Objectif Déterminer les indications thérapeutiques de traitement médical systémique dans la prise en charge des carcinomes des glandes salivaires (hors carcinomes adénoïdes kystiques) en fonction des situations cliniques. Matériel et méthodes Un groupe de pilotage a rédigé un argumentaire et des propositions de recommandation en s’appuyant sur une revue non systématique de la littérature publiée sur Medline. Le niveau d’adhésion aux recommandations a ensuite été évalué par le groupe de cotation, selon la méthodologie de consensus formalisé d’experts. Résultats Les carcinomes des glandes salivaires sont des tumeurs rares et il n’y a actuellement pas suffisamment d’éléments pour indiquer une chimiothérapie au stade localisé. Au stade métastatique, la prise en charge initiale peut reposer sur une première phase de surveillance pour les maladies indolentes. Certains sous-types histologiques sont plus agressifs et nécessitent un traitement systémique d’emblée (carcinomes canalaires salivaires et adénocarcinomes). Pour guider le traitement systémique, il est recommandé d’effectuer des recherches en immunohistochimie et en biologie moléculaire (surexpression de HER2 et des récepteurs aux androgènes, fusion NTRK, next-generation sequencing). Conclusion Les carcinomes des glandes salivaires sont des tumeurs rares pour lesquelles il existe actuellement peu de traitements médicaux efficaces. Il est donc recommandé d’inclure les patients dans des essais cliniques.

Objectif Déterminer les indications de la radiothérapie pour les cancers des glandes salivaires et préciser ses modalités et les volumes cibles d’irradiation. Matériel et méthodes Un groupe de pilotage a rédigé un argumentaire et des propositions de recommandation en s’appuyant sur une revue non systématique de la littérature publiée sur Medline. Le niveau d’adhésion aux recommandations a ensuite été évalué par le groupe de cotation, selon la méthodologie de consensus formalisé d’experts. Résultats En situation postopératoire, la radiothérapie sur le site tumoral±les aires ganglionnaires est indiquée en cas de présence d’un ou plusieurs facteurs histopronostiques péjoratifs (risque>10 % de récidive locorégionale) parmi les suivants : stade T3–T4, envahissement ganglionnaire, envahissement extraglandulaire, marges de résection proches ou envahies, haut grade histologique, engainements périnerveux, emboles vasculaires, infiltration osseuse. La radiothérapie conformationnelle par modulation d’intensité (RCMI) est le standard. Pour les cancers non résécables ou les patients non opérables, la radiothérapie de type hadronthérapie (ions carbone) peut être envisagée. Conclusion La radiothérapie des cancers des glandes salivaires est indiquée en postopératoire en cas facteurs histopronostiques péjoratifs ou pour les tumeurs inopérables.

Background The PI3K/AKT pathway activation is an independent marker of poor outcome in head and neck squamous-cell carcinoma (HNSCC). It is involved in resistance to cetuximab and PI3KCA mutations (5% of HNSCC) may be a key event of this dysregulation. Buparlisib is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts. Methods This phase II evaluated the efficacy of oral buparlisib (100mg/d) in 2 parallel cohorts of refractory HNSCC (progression after platinum and cetuximab) with (PIK3CAmutated, exons 9/20) or without (PIK3CAnon-mutated) PI3KCA activating mutation. The primary endpoint was 2-month Disease Control Rate (DCR2m) as per centrally reviewed RECIST 1.1. Secondary endpoints included ORR, PFS, OS, and safety. Buparlisib would be considered ineffective if DCR2m ≤ 10% and promising if ≥ 30% (Simon’s optimal two-stage design; α: 5% unilateral, power: 90%): 7 successes/35 evaluable patients per cohort were required. Results 58 HNSCC heavily pre-treated (78% at least 2 prior lines) received at least one dose of buparlisib (PIK3CAnon-mutated, n = 36 and PIK3CAmutated, n = 22) The PIK3CAmutated cohort was prematurely closed because of slow accrual). The DCR2m was 38.9% (95% CI [25.5; + ∞[) for PIK3CAnon-mutated and 36.4% (95% CI [19.5; + ∞[) for PIK3CAmutated. No objective response was observed. Median PFS was 1.8 m (95% CI [1.6; 3.5]) and 1.7 m (95% CI [1.1; 4.1]) for PIK3CAnon-mutated and PIK3CAmutated respectively. Median OS was 5.8 m (95% CI [3.7; 9.2]) and 3.4 m (95% CI [2.6; 7.9]) for PIK3CAnon-mutated and PIK3CAmutated. Most common related AEs (>25%) included hyperglycemia, asthenia, anxiety, depression, lymphopenia, anemia, leucocyte increase, hematocrite decrease, Na decrease, nausea and diarrhea. Most frequent related AE ≥ Grade 3 (>5%) were hyperglycemia, lymphopenia, asthenia, Na decrease, depression, dermatitis. 14 pts (24.1%) discontinued buparlisib due to an AE. Conclusions Buparlisib had limited antitumor activity in heavily pre-treated HNSCC patients independent of PI3KCA mutational status. Clinical trial identification NCT01737450. Legal entity responsible for the study Centre Leon Berard. Funding INCA et Fondation ARC. Disclosure J. Fayette: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Honoraria (self): Merck Serono; Advisory / Consultancy: innate pharma; Advisory / Consultancy: Biogen. A. Daste: Honoraria (self), Advisory / Consultancy: BMS. C. Even: Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self): Merck Serono. F. Peyrade: Honoraria (self): BMS; Honoraria (self): Merck Serono. C. Le Tourneau: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca.

Background: Head and neck mucosal melanoma (HNMM) is aggressive and rare, with a poor prognosis because of its high metastatic potential. The two main subtypes are sinonasal (sinonasal mucosal melanoma [SNMM]) and oral cavity (oral cavity mucosal melanoma [OCMM]). Consensual therapeutic guidelines considering the primary tumour site and tumour-node-metastasis (TNM) stage are not well established. Material & methods: Patients with HNMM from the prospective national French Rare Head and Neck Cancer Expert Network database between 2000 and 2017 were included. Clinical characteristics, treatment modalities, outcomes and prognostic factors were analysed. Results: In total, 314 patients were included. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 49.4% and 24.7%, respectively, in the surgery group; no long-term survivors were observed when surgery was not feasible. Moreover, even after surgery, a high recurrence rate was reported with a median PFS of 22 months. In multivariate analysis, Union for International Cancer Control (UICC) stage and tumour site correlated with PFS and OS. Postoperative radiotherapy (PORT) improved the PFS but not OS in patients with small (T3) SNMM and OCMM tumours. Nodal involvement was more frequent in patients with OCMM (p < 10(-4)), although, as in SNMM, it was not a significant prognostic predictor. Conclusion: Even early HNMM was associated with poor oncologic outcomes due to distant metastases despite surgical resection with clear margins. Lymph node metastases had no impact on the prognosis, suggesting treatment de-escalation in cervical node management. PORT might be useful for local control. (C) 2019 Elsevier Ltd. All rights reserved.

In EXTREME pivotal Phase III trial, Cetuximab (CTX) associated with chemotherapy (CT) based on platinum (cisplatin or carboplatin) + 5-fluorouracil (5-FU), followed by cetuximab single agent (maintenance) has demonstrated improved survival outcomes compared to CT alone in R/M SCCHN in first-line therapy. DIRECT is the first observational, prospective study evaluating CTX RDI in this setting. Here, we focus on CTX maintenance phase and every two weeks usage (administration frequency at physician discretion). 157 adult patients with R/M SCCHN treated in first-line with CTX according to the scheme of the pivotal study in usual medical practice were included in this national multicenter study (56 centers in France) over two years (Nov 2012-June 2014) and were followed-up during a maximum period of 12 months. 45.8 % (n = 72) of the patients have received CTX maintenance. The median duration of maintenance was 15.8 ± 10.5 weeks (n = 72). 12-month-PFS rate was 23.1% (CI95% [14.0%; 33.5%]). 12-month-OS rate was 70.1% ([57.5%; 79.6%]). For patients with disease free interval less than 6 months (n = 55), 12-month-OS rate was 41.2% ([27.1%; 54.8]). During maintenance, 54.2% (n = 39) of patients have received CTX every two weeks (e2w) administration and 45.8 (n = 33) once a week. 12-month-PFS rate and 12-month-OS rate were not worse in patients with e2w versus weekly administration (weekly, n = 33 vs e2w, n = 39): 18.2% ([7.4% 32.8%]) vs 27.5% ([14.3%; 42.3%]), p = 0.2; 62.6% ([43.6% 76.8%]) vs 77% ([59.1%; 87.8%]), p = 0.2 respectively for PFS and OS rates. Cutaneous toxicities (grade ≥ 3) were observed in 12/157 patients (7.6%). This real life data indicates that CTX maintenance treatment every other week is feasible in R/M SCCHN patients and seems not to result in a reduced efficacy compared with weekly administration. In addition, cutaneous toxicity rate (grade ≥ 3) was similar in the Extreme study.

SGC of head and neck (SGCHN) are rare tumors including adenoid cystic carcinoma (ACC) and non-ACC, with no standard treatment for R/M patients (pts). Pazopanib (Pb) is an oral inhibitor of VEGFR, PDGFR and KIT. We conducted a phase II trial to assess Pb efficacy in SGCHN, and present here results of the ancillary GR study. Pts with confirmed progressive R/M SGCHN received Pb 800 mg daily until progression (PD). Primary endpoint was 6-mo PFS rate, with inacceptable and promising rates of 20% and 40%. Tumor volumes were assessed with a medical imaging workstation (Advantage Workstation, GE Healthcare) Assuming exponential growth, GR was defined as log10(Vt/V0)/dt, where V0 and Vt are tumour volumes at time 0 and t and dt the time in months between time 0 and t. Two time periods: pretrial period, from 3-6 mo before inclusion to inclusion (GRpre) and trial period, from inclusion to 3 mo later (GRpost). GR variation was defined as the difference GRpost minus GRpre., a negative difference means a GR break (GRpost < GRpre). GRpost < 0 means a tumor volume decrease. From 2013 to 2015, 72 pts were enrolled: 49 ACC and 20 non-ACC (3 ineligible excluded), M:F = 32:37, median age 59 yrs (range 27-84), PS 0-1 = 42:27. Pb tolerance was as expected. Among 63 pts (45 ACC, 18 non-ACC) evaluable for efficacy (6 non progressive excluded), 6-mo PFS rate was 47% (95%CI = 36;60) with 30 pts without PD at 6 mo, median PFS was 5.9 mo. Median OS was 17 mo. The 6-mo PFS met the criteria for efficacy conclusion of the trial. GR study was performed among 31 patients (24 ACC, 7 non-ACC). 6-mo PFS was 61% [IC95%:43;76] with 19 pts without PD at 6 mo. Median PFS was 8.2 mo. GR variation analysis showed a significant GR break 3 mo after Pb start (median -0.06 (range -0.37; + 0.10) p < 0.0001) with 26 pts (84% [IC95%:66;95]) having a GR break. 15 pts (48% [IC95%: 30;67]) had a volume decrease after Pb start. GRpre and GR variation were not associated with PD at 6 mo. There is a significant decrease in GR between evaluations done before inclusion and 3 months after Pb start, i.e. a break in tumor growth rate, in agreement with the PFS based conclusion of promising efficacy of Pb in R/M SGCHN.

The PI3K/AKT pathway activation is an early event in HNSCC and an independent marker of poor outcome that seems to be involved in resistance to cetuximab. BKM120 is an oral, pan-Class I PI3K inhibitor that inhibits tumor growth in HNSCC xenografts. This Phase II evaluates the clinical benefit of BKM120 (100mg/d, po) in 2 parallel cohorts of HNSCC pts with or without mutation in PI3KCA. Eligible pts progressed after platin and cetuximab or anti-EGFR therapy, and had documented PIK3CA status (exons 9 and 20). The primary endpoint was 2-month Disease Control Rate (DCR2m) as per RECIST 1.1. Secondary endpoints were ORR, PFS, OS, and safety. Blood and tumor samples were obtained for pharmacodynamics (PD). Imaging data were centrally reviewed. Considering that BKM120 would be uninteresting if DCR2m ≤ 10% and promising if ≥ 30% and using Simon's optimal two-stage design (&agr;: 5% unilateral, power: 90%), 7 successes/35 evaluable pts were required for each cohort. Only results of the cohort without PI3KCA mutation are presented. 36 HNSCC pts without PI3KCA mutation (median age: 58.6 yrs) received at least one dose of BKM120. They were heavily pretreated (33% with at least 3 previous lines). Median treatment duration was 8 wks [min-max: 4 d-55.9 wks]. At the end of 2nd Simon's Stage, the DCR2m was 38.9% (14/36pts). No OR was observed. The most common related AE (>25%) included hyperglycemia, asthenia, anxiety, depression, lymphopenia, anemia, leucocyte increase, hematocrit decrease, nausea and diarrhea. 20 pts (55.6%) presented at least one related AE ≥ Grade 3 (>5%: hyperglycemia, lymphopenia, asthenia, Na or K decrease) and 10 pts (27.8%) prematurely discontinued BKM120 due to an AE. 11pts (30.6%) experienced a related SAE including 3 SUSARs (1 fatal hyperglycemic coma, 1 death of uncertain relationship, 1 severe dehydration). PFS, OS and PD data will be presented at the meeting. Cohort with PI3KCA mutation is ongoing (n = 17). BKM120 deserves further investigation in relapsing HNSCC pts without PI3KCA mutation, nevertheless with close monitoring of metabolic tolerance.

La tumeur germinale du testicule (TGT) est une tumeur rare. Avec une prise en charge adaptée, le taux de survie spécifique à 5 ans de cette maladie est excellent, supérieur à 90 % tous stades confondus. L’objectif de cet audit était de réaliser une première mesure des éventuels écarts existant entre les recommandations de prise en charge des TGT et les pratiques en Aquitaine en 2012. Un groupe de travail pluridisciplinaire, constitué par appel à candidature dans les Groupes thématiques régionaux du RCA (Réseau de cancérologie d’aquitaine) a déterminé, à partir des recommandations en vigueurs, les indicateurs les plus pertinents pour mesurer la qualité de la prise en charge de TGT (périodes péri-opératoires, anatomopathologie, stadification, traitements). Les patients atteints d’une TGT dont le dossier a été présenté en RCP en 2012 dans un des 10 centres participant ont été inclus. Les patients pris en charge pour une récidive d’une tumeur germinale du testicule, ou qui ont été pris en charge hors Aquitaine, ont été exclus. Parmi les 102 dossiers de RCP, 92 répondaient aux critères d’inclusion. Cinquante-cinq (60 %) avaient une tumeur séminomateuse (TGS) et 37 (40 %) une tumeur non séminomateuse (TGNS). Pour 39 patients (42 %), le stade AJCC n’a pas été retrouvé. La prise en charge thérapeutique a donc été étudiée pour 53 patients (58 %). Parmi les 23 patients avec une TGS localisée, 11 (48 %) ont été traités par chimiothérapie, 7 (30 %) par radiothérapie et 5 (22 %) étaient en surveillance. Six patients métastatiques ont été traités par chimiothérapie et un par radiothérapie. Parmi les 7 patients avec une TGNS localisée, 4 ont reçu une chimiothérapie, 2 étaient surveillés et un a eu un curage ganglionnaire ; 14 patients avec une TGNS métastatique ont été traités par chimiothérapie et 2 n’ont pas eu de traitement. Ces résultats donnent un état des lieux de la prise en charge initiale des TG du testicule en Aquitaine en 2012. Pour les patients dont la prise en charge thérapeutique a pu être étudiée (58 %), celle-ci est conforme aux recommandations ; en revanche, certains points de la période diagnostique doivent être améliorés (diffusion de compte rendu échographique et anatomopathologique standardisé AFU/INCa).

Positron emission tomography (PET) with [18F]-fluoromisonidazole ([18F]-FMISO) provides a non-invasive assessment of hypoxia. The aim of this study is to assess the feasibility of a dose escalation with volumetric modulated arc therapy (VMAT) guided by [18F]-FMISO-PET for head-and-neck cancers (HNC).

Aim: Cetuximab combined with platinum is the standard first-line therapy in patients (pts) with R/M SCCHN. DIRECT is the first multicenter prospective observational study evaluating cetuximab RDI in this setting.

Introduction: Elderly patients have long been excluded from oncology clinical trials and specific studies devoted to them are rare. The result is a lack of consensus in many clinical situations for their management.

La voie mTOR (mammalian target of rapamycin) est une voie de signalisation majeure dans la physiologie cellulaire et la pathologie cancéreuse impliquée dans la croissance cellulaire, la prolifération cellulaire, le métabolisme cellulaire, la synthèse des protéines et l’angiogenèse. Le temsirolimus a montré dans un essai de phase III, chez des patients de pronostic défavorable présentant un cancer du rein métastatique, un gain significatif de survie en comparaison de celle obtenue par interféron alpha seul en première ligne de traitement (7,3 à 10,9 mois ; HR : 0,73 ; p < 0,006 9). L’évérolimus a montré dans un essai de phase III, chez des patients présentant un cancer du rein métastatique, un gain significatif de survie sans progression en comparaison de celle obtenue par placebo suite à une progression sous inhibiteur de tyrosine-kinase de VEGFR (1,8 à 4,6 mois ; HR : 0,33 ; p < 0,001). Le temsirolimus et l’évérolimus sont maintenant des traitements de référence en première ligne de traitement chez les patients de mauvais pronostic pour l’un et après échec des inhibiteurs de tyrosine-kinase de VEGFR pour l’autre. Cet article est une revue de ces deux traitements dans le cancer du rein.

mTOR signaling pathway (mammalian target of rapamycin) is a major pathway in cell physiology and malignant behavior implicated in cell growth, cell proliferation, cell metabolism, protein synthesis and angiogenesis. Temsirolimus has shown in a randomized phase III trial for patients with poor risk feature of metastatic renal cell carcinoma, a significant gain in overall survival compared to this obtained with alpha interferon (7.3 à 10.9 months; HR: 0.73; P < 0.0069). Everolimus has shown in a randomized phase III trial for patients with metastatic renal cell carcinoma having failed under VEGFR tyrosine kinase inhibitor a significant gain in progression-free survival compared to this obtained with placebo VEGFR (1,8 à 4,6 months; HR: 0.33; P < 0.001). Temsirolimus and everolimus are now part of the reference treatments in renal cell carcinoma. This paper is a review of these two drugs in this setting.