical trial.Conclusion: The survival outcomes of patients treated in the first-line setting with chemotherapy regimens adapted to their functional status, followed by several subsequent regimens were comparable with published outcomes of patients treated by platinum, 5-FU and cetuximab.

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

UNLABELLED The objective of this study was to evaluate the efficacy and tolerability of capecitabine as a single agent in the treatment of recurrent/metastatic head and neck squamous cell carcinoma. Patients were treated with oral capecitabine according to good clinical practice. Efficacy and safety outcomes were analyzed retrospectively. The response and adverse events rates and their exact confidence intervals (CIs) were calculated. Survival distributions were estimated using the Kaplan-Meier method. Twenty-nine patients were included in the study. Twenty-five patients (86%) had received at least three previous lines of chemotherapy. The disease control rate was 48% (95% CI: 29-67%). The median progression-free survival was 2.0 months (95% CI: 0.1-3.9 months) and the median overall survival was 7.0 months (95% CI: 4.1-9.9 months). Hand-foot syndrome, fatigue, and mucositis were the most frequent severe side effects. No patient died, and only three patients discontinued treatment because of side effects. Capecitabine seems to be an active and well-tolerated regimen, even in heavily pretreated, frail patients. LEVEL OF EVIDENCE 2C 'Outcomes Research'.

The addition of cetuximab (CTX) to the combination of cisplatin and 5-fluorouracil increases the overall survival (OS) in recurrent/metastatic head and neck squamous cell carcinoma. Only a few patients are eligible for this treatment because of its toxicity. The combination of CTX and paclitaxel (TXL) could be included in sequential treatment strategies. Patients were treated with CTX (400/250 mg/m) and TXL (60-80 mg/m) weekly until disease progression or unacceptable toxicity. Efficacy and safety outcomes were determined retrospectively. A total of 42 patients were included in this analysis. The overall response rate was 38% [95% confidence interval (CI); 23-53%]. The disease control rate with TXL and CTX combination was 74%. Seven (17%) patients progressed before the first evaluation. The median progression-free survival was 3.9 months [95% CI; 3.1-4.7 months] and the median OS was 7.6 months [95% CI; 5.3-9.9 months]. Neurotoxicity and skin rash were the most frequent grade≥2 toxicities, reported in 17 and 12% of patients, respectively. Previous chemotherapy seems to be associated with a lower response rate and progression-free survival but not with the OS. The combination of CTX and TXL was an active and well-tolerated treatment in this series of patients with a poor prognosis and who were mostly symptomatic.